Methods of treating obesity, diabetes, and related diseases comprising pyruvate kinase activators

Abstract

The present disclosure relates to methods of treating obesity and / or treating or preventing Type 2 diabetes mellitus (T2D) or other obesity-related disease, disorder, or condition in a subject in need thereof, the methods comprising administering to the subject a pyruvate kinase (PK) activator.

Description

[0001] Attorney Docket No. 047162-7543WO1(02791)

[0002] METHODS OF TREATING OBESITY, DIABETES, AND RELATED DISEASES COMPRISING PYRUVATE KINASE ACTIVATORS

[0003] CROSS REFERENCE

[0004] This application claims the benefit of U. S. Provisional Application No. 63 / 727,880, filed December 4, 2024, which is incorporated by reference in its entirety.

[0005] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0006] This invention was made with government support under grant DK127637 and DK113103 awarded by the National Institutes of Health. The government has certain rights in the invention.

[0007] BACKGROUND

[0008] By 2030, half of Americans will have obesity (Ward, N Engl J Med 2019;381:2440-2450). Obesity a primary cause if not main contributor to over two hundred obesity-related disease, including of Type 2 Diabetes (T2D). As of 2021, greater than 10% of the U. S. population have diabetes, and about 90% to 95% of these individuals have T2D. T2D most often develops in people 45 or older, but children, teens, and young adults are also increasingly developing this chronic disease. It has been established that obesity or excessive weight gain is the most important and significant risk factor in the development and progression of T2D in all age groups (Chandrasekaran and Weiskirechen, Int. J. Mol. Sei., 2024, 25(3): 1882). Current estimates predict that a quarter of the global population will have obesity by 2035. Thus, the prevalence of T2D in the U. S. and worldwide is also expected to continue to increase.

[0009] Incretin hormones are gut peptides that are secreted after oral nutrient intake and amplify insulin secretion when glucose is elevated (Nauck and Meier, Diabetes Obes. Metab., 2018 Feb: 20 Suppl 1:5-21). Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are incretin hormones from the upper gut (GIP, K cells) and lower gut (GLP-1, L cells), respectively. GIP and GLP-1 bind to their respective receptors (GIPR and GLP-1 R), which belong to the G-protein coupled receptor GPCR) family. Together, GIP and GLP-1 are responsible for the ‘incretin effect’: a two- to three-fold higher insulin secretory response to oral as compared to intravenous glucose administration. In individuals with T2D, this incretin effect is diminished or no longer present. In some individuals following some bariatric procedures, the incretin effect is partially or completely restored. Obesity and Attorney Docket No. 047162-7543WO1(02791)

[0010] T2D is, in part, the consequence of a substantially reduced effectiveness of GIP on the diabetic endocrine pancreas, and of the negligible physiological role of GLP-1 in mediating the in cretin effect even in healthy individuals, but also extends beyond the glucose regulating effect of such hormones. Notably, the insulinotropic and glucagonostatic effects of GLP-1 are preserved in individuals with T2D to the degree that pharmacological stimulation of GLP-1 receptors significantly reduces plasma glucose and improves glycemic control (Nauck and Meier, Diabetes Obes. Metab., 2018 Feb: 20 Suppl 1:5-21). Glucagon (GCG) is a hormone secreted from the pancreatic islet that responds to amino acids, glucose, and exercise that also contributes to energy balance. Collectively, these Nutrient Stimulated Hormones (NuSHs) contribute to the acute disposal of nutrients but also have been identified as targets for the treatment of T2D and obesity. The current FDA approved GLP-1 receptor agonists and other related agents (GLP-1 RAs, also known as GLP-1 agonists, incretin mimetics, nutrient-stimulated hormones (NuSH or NuSHs), nutrient-stimulated hormone-based medications, or GLP-1 analogs) include, e.g., Semaglutide (injectables Ozempic and Wegovy, as well as Rybelsus - an oral semaglutide), Tirzepatide (Mounjaro, Zepbound), Exenatide (Byetta, Bydureon), Liraglutide (Victoza, Saxenda), Dulaglutide (Trulicity). Lixisenatide (Lyxumia, Adlyxin), Retatrutide, and albiglutide (e g., Eperzan, Tanzeum), with many more in development.

[0011] NuSHs receptor modulators have shown promise as single agents in the treatment of both obesity and T2D. For instance, the STEP-1 Trial (Wilding, et al NEJM 2021 - semaglutide obesity Phase 3) was in subjects with obesity and no diabetes. Another example, in a randomized controlled trial of Semaglutide which tested its long-term efficacy and safety in adults with obesity and T2D, the participants achieved a weight reduction of greater than 5% from the baseline at week 104, and also experienced improvements in diastolic blood pressure, HbAlc, fasting blood glucose, fasting serum insulin, total cholesterol, triglycerides, VLDL and LDL (Garvey, et al., Nature Medicine, 2022, ). Other NuSHs in late stage, includes agonists of the GPCR for amylin and calcitonin, cagrilintide, in a phase 2 study in subjects with obesity, where the highest dose of 4.5 mg demonstrated 10.8% weight loss after 26 weeks (Lau D, Lancet, 2021). Eloralintide is also in development as an agonist for amylin / cal ci tonin receptors. Additionally, cagrilintide is in development for pairing with semaglutide. Further, there are more combination molecules (such as amy cretin) which target both GLP-1 and amylin / calcitonin receptors.

[0012] Combinations of GLP-1 RA with other NuSHs have also shown promise as either single or multiple molecules. A randomized phase 3 clinical trial of Tirzepatide, a single molecule Attorney Docket No. 047162-7543WO1(02791)

[0013] dual GLP-1 RA and GIP receptor agonist, conducted for 72 weeks on participants with obesity showed a weight reduction of 22.5% along with improvements in fasting insulin and lipid levels (Jastreboff, et al., N. Engl. J. Med., 2022, 387:205-216). An extension of this study to 176 weeks in participants with prediabetes, demonstrated sustained weight reduction and protection from developing T2D, both worsening when the medication was withdrawn (Jastreboff, et al., N. Engl. J. Med., 2024, 10.1056 / NEJMoa2410819). The phase 2 clinical trial for retatrutide. a triple hormone agonist targeting the GLP-1, GIP, and GCG receptors, in subjects with obesity led to a 24.2% weight reduction after 48 weeks (Jastreboff, et al., N. Engl. J. Med., 2023, 389:514-526). A 20-week Phase lb demonstrated that the combination of the two molecules, semaglutide and cagrilintide, in subjects with obesity lost 17.1% of their body weight (Enebo et al, Lancet, 2021). A 46-week Phase 2 trial with a GLP-l / GCG receptor agonist, survodutide, resulted in 18.7% body weight reduction (Le Roux, Lancet Diabetes and Endocrinology. 2024).

[0014] Any form of weight loss is associated with a reduction in lean body mass, in part because the individual is carrying less weight and therefore needs less muscle to perform physical work. Minimizing the amount of “extra” muscle loss is an important therapeutic consideration, especially in elderly, frail, or sarcopenic individuals who for health reasons need to reduce their adiposity. Sustaining or increasing lean mass also contributes to the basal metabolic rate and is an important contributor to maintaining weight loss and metabolic homeostasis.

[0015] Injectable NuSHs, however, suffer from significant limitations, including that they are injectable, have dose-limiting adverse effects, they are expensive to manufacture / store / deliver, and can still fall short of treatment goals. Likewise, oral NuSH-based therapies also may have dose-limiting adverse effects and may fall short of treatment goals. As such, there is a need in the art for alternative and / or complementary treatments which are effective alone and / or increase efficacy of GLP-1 RAs (alone or in combination with GIP or GCG or amylin or other agonist or antagonist nutrient-stimulated hormone-based therapies) or non-NuSH therapies in the treatment of obesity and T2D, and other obesity-related diseases with injectable or, preferably, with orally administered small molecule-based therapeutics. The present disclosure addresses this unmet need.

[0016] SUMMARY

[0017] In some aspects, provided herein is a method comprising administering a pyruvate kinase (PK) activator (PKa), wherein the method results in a reduction in fat mass and a maintenance or increase in muscle mass. Attorney Docket No. 047162-7543WO1(02791)

[0018] In some aspect provided herein is a method of treating obesity in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a pyruvate kinase (PK) activator. In some embodiments, the method comprises maintaining or increasing muscle mass.

[0019] In some aspects, provided herein is a method of reducing fat mass and maintaining or increasing muscle mass in a subject in need thereof, wherein the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa). In some embodiments, the reducing fat mass comprises reducing a level of fat mass measured when the PKa is administered by at least 5% as compared to a level of fat mass measured when the PKa is not administered. In some embodiments, the maintaining or increasing muscle mass comprises between a decrease in muscle mass when the PKa is administered of less than 10% as compared to a level of muscle mass measured when the PKa is not administered.

[0020] In some aspects, provided herein is a method of increasing mitochondrial membrane potential in a subject in need thereof, wherein the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa).

[0021] In some aspects, provided herein is a method of reducing fat mass and maintaining or increasing muscle mass in a subject in need thereof, wherein the method comprises administering a pyruvate kinase (PK) activator (PKa) to the subject, wherein the method results in a reduction in fat mass in the subject and a maintenance or increase in muscle mass in the subject. In some embodiments, the obesity-related disease, disorder, or condition is Type 2 diabetes mellitus (T2D).

[0022] In some aspects, provided herein is a method of treating a disease, disorder, or condition in a subject in need thereof, wherein the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa). In some embodiments, the disease, disorder, or condition is Type 2 diabetes mellitus (T2D).

[0023] In some aspects, provided herein is a method of modulating pyruvate kinase (PK) activity and modulating NuSH receptor activity, wherein the method comprises administering a pyruvate kinase (PK) activator (PKa).

[0024] In some aspects, provided herein is a method of improving pancreatic islet function in a subject in need thereof, wherein the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa). Attorney Docket No. 047162-7543WO1(02791)

[0025] In some aspects, provided herein is a method of improving glucose tolerance in a subject in need thereof, wherein the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa).

[0026] In some aspects, provided herein is a method of reducing insulin resistance in a subject in need thereof, wherein the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa).

[0027] In some aspects, provided herein is a method of increasing insulin release in a subject in need thereof, wherein the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa).

[0028] In some aspects, provided herein is a method of reducing blood glucose levels and / or blood lipid levels in a subject in need thereof, wherein the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa).

[0029] In some aspects, provided herein is a method of reducing hepatic lipids in a subject in need thereof, wherein the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa).

[0030] In some aspects, provided herein is a method of reducing fat mass in a subject in need thereof, wherein the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa). In some embodiments, the reducing fat mass comprises reducing a level of fat mass measured when the PKa is administered by at least 5% as compared to a level of fat mass measured when the PKa is not administered.

[0031] In some aspects, provided herein is a method of increasing muscle mass in a subject in need thereof, wherein the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa). In some embodiments, the increasing muscle mass comprises an increase in muscle mass of at least 5% as compared to a level of muscle mass measured when the PKa is not administered.

[0032] In some aspects, provided herein is a method of increasing muscle function in a subject in need thereof, wherein the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa). In some embodiments, the increasing muscle function comprises an increase in muscle function of at least 5% as compared to a level of muscle function measured when the PKa is not administered. Attorney Docket No. 047162-7543WO1(02791)

[0033] In some aspects, provided herein is a method of increasing lean-to-fat mass ratio in a subject in need thereof, wherein the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa).

[0034] In some aspects, provided herein is a method of reducing body mass index (BMI) in a subject in need thereof, wherein the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa).

[0035] In some embodiments of any of the above aspects, the PKa is administered as a monotherapy. In some embodiments of any of the above aspects, the method further comprises administering to the subj ect a nutrient stimulated hormone (NuSH) receptor modulator. In some embodiments of any of the above aspects, the method further comprises administering to the subject at least one additional agent or therapy useful for treating obesity and / or T2D and / or other obesity-related disease, disorder, or condition. In some embodiments, the at least one additional agent or therapy comprises leptin, ghrelin, mc4RA, myostatin inhibitors, activin inhibitors, NRLP3. and metformin.

[0036] In some aspects, provided herein is a method of treating obesity in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a pyruvate kinase (PK) activator and a nutrient stimulated hormone (NuSH) receptor modulator.

[0037] In some aspects, provided herein is a method of treating obesity in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a pyruvate kinase (PK) activator (PKa), wherein the subject has been previously administered a nutrient stimulated hormone (NuSH) receptor modulator.

[0038] In some aspects, provided herein is a method of treating obesity in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a nutrient stimulated hormone (NuSH) receptor modulator, wherein the subject has been previously administered a pyruvate kinase (PK) activator (PKa). In some embodiments, the method does not result in a loss of muscle mass. In some embodiments, the method increases a lean-to-fat mass ratio of the subject.

[0039] In some aspects, provided herein is a method of treating an obesity-related disease, disorder, or condition in a subj ect in need thereof, wherein the method comprises administering to the subject a pyruvate kinase (PK) activator and a nutrient stimulated hormone (NuSH) receptor modulator. Attorney Docket No. 047162-7543WO1(02791)

[0040] In some aspects, provided herein is a method of treating an obesity-related disease, disorder, or condition in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a pyruvate kinase (PK) activator (PKa), wherein the subject has been previously administered a nutrient stimulated hormone (NuSH) receptor modulator.

[0041] In some aspects, provided herein is a method of treating an obesity-related disease, disorder, or condition in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a nutrient stimulated hormone (NuSH) receptor modulator, wherein the subject has been previously administered a pyruvate kinase (PK) activator (PKa).

[0042] In some embodiments of any of the above aspects, the obesity-related disease, disorder, or condition is a metabolic disease, disorder, or condition selected from the group consisting of cardiovascular disease, Heart Failure with Preserved Ejection Fraction, Heart Failure with Reduced Ejection Fraction (HFrEF), Chronic Kidney Disease (CKD), Cardiovascular-Kidney-Metabolic (CKM) Syndrome, hypertension, hyperlipidemia, Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD), Metabolic-Associated Steatohepatitis (MASH), infertility, Polycystic Ovary Syndrome (PCOS), and cancer. In some embodiments of any of the above aspects, the obesity-related disease, disorder, or condition is a functional disease, disorder, or condition selected from the group consisting of osteoarthritis (OA), Obstructive sleep apnea (OSA), back pain, and incontinence.

[0043] In some aspects, provided herein is a method of treating or preventing a disease, disorder, or condition in a subject in need thereof, the method comprises administering to the subject a pyruvate kinase (PK) activator and nutrient stimulated hormone (NuSH) receptor modulator.

[0044] In some aspects, provided herein is a method of treating a disease, disorder, or condition in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a pyruvate kinase (PK) activator (PKa), wherein the subject has been previously administered a nutrient stimulated hormone (NuSH) receptor modulator.

[0045] In some aspects, provided herein is a method of treating a disease, disorder, or condition in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a nutrient stimulated hormone (NuSH) receptor modulator, wherein the subject has been previously administered a pyruvate kinase (PK) activator (PKa). In some embodiments, the disease, disorder or condition is Type 2 diabetes mellitus (T2D). Attorney Docket No. 047162-7543WO1(02791)

[0046] In some aspects, provided herein is a method of modulating pyruvate kinase (PK) activity and modulating NuSH-R activity in a cell, wherein the method comprises contacting the cell with a pyruvate kinase (PK) activator (PKa) and a nutrient stimulated hormone (NuSH) receptor modulator.

[0047] In some aspects, provided herein is a method of modulating pyruvate kinase (PK) activity and modulating NuSH-R activity in a cell, wherein the method comprises contacting the cell with a pyruvate kinase (PK) activator (PKa), wherein the cell has been previously contacted with a nutrient stimulated hormone (NuSH) receptor modulator.

[0048] In some aspects, provided herein is a method of modulating pyruvate kinase (PK) activity and modulating NuSH-R activity in a cell, wherein the method comprises contacting the cell with a nutrient stimulated hormone (NuSH) receptor modulator, wherein the cell has been previously contacted with a pyruvate kinase (PK) activator (PKa).

[0049] In some aspects, provided herein is a method of improving pancreatic islet function in a subject in need thereof, wherein the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa) and a nutrient stimulated hormone (NuSH) receptor modulator.

[0050] In some aspects, provided herein is a method of improving pancreatic islet function in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a pyruvate kinase (PK) activator (PKa), wherein the subject has been previously administered a nutrient stimulated hormone (NuSH) receptor modulator.

[0051] In some aspects, provided herein is a method of improving pancreatic islet function in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a nutrient stimulated hormone (NuSH) receptor modulator, wherein the subject has been previously administered a pyruvate kinase (PK) activator (PKa). In some embodiments, improving pancreatic islet function comprises increasing insulin release from pancreatic islet cells.

[0052] In some aspects, provided herein is a method of improving glucose tolerance in a subject in need thereof, wherein the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa) and a nutrient stimulated hormone (NuSH) receptor modulator.

[0053] In some aspects, provided herein is a method of improving glucose tolerance a subject in need thereof, wherein the method comprises administering to the subject in need thereof a Attorney Docket No. 047162-7543WO1(02791)

[0054] pyruvate kinase (PK) activator (PKa), wherein the subject has been previously administered a nutrient stimulated hormone (NuSH) receptor modulator.

[0055] In some aspects, provided herein is a method of improving glucose tolerance in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a nutrient stimulated hormone (NuSH) receptor modulator, wherein the subject has been previously administered a pyruvate kinase (PK) activator (PKa). In some embodiments, improving glucose tolerance comprises reducing glucose levels to a baseline level within 60 minutes. In some embodiments, the baseline level is substantially similar to a level of glucose measured in the subject following a six-hour fast.

[0056] In some aspects, provided herein is a method of increasing insulin release in a subject in need thereof, wherein the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa) and a nutrient stimulated hormone (NuSH) receptor modulator.

[0057] In some aspects, provided herein is a method of increasing insulin release in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a pyruvate kinase (PK) activator (PKa), wherein the subject has been previously administered a nutrient stimulated hormone (NuSH) receptor modulator.

[0058] In some aspects, provided herein is a method of increasing insulin release in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a nutrient stimulated hormone (NuSH) receptor modulator, wherein the subject has been previously administered a pyruvate kinase (PK) activator (PKa). In some embodiments, the increasing insulin release comprises at least 10% increase in insulin release as compared to a subject not administered the PKa.

[0059] In some aspects, provided herein is a method of reducing blood glucose levels and / or blood lipid levels in a subject in need thereof, wherein the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa) and a nutrient stimulated hormone (NuSH) receptor modulator.

[0060] In some aspects, provided herein is a method of reducing blood glucose levels and / or blood lipid levels in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a pyruvate kinase (PK) activator (PKa), wherein the subject has been previously administered a nutrient stimulated hormone (NuSH) receptor modulator. Attorney Docket No. 047162-7543WO1(02791)

[0061] In some aspects, provided herein is a method of reducing blood glucose levels and / or blood lipid levels in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a nutrient stimulated hormone (NuSH) receptor modulator, wherein the subject has been previously administered a pyruvate kinase (PK) activator (PKa).

[0062] In some aspects, provided herein is a method of reducing hepatic lipids in a subject in need thereof, wherein the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa) and a nutrient stimulated hormone (NuSH) receptor modulator.

[0063] In some aspects, provided herein is a method of reducing hepatic lipids in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a pyruvate kinase (PK) activator (PKa), wherein the subject has been previously administered a nutrient stimulated hormone (NuSH) receptor modulator.

[0064] In some aspects, provided herein is a method of reducing hepatic lipids in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a nutrient stimulated hormone (NuSH) receptor modulator, wherein the subject has been previously administered a pyruvate kinase (PK) activator (PKa).

[0065] In some aspects, provided herein is a method of reducing fat mass in a subject in need thereof, wherein the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa) and a nutrient stimulated hormone (NuSH) receptor modulator.

[0066] In some aspects, provided herein is a method of reducing fat mass in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a pyruvate kinase (PK) activator (PKa). wherein the subject has been previously administered a nutrient stimulated hormone (NuSH) receptor modulator.

[0067] In some aspects, provided herein is a method of reducing fat mass in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a nutrient stimulated hormone (NuSH) receptor modulator, wherein the subject has been previously administered a pyruvate kinase (PK) activator (PKa).

[0068] In some aspects, provided herein is a method of increasing muscle mass in a subject in need thereof, wherein the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa) and a nutrient stimulated hormone (NuSH) receptor modulator. Attorney Docket No. 047162-7543WO1(02791)

[0069] In some aspects, provided herein is a method of increasing muscle mass in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a pyruvate kinase (PK) activator (PKa), wherein the subject has been previously administered a nutrient stimulated hormone (NuSH) receptor modulator.

[0070] In some aspects, provided herein is a method of increasing muscle mass in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a nutrient stimulated hormone (NuSH) receptor modulator, wherein the subject has been previously administered a pyruvate kinase (PK) activator (PKa).

[0071] In some aspects, provided herein is a method of increasing lean-to-fat mass ratio in a subject in need thereof, wherein the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa) and a nutrient stimulated hormone (NuSH) receptor modulator.

[0072] In some aspects, provided herein is a method of increasing lean-to-fat mass ratio in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a pyruvate kinase (PK) activator (PKa), wherein the subject has been previously administered a nutrient stimulated hormone (NuSH) receptor modulator.

[0073] In some aspects, provided herein is a method of increasing lean-to-fat mass ratio in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a nutrient stimulated hormone (NuSH) receptor modulator, wherein the subject has been previously administered a pyruvate kinase (PK) activator (PKa).

[0074] In some aspects, provided herein is a method of reducing body mass index (BMI) in a subject in need thereof, wherein the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa) and a nutrient stimulated hormone (NuSH) receptor modulator.

[0075] In some aspects, provided herein is a method of reducing body mass index (BMI) in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a pyruvate kinase (PK) activator (PKa), wherein the subject has been previously administered a nutrient stimulated hormone (NuSH) receptor modulator.

[0076] In some aspects, provided herein is a method of reducing body mass index (BMI) a subject in need thereof, wherein the method comprises administering to the subject in need thereof a nutrient stimulated hormone (NuSH) receptor modulator, wherein the subject has been previously administered a pyruvate kinase (PK) activator (PKa). Attorney Docket No. 047162-7543WO1(02791)

[0077] In some embodiments of any of the above aspects, the pyruvate kinase activator (PKa) is red blood cell pyruvate kinase activator (PKR) (e.g., mitapivat, etavopivat, or tebapivat) or an activator of a pyruvate kinase M2 (PKM2) isoform (e.g., TEPP-46, DASA-58, or ML-265). In some embodiments of any of the above aspects, the PKa is TEPP-46, mitapivat, etavopivat, or a compound represented by the following structural formula Formula A:

[0078]

[0079] (Formula A).

[0080] or a pharmaceutically acceptable salt thereof, wherein:

[0081] U1, U2, and U3 are each independently N, O, S, C, or CR1, as valency permits;

[0082] U4, U6, and U7are each independently N or C, as valency permits;

[0083] U5 is N, NR3, or CR4, as valency permits;

[0084] m is 1 or 2;

[0085]

[0086] Ring A is phenyl,

[0087] U8 is N or CR1;

[0088] each instance of Ri is independently hydrogen or Ci— Ce alkyl;

[0089] L1 is —S—, —S—CH2—, —CH2—S—, —S(=O)2—, —S(=O)—, —S(=O)2O—, —OS(=O)2—, —S(=O)O—, —OS(=O)—, —S(=O)CH2—, —CH2S(=O)—, —S(=O)2CH2—, —CH2S(=O)2—, —S(=O)2NR5—, —NR5S(=O)2—, —S(=O)NR5—, —NR5S(=O)—, —NR5S(=O)2O—, —OS(=O)2NR5—, —NR5S(=O)O—, —OS(=O)NR5—, —S(=O)(=NR5)—, —C(=O)—, Attorney Docket No. 047162-7543WO1(02791)

[0090] —C(=O)O—, —OC(=O)—, —C(=O)NR5—, —N(R5)C(=O)—, —NR5C(=O)O—, —OC(=O)NR5—, —NR5C(=O)NR5—, —NR5—, —C(=S)NR5—, —N(R5)C(=S)—, or —(CRjRk)q—;

[0091] R2 is C1—C6 alkyl, C3—C12 cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 14-membered aryl, or 5- to 14-membered heteroaryl, wherein the alkyl is optionally substituted with 0 to 3 groups each independently selected from halogen, OH, CN, and NR5R5, and wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted at each substitutable ring carbon atom with Rp and optionally substituted at each substitutable ring nitrogen atom by Rnc; or

[0092] —L1—R2 is —H, —CN, —CH3, —OH, Br, C1—C6 haloalkyl, C2—C6 alkenyl, C1—C6 alkyl, C3—C12 cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 14-membered aryl, or 5- to 14-membered heteroaryl; wherein each alkyl and alkenyl is optionally substituted with 0 to 3 groups each independently selected from halogen, OH, CN, and NR5R5, and wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted at each substitutable ring carbon atom with Rp and optionally substituted at each substitutable ring nitrogen atom by Rnc;

[0093] each instance of Rp is independently hydrogen, halogen, —CN, —NO2, —N3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -ORc3, -SRc3, -N(Rc3)2, -C(=O)N(Rc3)2, -N(Rc3)C(=O)Rc3, -C(=O)Rc3, -C(=O)ORc3, -OC(=O)Rc3, -S(=O)Rc3, -S(=O)2Rc3, -S(=O)ORc3, -OS(=O)Rc3, -S(=O)2ORc3, -OS(=O)2Rc3,

[0094] —S(=O)N(Rc3)2, —S(=O)2N(Rc3)2, —N(Rc3)S(=O)Rc3, —N(Rc3)S(=O)2Rc3, —N(Rc3)C(=O)ORc3, ─OC(=O)N(Rc3)2, ─N(Rc3)C(=O)N(Rc3)2, ─N(Rc3)S(=O)N(Rc3)2, ─N(Rc3)S(=O)2N(Rc3)2, ─N(Rc3)S(=O)ORc3, ─N(Rc3)S(=O)2ORc3, ─OS(=O)N(Rc3)2, ─OS(=O)2N(Rc3)2; or alternatively

[0095] two instances of Rpattached to the adjacent ring carbon atoms, can be taken together with the carbon atoms to which they are attached to form 3- to 8-membered cycloalkyl, 5- to 6-membered saturated or partially saturated monocyclic heterocyclyl, or 5- to 6-membered monocyclic heteroaryl; wherein:

[0096] each instance of Rc3 is independently hydrogen or C₁─C₆ alkyl;

[0097] L2 is —S—, —S—CH2—, —CH2—S—, —S(=O)2—, —S(=O)—, —S(=O)2O—, —OS(=O)2—, —S(=O)O—, —OS(=O)—, —S(=O)CH2—, —CH2S(=O)—, —S(=O)2CH2—, —CH2S(=O)2—, —S(=O)2NR5—, —NR5S(=O)2—, —S(=O)NR5—, —NR5S(=O)—, —NR5S(=O)2O—, —OS(=O)2NR5—, —NR5S(=O)O—, —OS(=O)NR5—, —S(=O)(=NR5)—, —C(=O)—, —C(=O)O—, —OC(=O)—, —C(=O)NR5—, —N(R5)C(=O)—, —NR5C(=O)O—, —OC(=O)NR5—, —NR5C(=O)NR5—, —NR5—, —C(=S)NR5—, —N(R5)C(=S)—, or —(CRaRb)r—; Attorney Docket No. 047162-7543WO1(02791)

[0098] each instance of Ra and Rb are independently hydrogen, halogen, CN, OH, NO2, N3, or C1—C6 alkyl; wherein the C1—C6 alkyl represented by Ra or Rb are each optionally substituted with 0 to 3 groups each independently selected from halogen, OH, CN, and NR5R5;

[0099] each instance of Rj and Rk are independently hydrogen, halogen, CN, OH, NO2, N3, or C1—C6 alkyl; wherein the C1—C6 alkyl represented by Ra or Rb are each optionally substituted with 0 to 3 groups each independently selected from halogen, OH, CN, and NR5R5;

[0100] q is 1 or 2;

[0101] r is 1 or 2;

[0102] Q is C3—C12 cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 14-membered aryl, or 5-to 14-membered heteroaryl, each of which is optionally substituted at each substitutable ring carbon atom with Rn and optionally substituted at each substitutable ring nitrogen atom by Rna; or

[0103] —L2—Q is —H, —CN, —CH3, —OH, Br, C1—C6 haloalkyl, C2—C6 alkenyl, C1—C6 alkyl, C3—C12 cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 14-membered aryl, or 5- to 14-membered heteroaryl; wherein each alkyl and alkenyl is optionally substituted with 0 to 3 groups each independently selected from halogen, OH, CN, and NR5R5, and wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted at each substitutable ring carbon atom with Rn and optionally substituted at each substitutable ring nitrogen atom by Rna;

[0104] each instance of Rn is independently hydrogen, halogen, —CN, —NO2, —N3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -ORc4, -SRc4, -N(Rc4)2, -C(=O)N(Rc4)2, -N(Rc4)C(=O)Rc4, —C(=O)Rc4, -C(=O)ORc4, -OC(=O)Rc4, -S(=O)Rc4, -S(=O)2Rc4, -S(=O)ORc4, -OS(=O)Rc4, -S(=O)2ORc4, -OS(=O)2Rc4, -S(=O)N(Rc4)2, -S(=O)2N(Rc4)2, -N(Rc4)S(=O)Rc4, —N(Rc4)S(=O)2Rc4, -N(Rc4)C(=O)ORc4, -OC(=O)N(Rc4)2, -N(Rc4)C(=O)N(Rc4)2, -N(Rc4)S(=O)N(Rc4)2, -N(Rc4)S(=O)2N(Rc4)2, -N(Rc4)S(=O)ORc4, -N(Rc4)S(=O)2ORc4, -OS(=O)N(Rc4)2, or -OS(=O)2N(Rc4)2; or alternatively two instances of Rn attached to the adjacent ring carbon atoms, can be taken together with the carbon atoms to which they are attached to form an optionally substituted 3— to 8—membered cycloalkyl, 5— to 6—membered saturated or partially saturated monocyclic heterocyclyl, or 5- to 6—membered monocyclic heteroaryl; wherein:

[0105] each instance of Rc4 is independently hydrogen or C1—C6 alkyl; Attorney Docket No. 047162-7543WO1(02791)

[0106] R3 is hydrogen or C1—C6 alkyl;

[0107] R4 is hydrogen, C1—C6 alkyl, C1—C6 haloalkyl, C2—C6 alkynyl, halogen, CN, —C(=O)NR5R5, or C≡C(CH2)wOH, wherein w is 1, 2, 3, 4, 5, or 6, and wherein each alkyl, haloalkyl, and alkynyl is independently optionally substituted with 1—3 instances of C1—C4 alkyl or halogen;

[0108] each instance of Rna and Rnc is independently hydrogen, C1—C6 alkyl, or C1—C6 haloalkyl; and

[0109] each instance of R5 is independently hydrogen or C1—C6 alkyl;

[0110]

[0111] ’ L2 is — (CR.iRb)r— and Q is phenyl optionally substituted with Rnand Rna, then Li is — (CRjRk)q— and R2 is cycloalkyl, heterocyclyl. aryl, or heteroaryl optionally substituted with Rpand Rnc. In some embodiments, the PKa is TEPP-46. In some embodiments, the PKa is mitapivat. In some embodiments, the PKa is etavopivat. In some embodiments, the PKa is a compound represented by the following structural formula: Attorney Docket No. 047162-7543WO1(02791)

[0112]

[0113] or a pharmaceutically acceptable salt thereof, wherein:

[0114] U1, U2, and U3 are each independently N, O, S, C, or CR1, as valency permits;

[0115] U4, U6, and U7are each independently N or C, as valency permits;

[0116] U5 is N, NR3, or CR4, as valency permits;

[0117] m is 1 or 2;

[0118]

[0119] Ring A is phenyl,

[0120] U8 is N or CR1;

[0121] each instance of R1 is independently hydrogen or C1—C6 alkyl;

[0122] L1 is —S—, —S—CH2—, —CH2—S—, —S(=O)2—, —S(=O)—, —S(=O)2O—, —OS(=O)2—, —S(=O)O—, —OS(=O)—, —S(=O)CH2—, —CH2S(=O)—, —S(=O)2CH2—, —CH2S(=O)2—, —S(=O)2NR5—, —NR5S(=O)2—, —S(=O)NR5—, —NR5S(=O)—, —NR5S(=O)2O—, —OS(=O)2NR5—, —NR5S(=O)O—, —OS(=O)NR5—, —S(=O)(=NR5)—, —C(=O)—, —C(=O)O—, —OC(=O)—, —C(=O)NR5—, —N(R5)C(=O)—, —NR5C(=O)O—, —OC(=O)NR5—, —NR5C(=O)NR5—, —NR5—, —C(=S)NR5—, —N(R5)C(=S)—, or —(CRjRk)q—;

[0123] R2 is C1—C6 alkyl, C3—C12 cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 14-membered aryl, or 5- to 14-membered heteroaryl, wherein the alkyl is optionally substituted with 0 to 3 groups each independently selected from halogen, OH, CN, and NR5R5, and wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted at each substitutable ring carbon atom with Rp and optionally substituted at each substitutable ring nitrogen atom by Rnc; or Attorney Docket No. 047162-7543WO1(02791)

[0124] —L1—R2 is —H, —CN, —CH3, —OH, Br, C1—C6 haloalkyl, C2—C6 alkenyl, C1—C6 alkyl, C3—C12 cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 14-membered aryl, or 5- to 14-membered heteroaryl; wherein each alkyl and alkenyl is optionally substituted with 0 to 3 groups each independently selected from halogen, OH, CN, and NR5R5, and wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted at each substitutable ring carbon atom with Rp and optionally substituted at each substitutable ring nitrogen atom by Rnc;

[0125] each instance of Rp is independently hydrogen, halogen, —CN, —NO2, —N3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -ORc3, -SRc3, -N(Rc3)2, -C(=O)N(Rc3)2, -N(Rc3)C(=O)Rc3, -C(=O)Rc3, -C(=O)ORc3, -OC(=O)Rc3, -S(=O)Rc3, -S(=O)2Rc3, -S(=O)ORc3, -OS(=O)Rc3, -S(=O)2ORc3, -OS(=O)2Rc3,

[0126] -S(=O)N(Rc3)2, -S(=O)2N(Rc3)2, -N(Rc3)S(=O)Rc3, -N(Rc3)S(=O)2Rc3, -N(Rc3)C(=O)ORc3, -OC(=O)N(Rc3)2, -N(Rc3)C(=O)N(Rc3)2, -N(Rc3)S(=O)N(Rc3)2, -N(Rc3)S(=O)2N(Rc3)2, -N(Rc3)S(=O)ORc3, —N(Rc3)S(=O)2ORc3, —OS(=O)N(Rc3)2, —OS(=O)2N(Rc3)2; or alternatively

[0127] two instances of Rpattached to the adjacent ring carbon atoms, can be taken together with the carbon atoms to which they are attached to form 3- to 8-membered cycloalkyl, 5- to 6-membered saturated or partially saturated monocyclic heterocyclyl, or 5- to 6-membered monocyclic heteroaryl; wherein:

[0128] each instance of Rc3 is independently hydrogen or C₁─C₆ alkyl;

[0129] L2 is —S—, —S—CH2—, —CH2—S—, —S(=O)2—, —S(=O)—, —S(=O)2O—, —OS(=O)2—, —S(=O)O—, —OS(=O)—, —S(=O)CH2—, —CH2S(=O)—, —S(=O)2CH2—, —CH2S(=O)2—, —S(=O)2NR5—, —NR5S(=O)2—, —S(=O)NR5—, —NR5S(=O)—, —NR5S(=O)2O—, —OS(=O)2NR5—, —NR5S(=O)O—, —OS(=O)NR5—, —S(=O)(=NR5)—, —C(=O)—, —C(=O)O—, —OC(=O)—, —C(=O)NR5—, —N(R5)C(=O)—, —NR5C(=O)O—, —OC(=O)NR5—, —NR5C(=O)NR5—, —NR5—, —C(=S)NR5—, —N(R5)C(=S)—, or —(CRaRb)r—;

[0130] each instance of Raand Rbare independently hydrogen, halogen, CN, OH, NO2, N3, or Ci— Ce alkyl: wherein the Ci— Ce alkyl represented by Raor Rbare each optionally substituted with 0 to 3 groups each independently selected from halogen, OH, CN, and NR5R5;

[0131] each instance of Rj and Rk are independently hydrogen, halogen, CN, OH, NO2, N3, or C1—C6 alkyl; wherein the C1—C6 alkyl represented by Ra or Rb are each optionally substituted with 0 to 3 groups each independently selected from halogen, OH, CN, and NR5R5;

[0132] q is 1 or 2; Attorney Docket No. 047162-7543WO1(02791)

[0133] r is 1 or 2;

[0134] Q is C3—C12 cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 14-membered aryl, or 5-to 14-membered heteroaryl, each of which is optionally substituted at each substitutable ring carbon atom with Rn and optionally substituted at each substitutable ring nitrogen atom by Rna; or

[0135] —L2—Q is —H, —CN, —CH3, —OH, Br, C1—C6 haloalkyl, C2—C6 alkenyl, C1—C6 alkyl, C3—C12 cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 14-membered aryl, or 5- to 14-membered heteroaryl; wherein each alkyl and alkenyl is optionally substituted with 0 to 3 groups each independently selected from halogen, OH, CN, and NR5R5, and wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted at each substitutable ring carbon atom with Rn and optionally substituted at each substitutable ring nitrogen atom by Rna;

[0136] each instance of Rn is independently hydrogen, halogen, —CN, —NO2, —N3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -ORc4, -SRc4, -N(Rc4)2, -C(=O)N(Rc4)2, -N(Rc4)C(=O)Rc4, —C(=O)Rc4, -C(=O)ORc4, —OC(=O)Rc4, -S(=O)Rc4, -S(=O)2Rc4, -S(=O)ORc4, -OS(=O)Rc4, -S(=O)2ORc4, -OS(=O)2Rc4, -S(=O)N(Rc4)2, -S(=O)2N(Rc4)2, -N(Rc4)S(=O)Rc4, -N(Rc4)S(=O)2Rc4, -N(Rc4)C(=O)ORc4, -OC(=O)N(Rc4)2, -N(Rc4)C(=O)N(Rc4)2, -N(Rc4)S(=O)N(Rc4)2, -N(Rc4)S(=O)2N(Rc4)2, -N(Rc4)S(=O)ORc4, -N(Rc4)S(=O)2ORc4, -OS(=O)N(Rc4)2, or -OS(=O)2N(Rc4)2; or alternatively two instances of Rn attached to the adjacent ring carbon atoms, can be taken together with the carbon atoms to which they are attached to form an optionally substituted 3— to 8—membered cycloalkyl, 5— to 6—membered saturated or partially saturated monocyclic heterocyclyl, or 5— to 6—membered monocyclic heteroaryl; wherein:

[0137] each instance of Rc4 is independently hydrogen or C1—C6 alkyl;

[0138] R3 is hydrogen or C1—C6 alkyl;

[0139] R4 is hydrogen, C1—C6 alkyl, C1—C6 haloalkyl, C2—C6 alkynyl, halogen, CN, —C(=O)NR5R5, or C≡C(CH2)wOH, wherein w is 1, 2, 3, 4, 5, or 6, and wherein each alkyl, haloalkyl, and alkynyl is independently optionally substituted with 1—3 instances of C1—C4 alkyl or halogen;

[0140] each instance of Rnaand Rncis independently hydrogen, Ci— Ce alkyl, or Ci— Ce haloalkyl; and

[0141] each instance of R5 is independently hydrogen or C1—C6 alkyl; Attorney Docket No. 047162-7543WO1(02791)

[0142]

[0143] L2is —(CRaRb)r— and Q is phenyl optionally substituted with Rn and Rna, then L1 is —(CRjRk)q— and R2 is cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted with Rp and Rnc.

[0144] In some embodiments of any of the above aspects, the NuSH receptor modulator is a human NuSH receptor modulator. In some embodiments of any of the above aspects, the NuSH receptor modulator is a NuSH receptor agonist. In some embodiments of any of the above aspects, the NuSH receptor modulator is a GLP-1 receptor agonist. In some embodiments of any of the above aspects, the GLP-1 receptor agonist is liraglutide, semaglutide, exenatide, dulaglutide, lixisenatide, Orforglipron, or albiglutide. In some embodiments of any of the above aspects, the NuSH receptor modulator is a GIP receptor agonist. In some embodiments of any of the above aspects, the NuSH receptor modulator is a dual agonist for GLP-1 receptor and GIP receptor. In some embodiments of any of the above aspects, the dual agonist for GLP-1 receptor and GIP receptor is tirzepatide. In some embodiments of any of the above aspects, wherein the NuSH receptor modulator is a GCG receptor agonist. In some embodiments of any of the above aspects, the NuSH receptor modulator is a triple agonist for GLP-1 receptor, GIP receptor, and GCG receptor. In some embodiments of any of the above aspects, the triple agonist for GLP-1 receptor, GIP receptor, and GCG receptor is retatrutide, mazdutide, or survodutide. In some embodiments of any of the above aspects, the method comprises administering TEPP-46 and liraglutide. In some embodiments of any of the above aspects, the Attorney Docket No. 047162-7543WO1(02791)

[0145] method comprises administering TEPP-46 and semaglutide. In some embodiments of any of the above aspects, method comprises administering TEPP-46 and tirzepatide. In some embodiments of any of the above aspects, the method comprises administering TEPP-46 and Orforglipron. In some embodiments of any of the above aspects, the method comprises administering mitapivat and liraglutide. In some embodiments of any of the above aspects, the method comprises administering mitapivat and semaglutide. In some embodiments of any of the above aspects, the method comprises administering mitapivat and tirzepatide. In some embodiments of any of the above aspects, the method comprises administering mitapivat and Orforglipron. In some embodiments of any of the above aspects, the method comprises administering etavopivat and liraglutide. In some embodiments of any of the above aspects, the method comprises administering etavopivat and semaglutide. In some embodiments of any of the above aspects, the method comprises administering etavopivat and tirzepatide. In some embodiments of any of the above aspects, the method comprises administering etavopivat and Orforglipron. In some embodiments of any of the above aspects, the method comprises administering the compound and liraglutide. In some embodiments of any of the above aspects, the method comprises administering the compound and semaglutide. In some embodiments of any of the above aspects, the method comprises administering the compound and tirzepatide. In some embodiments of any of the above aspects, the method comprises administering the compound and Orforglipron.

[0146] In some embodiments of any of the above aspects, the method further comprises administering at least one additional agent or therapy useful for treating obesity and / or T2D and / or other obesity-related disease, disorder, or condition. In some embodiments of any of the above aspects, the at least one additional agent or therapy comprises leptin, ghrelin, MC4RA, myostatin inhibitors, activin inhibitors, NRLP3, and metformin.

[0147] In some embodiments of any of the above aspects, the subject is an animal. In some embodiments of any of the above aspects, the subject is a non-human primate. In some embodiments of any of the above aspects, the subject is a livestock animal. In some embodiments of any of the above aspects, the livestock animal is a cow, a sheep, a goat, a horse, or a pig. In some embodiments of any of the above aspects, the subject is a companion animal. In some embodiments of any of the above aspects, the companion animal is a dog or a cat. In some embodiments of any of the above aspects, the subject is a human. Attorney Docket No. 047162-7543WO1(02791)

[0148] In some embodiments of any of the above aspects, the PKa is administered concurrently with the NuSH receptor modulator. In some embodiments of any of the above aspects, the PKa is administered prior to administration of the NuSH receptor modulator. In some embodiments of any of the above aspects, the PKa is administered after to administration of the NuSH receptor modulator.

[0149] In some embodiments of any of the above aspects, the NuSH receptor modulator is administered at a lower dosage when administered with the PKa than when the NuSH receptor modulator is administered without the PKa. In some embodiments of any of the above aspects, the NuSH receptor modulator is administered at a lower dosage when administered with the PKa than an FDA approved dose of the NuSH receptor modulator.

[0150] In some embodiments of any of the above aspects, the method further comprises terminating administration of the NuSH receptor modulator following administration of the PKa. In some embodiments of any of the above aspects, an amount of the NuSH receptor modulator is decreased or discontinued. In some embodiments of any of the above aspects, the amount of the NuSH receptor modulator is decreased or discontinued after the subject reaches a desired weight or is no longer losing weight. In some embodiments of any of the above aspects, the amount of the NuSH receptor modulator is decreased or discontinued after the subject reaches a desired glucose tolerance level. In some embodiments of any of the above aspects, the amount of the NuSH receptor modulator is decreased or discontinued if the subject experiences a negative side effect associated with the NuSH receptor modulator. In some embodiments of any of the above aspects, the amount of the NuSH receptor modulator is decreased or discontinued due to pricing of the NuSH receptor modulator.

[0151] In some aspects, provided herein is a method of treating obesity in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a nutrient stimulated hormone (NuSH) receptor modulator and an AMP kinase inhibitor, a phosphodiesterase inhibitor, or a calcium channel inhibitor.

[0152] In some aspects, provided herein is a method of reducing fat mass in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a nutrient stimulated hormone (NuSH) receptor modulator and an AMP kinase inhibitor, a phosphodiesterase inhibitor, or a calcium channel inhibitor. Attorney Docket No. 047162-7543WO1(02791)

[0153] In some aspects, provided herein is a method of increasing muscle mass in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a nutrient stimulated hormone (NuSH) receptor modulator and an AMP kinase inhibitor, a phosphodiesterase inhibitor, or a calcium channel inhibitor.

[0154] In some aspects, provided herein is a method of increasing a lean-to-fat mass ratio a subject in need thereof, wherein the method comprises administering to the subject in need thereof a nutrient stimulated hormone (NuSH) receptor modulator and an AMP kinase inhibitor, a phosphodiesterase inhibitor, or a calcium channel inhibitor.

[0155] In some aspects, provided herein is a method of improving insulin release a subject in need thereof, wherein the method comprises administering to the subject in need thereof a nutrient stimulated hormone (NuSH) receptor modulator and an AMP kinase inhibitor, a phosphodiesterase inhibitor, or a calcium channel inhibitor.

[0156] In some aspects, provided herein is a method of improving glucose tolerance mass ratio a subject in need thereof, wherein the method comprises administering to the subject in need thereof a nutrient stimulated hormone (NuSH) receptor modulator and an AMP kinase inhibitor, a phosphodiesterase inhibitor, or a calcium channel inhibitor.

[0157] In some embodiments of any of the above aspects, the method comprises administering a phosphodiesterase inhibitor, wherein the phosphodiesterase inhibitor is a PDE4B inhibitor.

[0158] In some aspects, provided herein is a pharmaceutical combination comprising a pyruvate kinase (PK) activator and a nutrient stimulated hormone (NuSH) receptor modulator.

[0159] In some aspects, provided herein is a pharmaceutical composition comprising a pyruvate kinase (PK) activator, a nutrient stimulated hormone (NuSH) receptor modulator, and a pharmaceutically acceptable excipient.

[0160] In some embodiments of any of the above aspects, the pyruvate kinase activator (PKa) is red blood cell pyruvate kinase activator (PKR) or an activator of a pyruvate kinase M2 (PKM2) isoform. In some embodiments of any of the above aspects, the PKa is mitapivat, etavopivat, or tebapivat. In some embodiments of any of the above aspects, the PKa is TEPP-46, DASA-58, or ML-265. In some embodiments of any of the above aspects, the PKa is a compound represented by the following structural formula Formula A: Attorney Docket No. 047162-7543WO1(02791)

[0161]

[0162] (Formula A),

[0163] or a pharmaceutically acceptable salt thereof, wherein:

[0164] U1, U2, and U3 are each independently N, O, S, C, or CR1, as valency permits;

[0165] U4, U6, and U7are each independently N or C, as valency permits;

[0166] U5 is N, NR3, or CR4, as valency permits;

[0167] m is 1 or 2;

[0168]

[0169] Ring A is phenyl,

[0170] U8 is N or CR1;

[0171] each instance of R1 is independently hydrogen or C1—C6 alkyl;

[0172] Li is -S-, -S-CH2-. CH2 S, -S(=O)2- -S(=O)-, -S(=O)2O-. -OS(=O)2- -S( O)O- -OS(-O)-. -S( O)CH2 -CH2S(=O)-. -S(=O)2CH2- -CH2S(=O)2- -S(=O)2NR5, -NR5S(=O)2, -S(=O)NR5. ~NR5S(=O)~ -NR5S(=O)2O- -OS(=O)2NR5- -NR5S(=O)O- -OS(=O)NR5- -S(=O)(=NR5)- C(=O), -C(=O)O- -OC(=O)-. -C(=O)NR5- -N(R5)C(=O)- -NR;C(=O)O- -OC(=O)NR5- -NR5C(=O)NR5“. -NRS, C(=S)NR5, N(R5)C(=S)-, or ~(CRjRk)q~;

[0173] R2 is C1—C6 alkyl, C3—C12 cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 14-membered aryl, or 5- to 14-membered heteroaryl, wherein the alkyl is optionally substituted with 0 to 3 groups each independently selected from halogen, OH, CN, and NR5R5, and wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted at each substitutable Attorney Docket No. 047162-7543WO1(02791)

[0174] ring carbon atom with Rpand optionally substituted at each substitutable ring nitrogen atom by Rnc; or

[0175] —L1—R2 is —H, —CN, —CH3, —OH, Br, C1—C6 haloalkyl, C2—C6 alkenyl, C1—C6 alkyl, C3—C12 cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 14-membered aryl, or 5- to 14-membered heteroaryl; wherein each alkyl and alkenyl is optionally substituted with 0 to 3 groups each independently selected from halogen, OH, CN, and NR5R5, and wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted at each substitutable ring carbon atom with Rp and optionally substituted at each substitutable ring nitrogen atom by Rnc;

[0176] each instance of Rp is independently hydrogen, halogen, —CN, —NO2, —N3, C1—C6 alkyl, C2—C6 alkenyl, C2—C6 alkynyl, —ORc3, —SRc3, —N(Rc3)2, —C(=O)N(Rc3)2, —N(Rc3)C(=O)Rc3, —C(=O)Rc3, —C(=O)ORc3, —OC(=O)Rc3, —S(=O)Rc3, —S(=O)2Rc3, —S(=O)ORc3, —OS(=O)Rc3, —S(=O)2ORc3, —OS(=O)2Rc3,

[0177] —S(=O)N(Rc3)2, —S(=O)2N(Rc3)2, —N(Rc3)S(=O)Rc3, —N(Rc3)S(=O)2Rc3, —N(Rc3)C(=O)ORc3, —OC(=O)N(Rc3)2, —N(Rc3)C(=O)N(Rc3)2, —N(Rc3)S(=O)N(Rc3)2, —N(Rc3)S(=O)2N(Rc3)2, —N(Rc3)S(=O)ORc3, —N(Rc3)S(=O)2ORc3, —OS(=O)N(Rc3)2, —OS(=O)2N(Rc3)2; or alternatively

[0178] two instances of Rpattached to the adjacent ring carbon atoms, can be taken together with the carbon atoms to which they are attached to form 3- to 8-membered cycloalkyl, 5- to 6-membered saturated or partially saturated monocyclic heterocyclyl, or 5- to 6-membered monocyclic heteroaryk wherein:

[0179] each instance of Rc3 is independently hydrogen or C1—C6 alkyl;

[0180] L2 is —S—, —S—CH2—, —CH2—S—, —S(=O)2—, —S(=O)—, —S(=O)2O—, —OS(=O)2—, —S(=O)O—, —OS(=O)—, —S(=O)CH2—, —CH2S(=O)—, —S(=O)2CH2—, —CH2S(=O)2—, —S(=O)2NR5—, —NR5S(=O)2—, —S(=O)NR5—, —NR5S(=O)—, —NR5S(=O)2O—, —OS(=O)2NR5—, —NR5S(=O)O—, —OS(=O)NR5—, —S(=O)(=NR5)—, —C(=O)—, —C(=O)O—, —OC(=O)—, —C(=O)NR5—, —N(R5)C(=O)—, —NR5C(=O)O—, —OC(=O)NR5—, —NR5C(=O)NR5—, —NR5—, —C(=S)NR5—, —N(R5)C(=S)—, or —(CRaRb)r—;

[0181] each instance of Raand Rbare independently hydrogen, halogen, CN, OH, NO2, N3, or Ci— Ci, alkyl; wherein the Ci— Ci, alkyl represented by Raor Rbare each optionally substituted with 0 to 3 groups each independently selected from halogen, OH, CN, and NR5R5;

[0182] each instance of Rj and Rk are independently hydrogen, halogen, CN, OH, NO2, N3, or C1—C6 alkyl; wherein the C1—C6 alkyl represented by Ra or Rb are each Attorney Docket No. 047162-7543WO1(02791)

[0183] optionally substituted with 0 to 3 groups each independently selected from halogen, OH, CN, and NR5R5;

[0184] q is 1 or 2;

[0185] r is 1 or 2;

[0186] Q is C3—C12 cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 14-membered aryl, or 5- to 14-membered heteroaryl, each of which is optionally substituted at each substitutable ring carbon atom with Rn and optionally substituted at each substitutable ring nitrogen atom by Rna; or

[0187] —L2—Q is —H, —CN, —CH3, —OH, Br, C1—C6 haloalkyl, C2—C6 alkenyl, C1—C6 alkyl, C3—C12 cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 14-membered aryl, or 5- to 14-membered heteroaryl; wherein each alkyl and alkenyl is optionally substituted with 0 to 3 groups each independently selected from halogen, OH, CN, and NR5R5, and wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted at each substitutable ring carbon atom with Rn and optionally substituted at each substitutable ring nitrogen atom by Rna;

[0188] each instance of Rn is independently hydrogen, halogen, —CN, —NO2, —N3, C1—C6 alkyl, C2—C6 alkenyl, C2—C6 alkynyl, —ORc4, —SRc4, —N(Rc4)2, —C(=O)N(Rc4)2, —N(Rc4)C(=O)Rc4, —C(=O)Rc4, —C(=O)ORc4, —OC(=O)Rc4, —S(=O)Rc4, —S(=O)2Rc4, —S(=O)ORc4, —OS(=O)Rc4, —S(=O)2ORc4, —OS(=O)2Rc4, —S(=O)N(Rc4)2, —S(=O)2N(Rc4)2, —N(Rc4)S(=O)Rc4, —N(Rc4)S(=O)2Rc4, —N(Rc4)C(=O)ORc4, —OC(=O)N(Rc4)2, —N(Rc4)C(=O)N(Rc4)2, —N(Rc4)S(=O)N(Rc4)2, —N(Rc4)S(=O)2N(Rc4)2, —N(Rc4)S(=O)ORc4, —N(Rc4)S(=O)2ORc4, —OS(=O)N(Rc4)2, or —OS(=O)2N(Rc4)2; or alternatively two instances of Rnattached to the adjacent ring carbon atoms, can be taken together with the carbon atoms to which they are attached to form an optionally substituted 3- to 8—membered cycloalkyl, 5- to 6—membered saturated or partially saturated monocyclic heterocyclyl, or 5— to 6—membered monocyclic heteroaryl; wherein:

[0189] each instance of Rc4 is independently hydrogen or C1—C6 alkyl;

[0190] R3 is hydrogen or C1—C6 alkyl;

[0191] R4 is hydrogen, C1—C6 alkyl, C1—C6 haloalkyl, C2—C6 alkynyl, halogen, CN, —C(=O)NR5R5, or C≡C(CH2)wOH, wherein w is 1, 2, 3, 4, 5, or 6, and wherein each alkyl, haloalkyl, and alkynyl is independently optionally substituted with 1—3 instances of C1—C4 alkyl or halogen; Attorney Docket No. 047162-7543WO1(02791)

[0192] each instance of Rna and Rnc is independently hydrogen, C1—C6 alkyl, or C1—C6 haloalkyl; and

[0193] each instance of R5 is independently hydrogen or C1—C6 alkyl;

[0194] is

[0195]

[0196] ’ L2 is — (CRaRb)r— and Q is phenyl optionally substituted with Rnand Rna, then Li is — (CR|Rk)q— and R2 is cycloalkyl, heterocyclyl. aryl, or heteroaryl optionally substituted with Rpand Rnc. In some embodiments of any of the above aspects, the NuSH receptor modulator is a human NuSH receptor modulator. In some embodiments of any of the above aspects, the NuSH receptor modulator is a NuSH receptor agonist. In some embodiments of any of the above aspects, wherein the NuSH receptor modulator is a GLP-1 receptor agonist. In some embodiments of any of the above aspects, the GLP-1 receptor agonist is liraglutide, semaglutide, exenatide, dulaglutide, lixisenatide, or albiglutide. In some embodiments of any of the above aspects, the NuSH receptor modulator is a GIP receptor agonist. In some embodiments of any of the above aspects, the NuSH receptor modulator is a dual agonist for GLP-1 receptor and GIP receptor. In some embodiments of any of the above aspects, the GLP-1 receptor and GIP receptor dual agonist is tirzepatide. In some embodiments of any of the above aspects, the NuSH receptor modulator is a GCG receptor agonist. In some embodiments of any of the above aspects, the NuSH receptor modulator is a triple agonist for GLP-1 receptor, GIP receptor, and GCG receptor. In some embodiments of any of the above Attorney Docket No. 047162-7543WO1(02791)

[0197] aspects, the GLP-1 receptor, GIP receptor, and GCG receptor triple agonist is retatrutide, mazdutide, or survodutide. In some embodiments of any of the above aspects, the combination or composition is formulated with a lower dose of the NuSH receptor modulator than a composition not comprising the PKa. In some embodiments of any of the above aspects, the pharmaceutical combination or composition comprises TEPP-46 and liraglutide. In some embodiments of any of the above aspects, the pharmaceutical combination or composition comprises TEPP-46 and semaglutide. In some embodiments of any of the above aspects, the pharmaceutical combination or composition comprises TEPP-46 and tirzepatide. In some embodiments of any of the above aspects, the pharmaceutical combination or composition comprises TEPP-46 and Orforglipron. In some embodiments of any of the above aspects, the pharmaceutical combination or composition comprises mitapivat and liraglutide. In some embodiments of any of the above aspects, the pharmaceutical combination or composition comprises mitapivat and semaglutide. In some embodiments of any of the above aspects, the pharmaceutical combination or composition comprises mitapivat and tirzepatide. In some embodiments of any of the above aspects, the pharmaceutical combination or composition comprises mitapivat and Orforglipron. In some embodiments of any of the above aspects, the pharmaceutical combination or composition comprises etavopivat and liraglutide. In some embodiments of any of the above aspects, the pharmaceutical combination or composition comprises etavopivat and semaglutide. In some embodiments of any of the above aspects, the pharmaceutical combination or composition comprises etavopivat and tirzepatide. In some embodiments of any of the above aspects, n the pharmaceutical combination or composition comprises etavopivat and Orforglipron. In some embodiments of any of the above aspects, the pharmaceutical combination or composition comprises the compound and liraglutide. In some embodiments of any of the above aspects, the pharmaceutical combination or composition comprises the compound and semaglutide. In some embodiments of any of the above aspects, the pharmaceutical combination or composition comprises the compound and tirzepatide. In some embodiments of any of the above aspects, the pharmaceutical combination or composition comprises the compound and Orforglipron.

[0198] In some aspects, provided herein is a pharmaceutical combination comprising a nutrient stimulated hormone (NuSH) receptor modulator and an AMP kinase inhibitor, a phosphodiesterase inhibitor, or a calcium channel inhibitor. Attorney Docket No. 047162-7543WO1(02791)

[0199] In some aspects, provided herein is a pharmaceutical composition comprising a nutrient stimulated hormone (NuSH) receptor modulator; an AMP kinase inhibitor, a phosphodiesterase inhibitor, or a calcium channel inhibitor; and a pharmaceutically acceptable excipient.

[0200] In some embodiments of any of the above aspects, the pharmaceutical combination or composition comprises the phosphodiesterase inhibitor, wherein the phosphodiesterase inhibitor is a PDE4B inhibitor.

[0201] BRIEF DESCRIPTION OF THE DRAWINGS

[0202] The foregoing and other features and advantages of the present invention will be more fully understood from the following detailed description of illustrative embodiments taken in conjunction with the accompanying drawings. The drawings illustrate generally, by way of example, but not by way of limitation, various embodiments of the present application.

[0203] FIG. 1 is a schematic showing the role of pyruvate kinase (PK) activation in improving metabolic health (as published in Abulizi, et al., Cell Metabolism, 2020, 32(5):751-766).

[0204] FIG. 2 is a graph showing that administration of the PK activator (PKa) TEPP-46 + GLP-1 RA (liraglutide) amplifies weight loss in diet induced obese (DIO) mice.

[0205] FIG.3 are DEXA body composition measurements of DIO mice following four weeks of treatment with vehicle, the PKa TEPP-46, liraglutide, or TEPP-46 + liraglutide.

[0206] FIG.4 shows intraperitoneal glucose tolerance test (IPGTT) graphs showing that daily (1 week and 4 week) administration of the PKa TEPP-46 + GLP-1 RA (liraglutide) improves glucose tolerance in DIO mice.

[0207] FIG. 5 shows data illustrating the finding that PK activation with TEPP-46 and GLP-1 RA (GLP-1) display the same calcium oscillation patterns in mouse islet β-cells. Treatment with glucose, glucokinase (GK) activator, and PK activator TEPP-46 are published in Lewandowski, et al., Cell Metabolism, 2020 32(5):736-750.

[0208] FIG. 6 is a series of charts showing that PKa (TEPP-46) amplifies target modulation (cAMP-dependent protein kinase A activity) in human islets and is synergistic with GLP-1 RA (GLP-1) (z.e., the combination of PKa (TEPP-46) and GLP-1 RA (GLP-1) is significantly better than either alone).

[0209] FIG. 7 is a chart showing that PKa (TEPP-46) amplifies insulin secretion from human islets and enhances the effect of with the GLP-1 RA exendin-4 / exenatide (Exen-4) (i.e., the combination of PKa and GLP-1 RA is significantly better than either alone). Attorney Docket No. 047162-7543WO1(02791)

[0210] FIG. 8 shows data illustrating the finding that deletion of PKm1 / 2 in mouse β-cells decreases insulin secretion in response to glucose and tirzepatide, which is rescued by administration of PKa (TEPP-46) together with tirzepatide.

[0211] FIG. 9 shows data illustrating the finding that PKa (TEPP-46) potentiates cAMP-dependent protein kinase A activity in mouse islet β-cells downstream of the GLP-1R, which was agonized by the neighboring α-cells using the glucagonotropic amino acids arginine and alanine (RA) (i.e., the effect of PKa (TEPP-46) to potentiate PKA activity in response to amino acids was blocked by the combination of glucagon receptor antagonist (GRA) and GLP-1R antagonist (Ex9, exendin-(9-39)), or the GLP-1R antagonist Ex9 alone).

[0212] FIG. 10 is a schematic showing that pyruvate kinase activator (PKa) is a downstream regulator of NuSH receptors that synergizes with incretins in pancreatic islets.

[0213] FIG. 11 shows an exemplary set of bar graphs demonstrating multiple PK activators increase mitochondrial membrane potential in four cell types.

[0214] FIG. 12A shows an exemplary set of bar graphs demonstrating PK activation (by TEPP-46) alone or with semaglutide treatment increases muscle. FIG. 12B shows an exemplary set of images and an exemplary bar graph demonstrating the mean diameter of the muscle fiber in the same treatment groups.

[0215] FIG. 13 shows an exemplary set of graphs demonstrating that a PKa (TEPP-46) increases cAMP levels in HEK293 cells stimulated with adenylate cyclase activator (forskolin). HEK293 cells were stimulated with the indicated amounts of forskolin (which stimulates adenylate cyclase to make cAMP) and with or without 10 pM TEPP-46 in the presence of 10 mM glucose, 2 mM glutamine and 0.5 mM leucine. TEPP-46 shifted the EC50 of forskolin from 1.76 pM to 0.93 pM (pO. OOOl). The measurements were performed using a plate reader to image H188 cAMP biosensors introduced into HEK293T cells with adenovirus. The data was normalized to baseline.

[0216] FIG. 14 shows an exemplary set of graphs demonstrating that a PKa (etavopivat) increases cAMP levels in HEK293 cells stimulated with adenylate cyclase activator (forskolin). HEK293 cells were stimulated with the indicated amounts of forskolin (which stimulates adenylate cyclase to make cAMP) and with or without 10 μM etavopivat in the presence of 10 mM glucose, 2 mM glutamine and 0.5 mM leucine. Etavopivat shifted the EC50 of forskolin from 5.05 μM to 2.41 μM (p=0.001). The measurements were performed using a plate reader to image H188 cAMP biosensors introduced into HEK293T cells with adenovirus. The data was normalized to baseline. Attorney Docket No. 047162-7543WO1(02791)

[0217] FIG. 15 shows an exemplary’ set of graphs demonstrating that a PKa (mitapivat) increases cAMP levels in HEK293 cells stimulated with adenylate cyclase activator (forskolin). HEK293 cells were stimulated with the indicated amounts of forskolin (which stimulates adenylate cyclase to make cAMP) and with or without 10 pM mitapivat in the presence of 10 mM glucose. 2 mM glutamine and 0.5 mM leucine. Mitapivat shifted the EC50 of forskolin from 2.50 pM to 1.68 pM (p=0.0005). The measurements were performed using a plate reader to image H188 cAMP biosensors introduced into HEK293T cells with adenovirus. The data was normalized to baseline.

[0218] FIG. 16 shows an exemplary set of graphs demonstrating that some PKas (TEPP-46 (10 μM)) synergistically amplify the effect of GLP-1 RA (liraglutide (10 nM)) on insulin secretion from mouse islets (top panel). Other PKas (mitapivat (10 μM) and etavopivat (10 μM)) had no effect on insulin release (bottom panel). The measurements were performed on mouse islets isolated from lean C57BL6 / J mice under the conditions indicated, and the insulin concentration was measured in the perifusate using a commercial plate reader assay.

[0219] FIG. 17 shows an exemplary set of graphs demonstrating that a PKa (TEPP-46 (10 μM)) synergistically amplifies the effect of glucose and multiple different NuSHs (glucagon (GCG (10 nM)), GLP-1(10 nM)) on insulin secretion from mouse islets. The measurements were performed on mouse islets isolated from lean C57BL6 / J mice under the conditions indicated, and the insulin concentration was measured in the perifusate using a commercial plate reader assay.

[0220] FIG. 18 shows an exemplary’ set of graphs demonstrating that a PKa (TEPP-46 (10 pM)) amplifies the effect of glucose and a GLP-1 RA (tirzepatide (30 nM)) on insulin secretion from mouse islets. The measurements were performed on mouse islets isolated from lean C57BL6 / J mice under the conditions indicated, and the insulin concentration was measured in the perifusate using a commercial plate reader assay.

[0221] FIG. 19 shows an exemplary set of bar graphs demonstrating that a PKa (TEPP-46 (10 μM)) amplifies target modulation (cAMP-dependent protein kinase A activity, y-axes) in human islets from multiple donors, both alone and in combination with glucagon (GCG (10 nM)). The combination of the PKa (TEPP-46 (10 μM)) and glucagon is significantly better than either alone. The measurements were performed by imaging cAMP-dependent protein kinase A biosensors introduced into β-cells of intact human islets from 6 donors (each graph is a different donor).

[0222] FIG. 20 shows an exemplary series of charts demonstrating that a PKa (TEPP-46 (10 μM)) amplifies target modulation (cAMP-dependent protein kinase A activity, y-axes) in Attorney Docket No. 047162-7543WO1(02791)

[0223] human islets from multiple donors, both alone and in combination with GLP-1 (10 nM). The combination of the PKa(TEPP-46 (10 pM)) and GLP-1 is significantly better than either alone. The measurements were performed by imaging cAMP-dependent protein kinase A biosensors introduced into P-cells of intact human islets from 6 donors (each graph is a different donor).

[0224] FIG. 21 shows an exemplary series of charts demonstrating that PKa (TEPP-46 (10 pM)) amplifies target modulation (cAMP-dependent protein kinase A activity, y-axes) in human islets from multiple donors, both alone and in combination with GIP (10 nM). The combination of PKa (TEPP-46 (10 pM)) and GIP is significantly better than either alone. The measurements were performed by imaging cAMP-dependent protein kinase A biosensors introduced into P-cells of intact human islets from 6 donors (each graph is a different donor).

[0225] FIG. 22 shows an exemplary series of charts demonstrating that PKa (TEPP-46 (10 pM)) amplifies target modulation (cAMP-dependent protein kinase A activity, y-axes) in human islets from multiple donors, both alone and in combination with tirzepatide (30 nM). The combination of PKa (TEPP-46 (10 pM)) and tirzepatide is significantly better than either alone. The measurements were performed by imaging cAMP-dependent protein kinase A biosensors introduced into P-cells of intact human islets from 6 donors (each graph is a different donor).

[0226] FIG. 23 shows an exemplary graph demonstrating that PKas (TEPP-46 (10 pM), and mitapivat (10 pM)) amplify target modulation (cAMP-dependent protein kinase A activity) in mouse islets and enhances the effect of a GLP-1 RA (liraglutide (10 nM)). The measurements were performed by imaging cAMP-dependent protein kinase A biosensors introduced into beta cells of intact mouse islets isolated from lean C57BL6 / J mice.

[0227] FIG. 24 shows an exemplary set of graphs demonstrating that a PKa (TEPP-46 (10 pM)) potentiates cAMP-dependent protein kinase A activity in mouse islet P-cells downstream of the GLP-1 R, which was agonized by endogenous glucagon released from the neighboring a-cells using the glucagonotropic amino acids arginine and alanine (RA). The effect of PKa (TEPP-46) to potentiate protein kinase A activity in response to arginine and alanine (RA) was blocked by the combination of a glucagon receptor antagonist (GRA, 10 pg / mL LY glucagon receptor antibody) and a GLP-1 R antagonist (Ex9, exendin-(9-39) (1 pM)), or the GLP-1 R antagonist Ex9 alone). The measurements were performed by imaging cAMP-dependent protein kinase A biosensors introduced into P-cells of intact mouse islets isolated from lean C57BL6 / J mice.

[0228] FIG. 25 shows an exemplary graph demonstrating that a PKa (TEPP-46 (10 pM)) potentiates insulin secretion from mouse islet P-cells downstream of the GLP-1R, which was Attorney Docket No. 047162-7543WO1(02791)

[0229] agonized by endogenous GCG released from the neighboring a-cells using the glucagonotropic amino acids arginine and alanine (RA). The effect of PKa (TEPP-46) to potentiate insulin secretion in response to arginine and alanine (RA) was blocked by a GLP-1R antagonist (Ex9, exendin-(9-39) (1 pM). The measurements were performed on mouse islets isolated from lean C57BL6 / J mice under the conditions indicated, and the insulin concentration was measured in the perifusate using a commercial plate reader assay.

[0230] FIG. 26 shows an exemplary set of graphs demonstrating that a PKa (TEPP-46 (10 pM)) potentiates insulin secretion from mouse islet P-cells downstream of GLP-1R / GCGR, which were agonized by endogenous GCG released from the neighboring a-cells using the glucagonotropic amino acids arginine and alanine (RA). The effect of PKa (TEPP-46) to potentiate insulin secretion in response to arginine and alanine (RA) was blocked by |3-cell deletion (KO) of GLP-1R and GCGR. The measurements were performed on mouse islets isolated from GLP1R / GCGR-PKO mice (Glplr-flox: Gcgr-flox: MIP-CreERT) and littermate controls (Glplr-flox: Gcgr-flox) under the conditions indicated, and the insulin concentration was measured in the perifusate using a commercial plate reader assay.

[0231] FIG. 27 shows an exemplary set of graphs demonstrating that a PKa (TEPP-46) increases cAMP levels in HEK293 cells in proportion to activation of the glucagon receptor (GCGR). HEK293 cells expressing GCGR were stimulated with the indicated amounts of glucagon (GCG, which stimulates adenylate cyclase to make cAMP) with or without 10 pM TEPP-46 in the presence of 10 mM glucose, 2 mM glutamine, 0.5 mM leucine, and 200 nM of adenylate cyclase activator forskolin. The measurements were performed using a plate reader to image H188 cAMP biosensors and glucagon receptors (GCGR) introduced into HEK293T cells with adenovirus.

[0232] FIG. 28 shows an exemplar}’ graph demonstrating that administration of a PKa TEPP-46 (30 mg / kg) + GLP-1 RA (semaglutide) reduces weight to lean levels in diet induced obese (DIO) mice.

[0233] FIG. 29 shows an exemplary graph demonstrating that pan-phosphodiesterase inhibition (using pan-phosphodiesterase inhibitor IB MX (250pM)) blocks the ability of a PKa (TEPP-46 (10 pM)) to increase cAMP levels in HEK293 cells stimulated with adenylate cyclase activator (forskolin (FSK)). TEPP-46 failed to shift the EC50 of FSK in the presence of IBMX (EC50 FSK. 1.27 pM; EC50 FSK+IBMX, 1.67 pM; not significant). The measurements were performed using a plate reader to image H188 cAMP biosensors introduced into HEK293T cells with adenovirus. These data indicate that pyruvate kinase Attorney Docket No. 047162-7543WO1(02791)

[0234] acting on cAMP by inhibiting phosphodiesterases is a potential mechanism by which pyruvate kinase interacts with NuSH receptor signaling

[0235] FIG. 30 shows an exemplary graph demonstrating that pan-phosphodiesterase inhibition (using pan-phosphodiesterase inhibitor IBMX (250 pM)) blocks the ability' of a PKa (etavopivat (10 pM)) to increase cAMP levels in HEK293 cells stimulated with adenylate cyclase activator (forskolin (FSK)). Etavopivat failed to shift the EC50 of FSK in the presence of IBMX (EC50 FSK, 2.96 pM; EC50 FSK+IBMX, 2.55 pM; not significant). The measurements were performed using a plate reader to image H188 cAMP biosensors introduced into HEK293T cells with adenovirus. These data indicate that pyruvate kinase acting on cAMP by inhibiting phosphodiesterases is a potential mechanism by which pyruvate kinase interacts with NuSH receptor signaling.

[0236] FIG. 31 shows an exemplary graph demonstrating that pan-phosphodiesterase inhibition (using pan-phosphodiesterase inhibitor IBMX (250pM)) blocks the ability of a PKa (mitapivat (10 pM)) to increase cAMP levels in HEK293 cells stimulated with adenylate cyclase activator (forskolin (FSK)). Mitapivat failed to shift the EC50 of FSK in the presence of IBMX (EC50 FSK, 1.49 pM; EC50 FSK+IBMX, 1.26 pM; not significant). The measurements were performed using a plate reader to image H188 cAMP biosensors introduced into HEK293T cells with adenovirus. These data indicate that pyruvate kinase acting on cAMP by inhibiting phosphodiesterases is a potential mechanism by which pyruvate kinase interacts with NuSH receptor signaling.

[0237] FIG. 32 shows an exemplary set of graphs demonstrating that deletion of PKM1 / 2 in mouse P-cells decreases cAMP-dependent protein kinase A activity in response to glucose, and is rescued by administration of a PKa (TEPP-46 (10 pM)). The measurements were performed by imaging cAMP-dependent protein kinase A biosensors (ExRaiAKAR2) within intact mouse islets isolated from PKM1 / 2-PKO mice (PKM-flox: Ucn3-Cre) and littermate controls (PKM-flox).

[0238] FIG. 33 shows an exemplary set of graphs demonstrating that deletion of PKM1 / 2 in mouse P-cells decreases mitochondrial membrane potential response to glucose, which is rescued by administration of a PKa (TEPP-46 (10 pM)). The measurements were performed by imaging mitochondrial membrane potential dye (Rhodamine- 1,2, 3) within intact mouse islets isolated from PKM1 / 2-PKO mice (PKM-flox: Ucn3-Cre) and littermate controls (PKM-flox).

[0239] FIGs.34A, 34B, and 34C show an exemplary set of graphs demonstrating the effect of PKa alone and combination treatment with a PKa and a NuSH receptor modulator Attorney Docket No. 047162-7543WO1(02791)

[0240] (semaglutide) on body composition and activity. FIG. 34A shows the exemplary body composition graphs for mice administered mitapivat, TEPP-46 (shown as PKa), or a vehicle control before semaglutide treatment, thus representing PKa-only treatment. FIG. 34B shows the exemplary body composition and bone mineral density graphs for mice administered mitapivat, TEPP-46 (shown as PKa), or a vehicle control after semaglutide treatment, thus representing PKa and NuSH receptor modulator combination treatment. FIG. 34C shows the exemplary graphs showing the change in body weight over time both pre- and post-semaglutide treatment for the same treatment groups, along with a semaglutide-only treatment group.

[0241] DETAILED DESCRIPTION

[0242] The present disclosure relates in part to the discoveries, as demonstrated herein in Examples 1-5, that small molecule pyruvate kinase activators synergize with GLP-1 RAs or other NuSH receptor modulators to improve glucose tolerance and amplify weight loss whilst preserving or increasing lean muscle mass or function as a monotherapy to similarly promote weight loss while maintaining or increasing lean muscle mass.

[0243] Without wishing to be bound by theory, the inventors identified a metabolism sensing pathway downstream from GLP-1 RA or other NuSH signaling pathways that incorporates a mitochondrial satiety ‘signal’ that is necessary' for and integrated into maintenance of weight and metabolic homeostasis. A key and governing feature of mitochondrial satiety is controlled by the regulatable forms of the enzyme pyruvate kinase that can be therapeutically modulated by small molecule activators (e.g., allosteric activators).

[0244] In one aspect, the present disclosure provides a method of treating obesity and / or treating or preventing Type 2 diabetes mellitus (T2D) or other obesity-related disease, disorder, or condition in a subject in need thereof, the method comprising administering to the subject a pyruvate kinase (PK) activator and a glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1 RA) or other NuSH receptor modulator.

[0245] In another aspect, the present disclosure provides a method of treating obesity and / or treating or preventing Type 2 diabetes mellitus (T2D) and / or obesity or other obesity-related disease, disorder, or condition in a subject in need thereof, the method comprising administering to the subject a pyruvate kinase (PK) activator.

[0246] It is to be understood that the methods and compositions described in this disclosure are not limited to particular methods and experimental conditions disclosed herein as such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. Attorney Docket No. 047162-7543WO1(02791)

[0247] Furthermore, the experiments described herein, unless otherwise indicated, use conventional chemical, molecular and cellular biological, and immunological techniques within the skill of the art. Such techniques are well known to the skilled worker and are explained fully in the literature. See, e.g., Ausubel, et al., ed., Current Protocols in Molecular Biology, John Wiley & Sons, Inc.. NY, N. Y. (1987-2008), including all supplements, Molecular Cloning: A Laboratory Manual (Fourth Edition) by Green and Sambrook, and Harlow et al., Antibodies: A Laboratory Manual, Chapter 14, Cold Spring Harbor Laboratory, Cold Spring Harbor (2013, 2nd edition).

[0248] Definitions

[0249] Unless otherwise defined, scientific and technical terms used herein have the meanings that are commonly understood by those of ordinary skill in the art. In the event of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. The use of “or” means "and / or’ unless stated otherwise. The use of the term “including,” as well as other forms, such as “includes” and “included,” is not limiting. The present disclosure also contemplates other embodiments “comprising,” “consisting of' and “consisting essentially of’ the embodiments or elements presented herein, whether explicitly set forth or not.

[0250] Generally, the nomenclature used herein and the laboratory procedures in pharmaceutical science, organic chemistry, cell and tissue culture, molecular biology, immunology, microbiology, genetics and protein and nucleic acid chemistry and hybridization described herein is well-known and commonly used in the art. The methods and techniques provided herein are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification unless otherwise indicated. Enzymatic reactions and purification techniques are performed according to manufacturer's specifications, as commonly accomplished in the art or as described herein. The nomenclatures used in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well-known and commonly used in the art. Standard techniques are used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients. Attorney Docket No. 047162-7543WO1(02791)

[0251] It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0252] That the disclosure may be more readily understood, select terms are defined below. The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0253] " About" as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±20% or ±10%, more preferably ±5%, even more preferably ±1%, and still more preferably ±0,1% from the specified value, as such variations are appropriate to perform the disclosed methods.

[0254] As used herein, “antibody’’ (Ab) is used in the broadest sense and specifically may include any immunoglobulin, whether natural or partly or wholly synthetically produced, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (for example, bispecific antibodies and polyreactive antibodies), and antibody fragments. Thus, the term “antibody” as used in any context within this specification is meant to include, but not be limited to, any specific binding member, immunoglobulin class and / or isotype (e.g., IgG1, IgG2a, IgG2b, IgG3, IgG4, IgM, IgAl, IgA2, IgD, and IgE) and biologically relevant fragment or specific binding member thereof, including but not limited to Fab, F(ab')2, scFv (single chain or related entity) and (scFv)2. The term “antibody fragments” as used herein may include those antibody fragments obtained using techniques readily know n and available to those of ordinary skill in the art, as reviewed herein. Therefore, in addition to the definition for “antibody” presented supra, the term “antibody” may further encompass any polypeptide or protein comprising a portion of an intact antibody, such as the antigen binding or variable region of the intact antibody. These can be derived from natural sources, or they may be partly or wholly synthetically produced. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv fragments; diabodies, and linear antibodies.

[0255] As used herein, the term "antigen" refers to a molecule to which an antibody can selectively bind. The target antigen may be a protein, carbohydrate, nucleic acid, lipid, hapten, or other naturally occurring or synthetic compound. Preferably, the target antigen is a protein or fragment thereof or a complex of proteins.

[0256] As used herein, the term “binding” refers to the adherence of molecules to one another, such as, but not limited to, enzymes to substrates, antibodies to antigens, DNA strands to their complementary strands. Binding occurs because the shape and chemical nature of parts of the Attorney Docket No. 047162-7543WO1(02791)

[0257] molecule surfaces are complementary. A common metaphor is the "lock-and-key" used to describe how enzymes fit around their substrate.

[0258] As used herein, the term "biological sample" refers to a sample obtained from an individual and used in a diagnostic or monitoring assay. Biological samples encompass, e.g., a clinical sample, cells in culture, cell supernatants, cell lysates, plasma, serum, biological fluid (e.g.. urine), and tissue samples. The source of the biological sample may be solid tissue (e.g., from a fresh, frozen, and / or preserved organ, tissue sample, biopsy, or aspirate), blood or any blood constituents such as serum or plasma, bodily fluids (such as, e.g., urine, lymph, cerebral spinal fluid, amniotic fluid, peritoneal fluid, or interstitial fluid, semen), or cells from any time in gestation or development of the individual. The biological sample may contain compounds that are not naturally intermixed with the tissue in nature, such as preservatives, anticoagulants, buffers, fixatives, nutrients, or antibiotics. In certain embodiments, the biological sample is a blood sample. In certain embodiments, the biological sample is whole blood. In certain embodiments, the biological sample is serum. In certain embodiments, the biological sample is plasma.

[0259] As used herein, the terms "biomarker" or "marker" generally refers to a nucleic acid molecule, clinical indicator, protein, or other analyte that is associated with a disease. In various embodiments, a biomarker is differentially present in a biological sample obtained from a subject having or at risk of developing a disease or disorder (e.g., a disease or disorder related to abnormal ovarian reserve level) relative to a reference. A marker is differentially present if the mean or median level of the biomarker present in the sample is statistically different from the level present in a reference. A reference level may be, for example, the level present in a sample obtained from a healthy control subject or the level obtained from the subject at an earlier timepoint, i.e., prior to treatment. Common tests for statistical significance include, among others, t-test, ANOVA, Kruskal-Wallis, Wilcoxon, Mann-Whitney and odds ratio. Biomarkers, alone or in combination, provide measures of relative likelihood that a subject belongs to a phenotypic status of interest. The differential presence of a marker of the invention in a subject sample can be useful in characterizing the subject as having or at risk of developing a disease, for determining the stage or type of a disease (e.g., acute disease or chronic disease), for determining the prognosis of the subject, for evaluating therapeutic efficacy, or for selecting a treatment regimen.

[0260] In this disclosure, "comprises." "‘comprising,” “containing” and “having” and the like have the meaning ascribed to them in U. S. Patent law and mean “includes,” “including,” and the like; “consisting essentially of’ or “consists essentially” likewise has the meaning ascribed Attorney Docket No. 047162-7543WO1(02791)

[0261] in U. S. Patent law and the term is open-ended, allowing for the presence of more than that which is recited so long as basic or novel characteristics of that which is recited is not changed by the presence of more than that which is recited, but excludes prior art embodiments.

[0262] As used herein, the term “disease” refers to a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal’s health continues to deteriorate. A “disease subtype” is a state of health of an animal wherein animals with the disease manifest different clinical features or symptoms.

[0263] A “disorder” as used herein, is used interchangeably with “condition,” and refers to a state of health in an animal, wherein the animal is able to maintain homeostasis, but in which the animal’s state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal’s state of health.

[0264] “Dynamic range” as used herein refers to range over which an assay readout is proportional to the amount of target molecule or analyte in the sample being analyzed. The dynamic range can be the range of linearity of the standard curve.

[0265] As used herein, the term “effective amount” refers to the amount required to reduce or improve at least one symptom of a condition, disease, or disorder relative to an untreated patient or to practice the methods of the invention with a successful or enhanced outcome. The effective amount of active compound(s) used to practice the present invention varies depending upon the manner of administration, the age, body w eight, and general health of the subject as w ell as requirements of the methods of the invention.

[0266] The term “elevated” as used herein when applied to a gene, protein or chemical reaction means that the expression, activity or concentration of the gene, protein or reaction is higher compared to an appropriate control.

[0267] The phrase “inhibit,” as used herein, means to reduce a molecule, a reaction, an interaction, a gene, an mRNA, and / or a protein’s expression, stability, function or activity by a measurable amount or to prevent entirely. Inhibitors are compounds that, e.g.. bind to, partially or totally block stimulation, decrease, prevent, delay activation, inactivate, desensitize, or down regulate a protein, a gene, and an mRNA stability, expression, function and activity, e.g., antagonists.

[0268] As used herein, the term “endogenous” refers to any material from or produced inside an organism, cell, tissue or system. Attorney Docket No. 047162-7543WO1(02791)

[0269] As used herein the term "immobilized" refers to bound directly or indirectly to a surface of, e.g., a device, including attachment by covalent binding or noncovalent binding (e.g., hydrogen bonding, ionic interactions, van der Waals forces, or hydrophobic interactions).

[0270] As used herein “instructional material'’ includes a publication, a recording, a diagram, or any other medium of expression that can be used to communicate the usefulness of the device in a kit. The instructional material of the kit may, for example, be affixed to a container that contains the device of the invention or be shipped together with a container that contains the device. Alternatively, the instructional material may be shipped separately from the container with the intention that the recipient uses the instructional material and the device cooperatively. Delivery of the instructional material may be, for example, by physical delivery of the publication or other medium of expression communicating the usefulness of the kit, or may alternatively be achieved by electronic transmission, for example by means of a computer, such as by electronic mail, or download from a website.

[0271] “Label” and “detectable label” as used herein refer to a moiety attached to an antibody or an analyte to render the reaction between the antibody and the analyte detectable, and the antibody or analyte so labeled is referred to as “detectably labeled.” A label can produce a signal that is detectable by visual or instrumental means. Various labels include signalproducing substances, such as chromagens, fluorescent compounds, chemiluminescent compounds, radioactive compounds, and the like. Representative examples of labels include moieties that produce light, e.g., acridinium compounds, and moieties that produce fluorescence, e.g., fluorescein. Other labels are described herein. In this regard, the moiety, itself, may not be detectable but may become detectable upon reaction with yet another moiety. Use of the term “detectably labeled” is intended to encompass such labeling. Any suitable detectable label as is known in the art can be used. For example, the detectable label can be a radioactive label (such as3H,14C,32P,33P,33S,90Y, " Tc,mIn,125I,131I,177Lu,166Ho, and153Sm), a stable isotope label (such as2H,13C,15N,18O), an enzymatic label (such as horseradish peroxidase, alkaline peroxidase, glucose 6-phosphate dehydrogenase, and the like), a chemiluminescent label (such as acridinium esters, thioesters, or sulfonamides; luminol, isoluminol, phenanthridinium esters, and the like), a fluorescent label (such as fluorescein ( e.g., 5-fluorescein, 6-carboxy-fluorescein, 3’6-carboxy-fluorescein, 5(6)-carboxy-fluorescein, 6-hexachloro-fluorescein, 6-tetrachloro-fluorescein, fluorescein isothiocyanate, and the like)), rhodamine, phycobiliproteins, R-phycoerythrin, quantum dots (e.g., zinc sulfide-capped cadmium selenide), a thermometric label, or an immuno-polymerase chain reaction label. An introduction to labels, labeling procedures and detection of labels is found in Polak and Van Attorney Docket No. 047162-7543WO1(02791)

[0272] Noorden. Introduction to Immunocytochemistry, 2nd ed., Springer Verlag, N. Y. (1997), and in Haugland, Handbook of Fluorescent Probes and Research Chemicals (1996), which is a combined handbook and catalogue published by Molecular Probes, Inc., Eugene, Oregon.

[0273] As used herein the term “level” is intended to refer to amount of a unit of a compound being measured, for example a protein. It is also intended to encompass “concentration” expressed as amount per volume or weight per volume and any other depiction of concentration as known in the art.

[0274] “Linking sequence” or “linking peptide sequence” refers to a natural or artificial polypeptide sequence that is connected to one or more polypeptide sequences of interest (e.g., full-length, fragments, etc.). The term “connected” refers to the joining of the linking sequence to the polypeptide sequence of interest. Such polypeptide sequences are preferably joined by one or more peptide bonds. Linking sequences can have a length of from about 4 to about 50 amino acids. Preferably, the length of the linking sequence is from about 6 to about 30 amino acids. Natural linking sequences can be modified by amino acid substitutions, additions, or deletions to create artificial linking sequences. Linking sequences can be used for many purposes, including in recombinant Fabs. Exemplarylinking sequences include, but are not limited to: (i) Histidine (His) tags, such as a 6X His tag (aka His tag), are useful as linking sequences to facilitate the isolation and purification of polypeptides and antibodies of interest; (ii) Enterokinase cleavage sites, like 6X His tags, are used in the isolation and purification of proteins and antibodies of interest. Often, enterokinase cleavage sites are used together with 6X His tags in the isolation and purification of proteins and antibodies of interest. Various enterokinase cleavage sites are known in the art. (iii) Miscellaneous sequences can be used to link or connect the light and / or heavy chain variable regions of single chain variable region fragments. Examples of other linking sequences can be found in Bird et al., Science 242:423-426 (1988); Huston et al., PNAS USA 85: 5879-5883 (1988); and McCafferty et al., Nature 348: 552-554 (1990). Linking sequences also can be modified for additional functions, such as attachment of detectable labels or drugs or attachment to solid supports. In the context of the present disclosure, the monoclonal antibody, for example, can contain a linking sequence, such as a His tag, an enterokinase cleavage site, or both.

[0275] As used herein, the term "pharmaceutical composition" or "composition" refers to a mixture of at least one compound useful within the invention with a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a subject. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, intradermal, transdermal, oral, aerosol, parenteral, ophthalmic, Attorney Docket No. 047162-7543WO1(02791)

[0276] pulmonary and topical administration. As such, a pharmaceutical composition can be formulated for any one or more of such routes of administration. In certain embodiments, the pharmaceutical composition is a topical formulation. In certain embodiments, the pharmaceutical composition is formulated for intradermal administration. In certain embodiments, the pharmaceutical composition is formulated for transdermal administration.

[0277] As used herein, the term "pharmaceutically acceptable" refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound useful within the invention, and is relatively non-toxic, i.e., the material may be administered to a subject without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0278] As used herein, the term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the invention within or to the subject such that it may perform its intended function. Typically, such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the invention, and not injurious to the subject. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as com starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin: talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. As used herein, "pharmaceutically acceptable carrier" also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound useful within the invention, and are physiologically acceptable to the subject. Supplementary active compounds may also be incorporated into the compositions. The "pharmaceutically acceptable carrier" may further include a pharmaceutically acceptable Attorney Docket No. 047162-7543WO1(02791)

[0279] salt of the compound useful within the invention. Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of the invention are known in the art and described, for example in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0280] As used herein, the language "pharmaceutically acceptable salt" refers to a salt of the administered compound prepared from pharmaceutically acceptable non-toxic acids and bases, including inorganic acids, inorganic bases, organic acids, inorganic bases, solvates, hydrates, and clathrates thereof.

[0281] As used herein, the terms ‘‘prevent,"’ “preventing,” “prevention,” and the like refer to reducing the probability of developing a disease or condition in a subject, who does not have, but is at risk of or susceptible to developing a disease, disorder, or condition.

[0282] As used herein the terms “purified” or “biologically pure” refer to material that is free to varying degrees from components which normally accompany it as found in its native state. “Purify” denotes a degree of separation that is higher than isolation. A “purified" or “biologically pure” protein is sufficiently free of other materials such that any impurities do not materially affect the biological properties of the protein or cause other adverse consequences. That is, a nucleic acid or peptide of this invention is purified if it is substantially free of cellular material, viral material, or culture medium when produced by recombinant DNA techniques, or chemical precursors or other chemicals when chemically synthesized. Purity and homogeneity are typically determined using analytical chemistry techniques, for example, polyacrylamide gel electrophoresis or high-performance liquid chromatography. The term “purified” can denote that a nucleic acid or protein gives rise to essentially one band in an electrophoretic gel. For a protein that can be subjected to modifications, for example, phosphorylation or glycosylation, different modifications may give rise to different isolated proteins, which can be separately purified.

[0283] “Quality control reagents” in the context of immunoassays and kits described herein, include, but are not limited to, calibrators, controls, and sensitivity panels. A “calibrator’ or “standard” typically is used (e.g., one or more, such as a plurality) in order to establish calibration (standard) curves for interpolation of the concentration of an analyte, such as an antibody or an analyte. Alternatively, a single calibrator, which is near a predetermined positive / negative cutoff, reference level or control level (e.g., “low,” “medium,"’ or “high” levels), can be used. Multiple calibrators (i.e., more than one calibrator or a varying amount of calibrators )) can be used in conjunction to comprise a "‘sensitivity panel.” Attorney Docket No. 047162-7543WO1(02791)

[0284] As used herein the term "‘reference” is meant a standard or control value often used as a basis for comparison. The terms “reference” and “control” are used interchangeably herein. A “reference” or “control” means a value or level measured in a sample obtained from a suitable subject (a “reference subject”). A “reference” or “control” also means a value or level that is a composite of values or levels obtained from a group of reference subjects as described herein, or as generated by an algorithm using multiple measured values or levels.

[0285] A “reference level” as used herein refers to an assay cutoff value that is used to assess diagnostic, prognostic, or therapeutic efficacy and that has been linked or is associated herein with various clinical parameters (e.g, presence of disease, stage of disease, severity of disease, progression, non-progression. or improvement of disease, etc.) This disclosure provides exemplary reference levels. However, it is well-known that reference levels may vary depending on the nature of the immunoassay (e.g., antibodies employed, reaction conditions, sample purity, etc.) and that assays can be compared and standardized. It further is well within the ordinary skill of one in the art to adapt the disclosure herein for other immunoassays to obtain immunoassay-specific reference levels for those other immunoassays based on the description provided by this disclosure. Whereas the precise value of the reference level may vary between assays, the findings as described herein should be generally applicable and capable of being extrapolated to other assays.

[0286] " Risk assessment," "risk classification," "risk identification," or "risk stratification" of subjects (e.g., patients) as used herein refers to the evaluation of factors including biomarkers, to predict the risk of occurrence of future events including disease onset or disease progression, so that treatment decisions regarding the subject may be made on a more informed basis.

[0287] " Sample," "test sample," "specimen," "sample from a subject," and "patient sample" as used herein may be used interchangeable and may be a sample of blood such as whole blood, tissue, urine, serum, plasma, amniotic fluid, cerebrospinal fluid, placental cells or tissue, endothelial cells, leukocytes, or monocytes. The sample can be used directly as obtained from a patient or can be pre-treated, such as by filtration, distillation, extraction, concentration, centrifugation, inactivation of interfering components, addition of reagents, and the like, to modify the character of the sample in some manner as discussed herein or otherwise as is known in the art. As used herein the term “blood sample” refers to whole blood or blood that has been pre-treated and / or processed to obtain serum or plasma.

[0288] " Sensitivity" of an assay as used herein refers to the proportion of subjects for whom the outcome is positive that are correctly identified as positive. Attorney Docket No. 047162-7543WO1(02791)

[0289] " Specificity" of an assay as used herein refers to the proportion of subjects for whom the outcome is negative that are correctly identified as negative.

[0290] As used herein the term ’‘signal” refers to light intensity (e.g., light generated by fluorescence, bioluminescence, or phosphorescence), ionizing radiation, particle emission, magnetism, staining, or a product of a reaction involving an enzyme. Diffraction, absorbance, polarization, reflection, deflection, increases, decreases, or amplification of a signal may be indicative of an event (e.g., binding of a biomarker or biomarker complex to an antibody immobilized on the surface of a diffraction-based device).

[0291] As used herein the term "single molecule detection" refers to the detection and / or measurement of a single molecule of an analyte in a test sample at very low levels of concentration (such as pg / mL or femtogram / mL levels). A number of different single molecule analyzers or devices are known in the art and include nanopore and nanowell devices. Examples of nanopore devices are described in International Patent Publication No. WO 2016 / 161402, which is hereby incorporated by reference in its entirety. Examples of nanowell device are described in International Patent Publication No. WO 2016 / 161400, which is hereby incorporated by reference in its entirety.

[0292] As used herein the term “specifically binds” refers to an antibody or fragment thereof that recognizes and binds an antigen, but that does not substantially recognize or bind to other molecules in a biological sample. Specific recognition of an antigen by an antibody may be assayed by using, e.g., light diffraction devices with an immobilized capture surface or using standard techniques known to one of skill in the art, such as immunoprecipitation, Western blotting, and ELISA.

[0293] " Solid phase" or "solid support" as used interchangeably herein, refers to any material that can be used to attach and / or attract and immobilize (1) one or more capture agents or capture specific binding partners, or (2) one or more detection agents or detection specific binding partners. The solid phase can be chosen for its intrinsic ability to attract and immobilize a capture agent. Alternatively, the solid phase can have affixed thereto a linking agent that has the ability to attract and immobilize the (1) capture agent or capture specific binding partner, or (2) detection agent or detection specific binding partner. For example, the linking agent can include a charged substance that is oppositely charged with respect to the capture agent (e.g., capture specific binding partner) or detection agent (e.g., detection specific binding partner) itself or to a charged substance conjugated to the (1) capture agent or capture specific binding partner or (2) detection agent or detection specific binding partner. In general, the linking agent can be any binding partner (preferably specific) that is immobilized on (attached to) the solid Attorney Docket No. 047162-7543WO1(02791)

[0294] phase and that has the ability to immobilize the (1) capture agent or capture specific binding partner, or (2) detection agent or detection specific binding partner through a binding reaction. The linking agent enables the indirect binding of the capture agent to a solid phase material before the performance of the assay or during the performance of the assay. For examples, the solid phase can be plastic, derivatized plastic, magnetic, or non-magnetic metal, glass or silicon, including, for example, a test tube, microtiter well, sheet, bead, microparticle, chip, and other configurations known to those of ordinary skill in the art.

[0295] As used herein the terms “subject,” “individual,” “patient,” and the like are used interchangeably herein, and refer to any vertebrate, including, but not limited to, a mammal (e.g., a human, cow. pig, camel, llama, horse, goat, rabbit, sheep, hamsters, guinea pig, cat, dog, rat, mouse, a non-human primate (for example, a monkey, such as a cynomolgous or rhesus monkey, chimpanzee, etc.)) or cells thereof, whether in vitro or in situ, amenable to the methods described herein. In some embodiments, the term “subject” refers to a mammal, including a human or non-human mammal. The term “subject” may refer to a human or other animal which is the object of treatment, observation, or experiment (e.g., a patient).

[0296] As used herein the terms “therapeutic” and “therapy” refers to a treatment and / or prophylaxis. A therapeutic effect is obtained by suppression, remission, or eradication of a disease state.

[0297] As used herein, the terms “treat,” “treating,” “treatment.” and the like refer to reducing or improving a disease or condition and / or symptom associated therewith. It will be appreciated that, although not precluded, treating a disease or condition does not require that the disease, condition or symptoms associated therewith be completely ameliorated or eliminated. The term also refers to reducing the severity of a disease or condition or symptoms associated with such disease or condition prior to affliction with the disease or condition. Such prevention or reduction of the severity of a disease or condition prior to affliction refers to administration of a pharmaceutical composition to a subject that is not at the time of administration afflicted with the disease. “Preventing” and “prevent” also refer to preventing the recurrence of a disease or condition or of one or more symptoms associated with such disease or condition.

[0298] Ranges provided herein are understood to be shorthand for all of the values within the range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting 1, 2. 3, 4, 5. 6, 7, 8, 9, 10. 11. 12. 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50. Attorney Docket No. 047162-7543WO1(02791)

[0299] The recitation of an embodiment for a variable or aspect herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.

[0300] Methods

[0301] Pyruvate kinase (PK) is the enzyme involved in the last step of glycolysis. It catalyzes the transfer of a phosphate group from phosphoenolpyruvate (PEP) to adenosine diphosphate (ADP), yielding one molecule of pyruvate and one molecule of ATP. Four isozy mes of pyruvate kinase are expressed in vertebrates: L (liver), R (erythrocytes), Ml (muscle and brain) and M2 (early fetal tissue and most adult tissues). The L and R isozymes are expressed by the PKLR gene, whereas the Ml and M2 isozymes are expressed by the PKM gene. The PKM gene consists of 12 exons and 11 introns (PKM1 contains exon 9 whereas PKM2 contains exon 10). PK is a tetrameric enzyme composed of four monomers that form a dimer of dimers in the final tetrameric structure that may also be post translationally modified. In general, the Ml isoform is not considered to be activatable. In humans, the M2, L, and R isozymes are activated by fructose- 1,6-bis phosphate (FBP) and other endogenous and exogenous small molecules that bind to a flexible loop region at the interface of the two dimers. Activation of PK shifts the enzyme to a state showing high affinity for PEP, whereas dimers have a lower affinity for PEP. Phosphorylation of some sites of the highly active tetramers of PKM2 results in dimers with lower enzymatic activity. Additionally, various phosphotyrosine peptides can bind to PKM2 near the activation loop that results in the removal of FBP from the enzyme which effectively down-regulates PKM2 activity. When PKM2 is activated in cells, it reduces restrictions or rate limitations by PKM2 in the conversion of glucose to pyruvate through the glycolytic pathway. In some instances, PK tetramers form from heterogenous combinations of Ml and M2 (e.g., 4M2, 1M1:3M2, 2M1:2M2, 3M1:1M2, 4M1).

[0302] The methods of the present invention comprise administering a pyruvate kinase activator. As used herein, “pyruvate kinase activator’'. “PK activator'’, and “PKa’" are used interchangeably and refer to any compound that increases the enzymatic activity’ of PK, such as but not limited to allosteric activators. In certain embodiments, the PK activator activates the PKM2 isoform including but not limited to lowering the Km, increasing the Vmax of the enzyme, changing the concentration of the enzyme or enzyme isoform, favoring the tetrameric state, and / or altering the subcellularylocation. Small molecule PK activators are known in the art and include, by way of non-limiting example, the compounds disclosed in W02010042867A2, US8,841,305B2, US8,937,067B2, US9,290,512B2, US9,707,230B2, Attorney Docket No. 047162-7543WO1(02791)

[0303] W02009025781A1, WO2010118063 A2, WO2011002816A1, and W02013056153AL each of which applications and / or patents is incorporated by reference in its entirety herein. Small molecule PK activators also include, e.g., SYX-5219, Pyrukynd (mitapivat, AG-348), etavopivat (NN7537, FT-4202), AG-946, and BT-119. As used herein, the term “PK activator” further includes indirect activators of PK (e.g., certain posttranslational modifications of PK that promote or enforce an activated state).

[0304] It is further contemplated herein that, in certain embodiments, the methods of the present invention comprise administering a therapy that reduces the PK Ml isoform, thereby increasing the absolute or relative PK M2 isoform in the subject. Methods of knocking down a gene of interest (e.g., PK Ml) are well known in the art and include, e.g.. RNA interference methods comprising siRNA and / or shRNA. Likewise, in some embodiments, augmenting regulatable PK M2 activity is achieved by ectopic over expression of the PKL or PKR isoforms. It is further contemplated herein that, in some embodiments, the methods of the present invention comprise administering a therapy that modifies the function or activity of monomeric or dimeric PK M2, thereby increasing PK activity.

[0305] As used herein, “glucagon-like peptide-1 receptor agonist”, “GLP-1 receptor agonist”, “GLP-1 RA”, “GLP-1 agonist”, “incretin mimetic”, or “GLP-1 analog” are used interchangeably and refer to any synthetic peptide or peptide analog of glucagon-like peptide-1 (GLP-1) and / or both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) and / or glucagon and / or any other NuSH receptor. GLP-1 RAs are known in the art and include, by way of non-limiting example, the following FDA-approved GLP-1 RAs: Semaglutide (e.g., Ozempic, Wegovy, Rybelsus - an oral semaglutide), Tirzepatide (e.g., Mounjaro, Zepbound), Exenatide (e.g., Byetta, Bydureon). Liraglutide (e.g., Victoza, Saxenda). Dulaglutide (e.g., Trulicity), hxisenatide (e.g., Lyxumia, Adlyxin), retatrutide, and albiglutide (e.g., Eperzan, Tanzeum).

[0306] The term “nutrient stimulated hormone” (NuSH) receptor modulators includes all known GLP-1 RAs as well as natural or synthetic modulators (e.g., NuSH analogs) of other receptors that are modulated by nutrient stimulated hormones (e.g., modulators of the receptors for any of the following NuSHs: glucose-dependent insulinotropic polypeptide (GIP), glucagon (GCG), oxyntomodulin or other proopiomelanocortin (POMC) product (i.e., a-MSH, 0-MSH, y-MSH, and ACTH), leptin, peptide YY (PYY). amylin, calcitonin, pancreatic polypeptide (PP), ghrelin, and others) that often signal fully or partially through G-protein-coupled receptors (GPCRs), as well as activators of other processes downstream of the GLP-1 Receptor (or other G-protein coupled receptors) (e.g., activation of adenylate cyclase). Attorney Docket No. 047162-7543WO1(02791)

[0307] In one aspect, the present disclosure provides a method of treating obesity and / or treating or preventing or ameliorating Type 2 diabetes mellitus (T2D) or other obesity-related disease, disorder, or condition and / or treating, preventing, or ameliorating an obesity-related disease, disorder, or condition and / or treating, preventing, or ameliorating a disease, disorder, or condition in a subject in need thereof, the method comprising administering to the subject a pyruvate kinase (PK) activator (PKa) and a glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1 RA) or other nutrient stimulated hormone (NuSH) receptor modulator. In some embodiments, the PKa and the GLP-1 RA or other NuSH receptor modulator are administered concurrently. In some embodiments, the PKa is administered prior to administration of the GLP- 1 RA or other NuSH receptor modulator. In some embodiments, the PKa is administered after administration of the GLP-1 RA or other NuSH receptor modulator. In some embodiments, the subject had previously been administered at least one GLP-1 RA or other NuSH receptor modulator, and the GLP-1 RA or other NuSH receptor modulator was ineffective or insufficient for treating the obesity and / or treating or preventing the T2D or other obesity-related disease, disorder, or condition in the subject and / or treating, preventing, or ameliorating the obesity-related disease, disorder, or condition in the subject. In some embodiments, the method comprises administering to the subject a PKa, wherein the subject has been previously administered a NuSH receptor modulator. In some embodiments, the method comprises administering to the subject a NuSH receptor modulator, wherein the subject has been previously administered a PKa.

[0308] In some embodiments, the other obesity-related disease, disorder, or condition is a metabolic disease, disorder, or condition (e.g., CVD [primary or secondary prevention], HFpEF, CKD, CKM syndrome, hypertension, hyperlipidemia, MAFLD / MASH, PCOS, infertility, cancer, etc.) or a functional disease, disorder, or condition (e.g., OA, OSA, back pain, incontinence, etc.)

[0309] In some embodiments, the PK comprises a PKM2 isoform (e.g., a PMK2 tetramer). In some embodiments, the PK comprises a PKM1 isoform. In some embodiments, the PK comprises a PKL isoform. In some embodiments, the PK comprises a PKR isoform.

[0310] In some embodiments, the PKa is an activator of a PKM1 isoform. In some embodiments, the PKa is an activator of a PKM2 isoform. In some embodiments, the PKa is an activator of a PKL isoform. In some embodiments, the PKa is an activator of a PKR isoform. Attorney Docket No. 047162-7543WO1(02791)

[0311] In some embodiments, the PK comprises at least one PKM2 isoform monomer (e.g., a PK heterodimer comprising one PKM2 monomer or a PK heterotetramer comprising at least one PKM2 monomer)

[0312] In some embodiments, the PK is a heterogenous tetramer with an allosteric or post-translationally activatable monomeric subunit.

[0313] In some embodiments, the PK activator is a small molecule activator of PK.

[0314] In some embodiments, the PK activator is an allosteric activator of PK.

[0315] In some embodiments, the PK activator selectively activates PKM2 or some combination of activatable PK multimer comprising at least one PKM2 monomer.

[0316] In some embodiments, the PK activator is characterized by central nervous system (CNS) penetrance.

[0317] In some embodiments, the PK activator amplifies weight loss in the subject:

[0318] (a) compared to weight loss level achieved by control subj ects who had been treated with at least one GLP-1 RA or other NuSH receptor modulator but no PK activator; and / or

[0319] (b) if the subject had previously been administered at least one GLP-1 RA or other NuSH receptor modulator but no PK activator, compared to weight loss level previously achieved by the subject.

[0320] In some embodiments, the PK activator improves glucose tolerance, or effects other metabolic improvements, in the subject:

[0321] (a) compared to glucose tolerance level, or other metabolic improvement, achieved by control subjects who had been treated with at least one GLP-1 RA or other NuSH receptor modulator but no PK activator; and / or

[0322] (b) if the subject had previously been administered at least one GLP-1 RA or other NuSH receptor modulator but no PK activator, compared to glucose tolerance level, or other metabolic improvement, previously achieved by the subject. In some embodiments, the method sustains muscle mass in the subject and / or reduces excess muscle loss in the subject compared to methods that do not comprise administration of a PK activator (e.g., methods comprising administration of only a GLP-1 RA or other NuSH receptor modulator). In some embodiments, the method does not result in a loss of muscle mass. In some embodiments, the method increases a lean-to-fat mass ratio of the subject.

[0323] In some embodiments, the method allows for a lower dose of the GLP-1 RA or other NuSH receptor agonist to be administered compared to methods that do not comprise administration of a PK activator (e.g., methods comprising administration of only a GLP-1 RA Attorney Docket No. 047162-7543WO1(02791)

[0324] or other NuSH receptor modulator), thereby reducing side effects from and / or amount of the GLP- 1 RA or NuSH receptor agonist.

[0325] In some embodiments, the PK activator is any small molecule PK activator known in the art, or a salt, solvate, stereoisomer, isotopologue, or tautomer thereof.

[0326] In some embodiments, the NuSH receptor modulator is a human NuSH receptor agonist. In some embodiments, the NuSH receptor modulator is a GLP- 1 receptor mono agonist (GLP-1 RA), a GIP receptor mono agonist (GIP RA), or a GCG receptor mono agonist (GCG RA). In some embodiments, the NuSH receptor modulator is a dual agonist for GLP-1 receptor and GIP receptor, GLP-1 receptor and GCG receptor, or GIP receptor and GCG receptor. In some embodiments, the NuSH receptor modulator is a triple agonist for GLP-1 receptor, GIP receptor, and GCG receptor. In some embodiments, the NuSH receptor modulator comprises one or more of a GLP-1 receptor mono agonist (GLP-1 RA), a GIP receptor mono agonist (GIP RA), a GCG receptor mono agonist (GCG RA), a dual agonist for GLP-1 receptor and GIP receptor, a dual agonist GLP-1 receptor and GCG receptor, or a dual agonist GIP receptor and GCG receptor, or a triple agonist for GLP-1 receptor, GIP receptor, and GCG receptor.

[0327] In some embodiments, the GLP-1 receptor mono agonist is selected from the group consisting of semaglutide (e.g., Ozempic, Wegovy, Rybelsus - an oral semaglutide), exenatide (e.g., Byetta, Bydureon), liraglutide (e.g., Victoza, Saxenda), dulaglutide (e.g., Trulicity), lixisenatide (e.g.. Lyxumia, Adlyxin), Orforglipron, and albiglutide (e.g.. Eperzan. Tanzeum).

[0328] In some embodiments, the GIP receptor mono agonist includes, but is not limited to, PF-07976016 (Pfizer).

[0329] In some embodiments, the GCG receptor mono agonist includes, but is not limited to, GCG analog HM15136.

[0330] In some embodiments, the GLP-1 and GIP dual receptor agonist includes, but is not limited to, tirzepatide (e.g., Mounjaro, Zepbound).

[0331] In some embodiments, the GLP-1 and GCG dual receptor agonist includes, but is not limited to, Cotadutide (MEDI0382), Efmopegdutide (MK-6024 / JNJ-64565111), Mazsutide (IBI-362), and Pemyidutide (ALT-801).

[0332] In some embodiments, the GLP-1, GIP, and GCG triple receptor agonist includes, but is not limited to, Retatrutide (LY3437943), Maridebart Cafraglutide (Amgen), and HM15211.

[0333] In some embodiments, the NuSH receptor modulator comprises an agonist of amylin or peptide YY. In some embodiments, the agonist of amylin or peptide YY includes, but is not limited to, pramlintide, Cagrilintide, and amycretin. Attorney Docket No. 047162-7543WO1(02791)

[0334] In some embodiments, the PKa is TEPP-46. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is tirzepatide.

[0335] In some embodiments, the PKa is a compound represented by the following structural formula Formula A:

[0336]

[0337] (Formula A)

[0338] or a pharmaceutically acceptable salt thereof, wherein:

[0339] U1, U2, and U3 are each independently N, O, S, C, or CR1, as valency permits;

[0340] U4, U6, and U7are each independently N or C, as valency permits;

[0341] U5is N, NR3, or CR4, as valency permits;

[0342] m is 1 or 2;

[0343]

[0344] Ring A is phenyl,

[0345] U8 is N or CR1;

[0346] each instance of R1is independently hydrogen or C1─C6alkyl;

[0347] L1is ─S─, ─S─CH2─, ─CH2─S─, ─S(=O)2─, ─S(=O)─, ─S(=O)2O─, ─OS(=O)2─, ─S(=O)O─, ─OS(=O)─, ─S(=O)CH2─, ─CH2S(=O)─, ─S(=O)2CH2─, ─CH2S(=O)2─, ─S(=O)2NR5─, ─NR5S(=O)2─, ─S(=O)NR5─, ─NR5S(=O)─, ─NR5S(=O)2O─, ─OS(=O)2NR5─, ─NR5S(=O)O─, ─OS(=O)NR5─, ─S(=O)(=NR5)─, ─C(=O)─, Attorney Docket No. 047162-7543WO1(02791)

[0348] —C(=O)O—, —OC(=O)—, —C(=O)NR5—, —N(R5)C(=O)—, —NR5C(=O)O—, —OC(=O)NR5—, —NR5C(=O)NR5—, —NR5—, —C(=S)NR5—, —N(R5)C(=S)—, or —(CRjRk)q—;

[0349] R2 is C1—C6 alkyl, C3—C12 cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 14-membered aryl, or 5- to 14-membered heteroaryl, wherein the alkyl is optionally substituted with 0 to 3 groups each independently selected from halogen, OH, CN, and NR5R5, and wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted at each substitutable ring carbon atom with Rp and optionally substituted at each substitutable ring nitrogen atom by Rnc; or

[0350] —L1—R2 is —H, —CN, —CH3, —OH, Br, C1—C6 haloalkyl, C2—C6 alkenyl, C1—C6 alkyl, C3—C12 cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 14-membered aryl, or 5- to 14-membered heteroaryl; wherein each alkyl and alkenyl is optionally substituted with 0 to 3 groups each independently selected from halogen, OH, CN, and NR5R5, and wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted at each substitutable ring carbon atom with Rp and optionally substituted at each substitutable ring nitrogen atom by Rnc;

[0351] each instance of Rp is independently hydrogen, halogen, —CN, —NO2, —N3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -ORc3, -SRc3, -N(Rc3)2, -C(=O)N(Rc3)2, -N(Rc3)C(=O)Rc3, -C(=O)Rc3, -C(=O)ORc3, -OC(=O)Rc3, -S(=O)Rc3, -S(=O)2Rc3, -S(=O)ORc3, -OS(=O)Rc3, -S(=O)2ORc3, -OS(=O)2Rc3,

[0352] —S(=O)N(Rc3)2, —S(=O)2N(Rc3)2, —N(Rc3)S(=O)Rc3, —N(Rc3)S(=O)2Rc3, —N(Rc3)C(=O)ORc3, ─OC(=O)N(Rc3)2, ─N(Rc3)C(=O)N(Rc3)2, ─N(Rc3)S(=O)N(Rc3)2, ─N(Rc3)S(=O)2N(Rc3)2, ─N(Rc3)S(=O)ORc3, ─N(Rc3)S(=O)2ORc3, ─OS(=O)N(Rc3)2, ─OS(=O)2N(Rc3)2; or alternatively

[0353] two instances of Rpattached to the adjacent ring carbon atoms, can be taken together with the carbon atoms to which they are attached to form 3- to 8-membered cycloalkyl, 5- to 6-membered saturated or partially saturated monocyclic heterocyclyl, or 5- to 6-membered monocyclic heteroaryl; wherein:

[0354] each instance of Rc3 is independently hydrogen or C₁─C₆ alkyl;

[0355] L2 is —S—, —S—CH2—, —CH2—S—, —S(=O)2—, —S(=O)—, —S(=O)2O—, —OS(=O)2—, —S(=O)O—, —OS(=O)—, —S(=O)CH2—, —CH2S(=O)—, —S(=O)2CH2—, —CH2S(=O)2—, —S(=O)2NR5—, —NR5S(=O)2—, —S(=O)NR5—, —NR5S(=O)—, —NR5S(=O)2O—, —OS(=O)2NR5—, —NR5S(=O)O—, —OS(=O)NR5—, —S(=O)(=NR5)—, —C(=O)—, —C(=O)O—, —OC(=O)—, —C(=O)NR5—, —N(R5)C(=O)—, —NR5C(=O)O—, —OC(=O)NR5—, —NR5C(=O)NR5—, —NR5—, —C(=S)NR5—, —N(R5)C(=S)—, or —(CRaRb)r—; Attorney Docket No. 047162-7543WO1(02791)

[0356] each instance of Ra and Rb are independently hydrogen, halogen, CN, OH, NO2, N3, or C1—C6 alkyl; wherein the C1—C6 alkyl represented by Ra or Rb are each optionally substituted with 0 to 3 groups each independently selected from halogen, OH, CN, and NR5R5;

[0357] each instance of Rj and Rk are independently hydrogen, halogen, CN, OH, NO2, N3, or C1—C6 alkyl; wherein the C1—C6 alkyl represented by Ra or Rb are each optionally substituted with 0 to 3 groups each independently selected from halogen, OH, CN, and NR5R5;

[0358] q is 1 or 2;

[0359] r is 1 or 2;

[0360] Q is C3—C12 cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 14-membered aryl, or 5-to 14-membered heteroaryl, each of which is optionally substituted at each substitutable ring carbon atom with Rn and optionally substituted at each substitutable ring nitrogen atom by Rna; or

[0361] —L2—Q is —H, —CN, —CH3, —OH, Br, C1—C6 haloalkyl, C2—C6 alkenyl, C1—C6 alkyl, C3—C12 cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 14-membered aryl, or 5- to 14-membered heteroaryl; wherein each alkyl and alkenyl is optionally substituted with 0 to 3 groups each independently selected from halogen, OH, CN, and NR5R5, and wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted at each substitutable ring carbon atom with Rn and optionally substituted at each substitutable ring nitrogen atom by Rna;

[0362] each instance of Rn is independently hydrogen, halogen, —CN, —NO2, —N3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -ORc4, -SRc4, -N(Rc4)2, -C(=O)N(Rc4)2, -N(Rc4)C(=O)Rc4, —C(=O)Rc4, -C(=O)ORc4, -OC(=O)Rc4, -S(=O)Rc4, -S(=O)2Rc4, -S(=O)ORc4, -OS(=O)Rc4, -S(=O)2ORc4, -OS(=O)2Rc4, -S(=O)N(Rc4)2, -S(=O)2N(Rc4)2, -N(Rc4)S(=O)Rc4, —N(Rc4)S(=O)2Rc4, -N(Rc4)C(=O)ORc4, -OC(=O)N(Rc4)2, -N(Rc4)C(=O)N(Rc4)2, -N(Rc4)S(=O)N(Rc4)2, -N(Rc4)S(=O)2N(Rc4)2, -N(Rc4)S(=O)ORc4, -N(Rc4)S(=O)2ORc4, -OS(=O)N(Rc4)2, or -OS(=O)2N(Rc4)2; or alternatively two instances of Rn attached to the adjacent ring carbon atoms, can be taken together with the carbon atoms to which they are attached to form an optionally substituted 3— to 8—membered cycloalkyl, 5— to 6—membered saturated or partially saturated monocyclic heterocyclyl, or 5- to 6—membered monocyclic heteroaryl; wherein:

[0363] each instance of Rc4 is independently hydrogen or C1—C6 alkyl; Attorney Docket No. 047162-7543WO1(02791)

[0364] R3is hydrogen or C1─C6alkyl;

[0365] R4is hydrogen, C1─C6alkyl, C1─C6haloalkyl, C2─C6alkynyl, halogen, CN, ─C(=O)NR5R5, or C≡C(CH2)wOH, wherein w is 1, 2, 3, 4, 5, or 6, and wherein each alkyl, haloalkyl, and alkynyl is independently optionally substituted with 1─3 instances of C1─C4alkyl or halogen;

[0366] each instance of Rna and Rnc is independently hydrogen, C1—C6 alkyl, or C1—C6 haloalkyl; and

[0367] each instance of R5 is independently hydrogen or C1—C6 alkyl;

[0368] is

[0369]

[0370] L2is ─(CRaRb)r─ and Q is phenyl optionally substituted with Rnand Rna, then L1is ─(CRjRk)q─ and R2is cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted with Rpand Rnc. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is tirzepatide. Attorney Docket No. 047162-7543WO1(02791)

[0371] In some embodiments, the PKa is mitapivat. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is tirzepatide.

[0372] In some embodiments, the PKa is etavopivat. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is tirzepatide. In some embodiments, the method further comprises administering to the subject at least one additional agent or therapy useful for treating obesity and / or treating or preventing T2D or other obesity-related disease, disorder, or condition in the subject. In some embodiments, the additional agent or therapy is administered concurrently with the PKa and / or the GLP-1 RA or other NuSH receptor modulator. In some embodiments, the additional agent or therapy is administered prior to administration of the PKa and / or the GLP-1 RA or other NuSH receptor modulator. In some embodiments, the additional agent or therapy is administered after administration of the PKa and / or the GLP-1 RA or other NuSH receptor modulator. In some embodiments, the at least one additional agent or therapy useful for treating obesity and / or treating or preventing T2D or other obesity-related disease, disorder, or condition includes, but is not limited to, islet-related therapies and islet transplantation therapies. In some embodiments, the islet-related therapies include, but is not limited to, therapies involving the gene editing of islet cells and transfection of islet cells with vectors to induce gene expression. In some embodiments, the additional agent or therapy includes, but is not limited, to leptin, ghrelin, MC4RA, myostatin inhibitors, activin inhibitors, myostatin / activin A inhibitors, NRLP3, and metformin.

[0373] In some embodiments, administration of the GLP-1 RA or other NuSH receptor agonist is decreased or discontinued after a desired weight and or glucose tolerance level is achieved, or if there is a desire or need to discontinue the GLP-1 RA or other NuSH receptor modulator, and administration of the PK activator is continued to achieve or to maintain the desired weight and / or glucose tolerance level of the subject. In some embodiments, an amount of the NuSH receptor modulator is decreased or discontinued. In some embodiments, the amount of the NuSH receptor modulator is decreased or discontinued after the subject reaches a desired weight or is no longer losing weight. In some embodiment, the amount of the NuSH receptor modulator is decreased or discontinued after the subj ect reaches a desired glucose tolerance Attorney Docket No. 047162-7543WO1(02791)

[0374] level. In some embodiments, wherein the amount of the NuSH receptor modulator is decreased or discontinued if the subject experiences a negative side effect associated with the NuSH receptor modulator. In some embodiments, the desire or need to discontinue the GLP-1 RA or other NuSH receptor modulator includes, but is not limited to, side effects associated with the GLP-1 RA or other NuSH receptor modulator. In some embodiments, the desire or need to discontinue the GLP-1 RA or other NuSH receptor modulator includes, but is not limited to, pricing of the GLP-1 RA or other NuSH receptor modulator.

[0375] In some embodiments, the desired weight of the subject was achieved by any one or more of the following mechanism(s): lifestyle of the subject, bariatric surgery, the GLP-1 RA or other NuSH receptor modulator administered to the subject, and / or other anti-obesity medication (e.g., phentermine, bupropion, naltrexone, topiramate, orlistat) administered to the subject. In some embodiments, the PK activator is administered to achieve or to maintain a desired weight and / or glucose tolerance level of the subject. In some embodiments, the PK activator is administered to improve or maintain better metabolic health.

[0376] In some embodiments, the subject previously experienced loss of lean body mass, unsatisfactory control of metabolic homeostasis, resolution hepatic steatosis, and / or loss of bone density by a prior GLP-1 RA or other NuSH receptor modulator therapy or a prior non-NuSH therapy.

[0377] In some embodiments, the subject is a mammal. In some embodiments, the subject is a companion animal. In some embodiments, the subject is a dog. In some embodiments, the subject is a cat. In some embodiments, the subject is a livestock animal. In some embodiments, the subject is a horse. In some embodiments, the subject is a sheep. In some embodiments, the subject is a pig. In some embodiments, the subject is a cow. In some embodiments, the subject is a goat. In some embodiments, the subject is a non -human primate. In some embodiments, the subject is a human.

[0378] In one aspect, the present disclosure provides a method of treating obesity and / or treating or preventing or ameliorating Type 2 diabetes mellitus (T2D) or other obesity-related disease, disorder, or condition and / or treating, preventing, or ameliorating an obesity-related disease, disorder, or condition and / or treating, preventing, or ameliorating a disease, disorder, or condition in a subject in need thereof, the method comprising administering to the subject a pyruvate kinase (PK) activator. In some embodiments, the PKa is administered as a monotherapy. Attorney Docket No. 047162-7543WO1(02791)

[0379] In some embodiments, the subject had previously been administered at least one glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1 RA) or other NuSH receptor modulator, and the GLP-1 RA or other NuSH receptor modulator was not well-tolerated and / or was ineffective or insufficient for treating the obesity and / or treating or preventing the T2D or other obesity-related disease, disorder, or condition in the subject and / or treating, preventing, or ameliorating the obesity-related disease, disorder, or condition in the subject.

[0380] In some embodiments, the PK comprises a PKM2 isoform (e.g., a PMK2 tetramer). In some embodiments, the PK comprises a PKM1 isoform. In some embodiments, the PK comprises a PKL isoform. In some embodiments, the PK comprises a PKR isoform.

[0381] In some embodiments, the PKa is an activator of a PKM1 isoform. In some embodiments, the PKa is an activator of a PKM2 isoform. In some embodiments, the PKa is an activator of a PKL isoform. In some embodiments, the PKa is an activator of a PKR isoform.

[0382] In some embodiments, the PK comprises at least one PKM2 isoform monomer (e.g., a PK heterodimer comprising one PKM2 monomer or a PK heterotetramer comprising at least one PKM2 monomer).

[0383] In some embodiments, the PK is a heterogenous tetramer with an allosteric or post-translationally activatable monomeric subunit.

[0384] In some embodiments, the PK activator is a small molecule activator of PK.

[0385] In some embodiments, the PK activator is an allosteric activator of PK.

[0386] In some embodiments, the PK activator selectively activates PKM2 or some combination of activatable PK multimer comprising at least one PKM2 monomer.

[0387] In some embodiments, the PK activator is characterized by central nervous system (CNS) penetrance.

[0388] In some embodiments, the PK activator amplifies weight loss in the subject:

[0389] (a) compared to weight loss level achieved by control subj ects who had been treated with at least one glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1 RA) or other NuSH receptor modulator but no PK activator; and / or (b) if the subject had previously been administered at least one GLP-1 RA or other NuSH receptor modulator but no PK activator, compared to weight loss level previously achieved by the subject.

[0390] In some embodiments, the PK activator improves glucose tolerance, or effects other metabolic improvements, in the subject:

[0391] (a) compared to glucose tolerance level, or other metabolic improvement, achieved by control subjects who had been treated with at least one glucagon-like Attorney Docket No. 047162-7543WO1(02791)

[0392] peptide- 1 (GLP-1) receptor agonist (GLP-1 RA) or other NuSH receptor modulator but no PK activator, and / or

[0393] (b) if the subject had previously been administered at least one GLP-1 RA or other NuSH receptor modulator but no PK activator, compared to glucose tolerance level, or other metabolic improvement, previously achieved by the subject. In some embodiments, the method sustains muscle mass in the subject and / or reduces excess muscle loss in the subject compared to methods that do not comprise administration of a PK activator (e.g., methods comprising administration of only a GLP-1 RA or other NuSH receptor modulator). In some embodiments, the method does not result in a loss of muscle mass. In some embodiments, the method increases a lean-to-fat mass ratio of the subject.

[0394] In some embodiments, the method further comprises administering a GLP-1 RA or other NuSH receptor modulator. In some embodiments, the PKa and the GLP-1 RA or other NuSH receptor modulator are administered concurrently. In some embodiments, the PKa is administered prior to administration of the GLP-1 RA or other NuSH receptor modulator. In some embodiments, the PKa is administered after administration of the GLP-1 RA or other NuSH receptor modulator. In some embodiments, the method allows for a lower dose of the GLP-1 RA or other NuSH receptor agonist to be administered compared to methods that do not comprise administration of a PK activator (e.g., methods comprising administration of only a GLP-1 RA or other NuSH receptor modulator), thereby reducing side effects from and / or amount of the GLP-1 RA or NuSH receptor agonist. In some embodiments, the method allows for administration of a lower dose of the NuSH receptor modulator than an FDA allowed dose of the NuSH receptor modulator.

[0395] In some embodiments, the PK activator is any small molecule PK activator known in the art, or a salt, solvate, stereoisomer, isotopologue, or tautomer thereof.

[0396] In some embodiments, the NuSH receptor modulator is a human NuSH receptor agonist. In some embodiments, the NuSH receptor modulator is a GLP-1 receptor agonist (GLP-1 RA), a GIP receptor agonist (GIP RA), or a GCG receptor agonist (GCG RA). In some embodiments, the NuSH receptor modulator is a dual agonist for GLP-1 receptor and GIP receptor, GLP-1 receptor and GCG receptor, or GIP receptor and GCG receptor. In some embodiments, the NuSH receptor modulator is an agonist for GLP-1 receptor, GIP receptor, and GCG receptor. In some embodiments, the NuSH receptor modulator comprises one or more of a GLP-1 receptor mono agonist (GLP-1 RA). a GIP receptor mono agonist (GIP RA), a GCG receptor mono agonist (GCG RA), a dual agonist for GLP-1 receptor and GIP receptor, Attorney Docket No. 047162-7543WO1(02791)

[0397] a dual agonist GLP-1 receptor and GCG receptor, or a dual agonist GIP receptor and GCG receptor, or a triple agonist for GLP-1 receptor, GIP receptor, and GCG receptor.

[0398] In some embodiments, the GLP-1 receptor mono agonist is selected from the group consisting of semaglutide (e.g., Ozempic, Wegovy, Rybelsus - an oral semaglutide), exenatide (e.g., Byetta, Bydureon), liraglutide (e.g., Victoza, Saxenda), and dulaglutide (e.g., Trulicity), lixisenatide (e.g.. Lyxumia, Adlyxin), Orforglipron, and albiglutide (e.g.. Eperzan. Tanzeum).

[0399] In some embodiments, the GIP receptor mono agonist includes, but is not limited to, PF-07976016 (Pfizer).

[0400] In some embodiments, the GCG receptor mono agonist includes, but is not limited to, GCG analog HM15136.

[0401] In some embodiments, the GLP-1 and GIP dual receptor agonist includes, but is not limited to, tirzepatide (e.g., Mounjaro, Zepbound).

[0402] In some embodiments, the GLP-1 and GCG dual receptor agonist includes, but is not limited to, Cotadutide (MEDI0382), Efinopegdutide (MK-6024 / JNJ-64565111), Mazsutide (IBI-362), and Pemyidutide (ALT-801).

[0403] In some embodiments, the GLP-1, GIP, and GCG triple receptor agonist includes, but is not limited to, Retatrutide (LY3437943), Maridebart Cafraglutide (Amgen), and HM15211.

[0404] In some embodiments, the NuSH receptor modulator comprises an agonist of amylin or peptide YY. In some embodiments, the agonist of amylin or peptide YY includes, but is not limited to, pramlintide, Cagrilintide, and amycretin.

[0405] In some embodiments, the PKa is TEPP-46. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is tirzepatide.

[0406] In some embodiments, the PKa is a compound represented by Formula A as described above.

[0407] In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is tirzepatide.

[0408] In some embodiments, the PKa is mitapivat. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is Attorney Docket No. 047162-7543WO1(02791)

[0409] mitapivat and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is tirzepatide.

[0410] In some embodiments, the PKa is etavopivat. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is tirzepatide.

[0411] In some embodiments, the method further comprises administering to the subject at least one additional agent or therapy useful for treating the obesity and / or treating or preventing the T2D or other obesity-related disease, disorder, or condition in the subject. In some embodiments, the additional agent or therapy is administered concurrently with the PKa. In some embodiments, the additional agent or therapy is administered prior to administration of the PKa. In some embodiments, the additional agent or therapy is administered after administration of the PKa. In some embodiments, the additional agent or therapy is administered concurrently with the PKa and / or the GLP-1 RA or other NuSH receptor modulator. In some embodiments, the additional agent or therapy is administered prior to administration of the PKa and / or the GLP-1 RA or other NuSH receptor modulator. In some embodiments, the additional agent or therapy is administered after administration of the PKa and / or the GLP-1 RA or other NuSH receptor modulator. In some embodiments, the at least one additional agent or therapy useful for treating obesity and / or treating or preventing T2D or other obesity-related disease, disorder, or condition includes, but is not limited to, islet-related therapies and islet transplantation therapies. In some embodiments, the islet-related therapies include, but is not limited to, therapies involving the gene editing of islet cells and transfection of islet cells with vectors to induce gene expression. In some embodiments, the additional agent or therapy includes, but is not limited, to leptin, ghrelin, MC4RA, myostatin inhibitors, activin inhibitors, myostatin / activin A inhibitors, NRLP3, and metformin.

[0412] In some embodiments, an amount of the NuSH receptor modulator is decreased or discontinued. In some embodiments, the amount of the NuSH receptor modulator is decreased or discontinued after the subject reaches a desired weight or is no longer losing weight. In some embodiment, the amount of the NuSH receptor modulator is decreased or discontinued after the subject reaches a desired glucose tolerance level. In some embodiments, wherein the amount of the NuSH receptor modulator is decreased or discontinued if the subject experiences a negative side effect associated with the NuSH receptor modulator. In some embodiments, the Attorney Docket No. 047162-7543WO1(02791)

[0413] desire or need to discontinue the GLP-1 RA or other NuSH receptor modulator includes, but is not limited to, side effects associated with the GLP-1 RA or other NuSH receptor modulator.

[0414] In some embodiments, the PK activator is administered to achieve or to maintain a desired weight and / or glucose tolerance level of the subject. In some embodiments, the PK activator is administered to improve or maintain better metabolic health.

[0415] In some embodiments, a desired weight of the subject was previously achieved by any one or more of the following mechanism(s): lifestyle of the subject, bariatric surgery, a GLP-1 RA or other NuSH receptor modulator administered to the subject, and / or other anti-obesity medication (e.g., phentermine, bupropion, naltrexone, topiramate, orlistat) administered to the subject. In some embodiments, the PKa is administered prior to bariatric surgery or an endoscopic procedure. In some embodiments, the PKa is administered following bariatric surgery or an endoscopic procedure.

[0416] In some embodiments, the subject previously experienced loss of lean body mass, unsatisfactory control of metabolic homeostasis, resolution hepatic steatosis, and / or loss of bone density by a prior GLP-1 RA or other NuSH receptor modulator therapy or a prior non-NuSH therapy.

[0417] In some embodiments, the subject is a mammal. In some embodiments, the subject is a companion animal. In some embodiments, the subject is a dog. In some embodiments, the subject is a cat. In some embodiments, the subject is a livestock animal. In some embodiments, the subject is a horse. In some embodiments, the subject is a sheep. In some embodiments, the subject is a pig. In some embodiments, the subject is a cow. In some embodiments, the subject is a goat. In some embodiments, the subject is a non-human primate. In some embodiments, the subject is a human.

[0418] In one aspect, the present disclosure provides a method of treating obesity and / or treating or preventing or ameliorating Type 2 diabetes mellitus (T2D) or other obesity-related disease, disorder, or condition and / or treating, preventing, or ameliorating an obesity-related disease, disorder, or condition and / or treating, preventing, or ameliorating a disease, disorder, or condition in a subject in need thereof, the method comprising administering to the subject an AMP kinase inhibitor, a phosphodiesterase inhibitor (e.g., PDE4B inhibitor), and / or a calcium channel inhibitor. In some embodiments, the AMP kinase inhibitor, the phosphodiesterase inhibitor, and / or the calcium channel inhibitor are administered with a NuSH receptor modulator. In some embodiments, the AMP kinase inhibitor, the phosphodiesterase inhibitor, and / or the calcium channel inhibitor and the NuSH receptor Attorney Docket No. 047162-7543WO1(02791)

[0419] modulator are administered concurrently. In some embodiments, the AMP kinase inhibitor, the phosphodiesterase inhibitor, and / or the calcium channel inhibitor is administered prior to administration of the NuSH receptor modulator. In some embodiments, the AMP kinase inhibitor, the phosphodiesterase inhibitor, and / or the calcium channel inhibitor is administered after administration of the NuSH receptor modulator.

[0420] In some embodiments, the subject had previously been administered at least one GLP-1 RA or other NuSH receptor modulator, and the GLP-1 RA or other NuSH receptor modulator was ineffective or insufficient for treating the obesity and / or treating or preventing the T2D or other obesity-related disease, disorder, or condition in the subject and / or treating, preventing, or ameliorating the obesity-related disease, disorder, or condition in the subject.

[0421] In some embodiments, the method comprises administering an AMP kinase inhibitor. In some embodiments, the AMP kinase inhibitor comprises Dorsomorphin, Doxorubicin, SBI-0206965, and BAY-3827.

[0422] In some embodiments, the method comprises administering a phosphodiesterase inhibitor. In some embodiments, the phosphodiesterase inhibitor comprises a PDE4B inhibitor, BI 1015550, Nerandomilast, Roflumilast, Apremilast, Crisaborole, Cilomilast, and Rolipram.

[0423] In some embodiments, the method comprises administering a calcium channel inhibitor. In some embodiments, the calcium channel inhibitor comprises Amlodipine, Nifedipine. Felodipine, Nicardipine. Nimodipine, Verapamil, and Diltiazem.

[0424] In some embodiments, the AMP kinase inhibitor, the phosphodiesterase inhibitor, and / or the calcium channel inhibitor amplifies weight loss in the subject:

[0425] (a) compared to weight loss level achieved by control subj ects who had been treated with at least one GLP-1 RA or other NuSH receptor modulator but no AMP kinase inhibitor, the phosphodiesterase inhibitor, and / or the calcium channel inhibitor; and / or

[0426] (b) if the subject had previously been administered at least one GLP-1 RA or other NuSH receptor modulator but no AMP kinase inhibitor, the phosphodiesterase inhibitor, and / or the calcium channel inhibitor, compared to weight loss level previously achieved by the subject.

[0427] In some embodiments, the AMP kinase inhibitor, the phosphodiesterase inhibitor, and / or the calcium channel inhibitor improves glucose tolerance, or effects other metabolic improvements, in the subject:

[0428] (a) compared to glucose tolerance level, or other metabolic improvement, achieved by control subjects who had been treated with at least one GLP-1 RA or other Attorney Docket No. 047162-7543WO1(02791)

[0429] NuSH receptor modulator but no AMP kinase inhibitor, the phosphodiesterase inhibitor, and / or the calcium channel inhibitor; and / or

[0430] (b) if the subject had previously been administered at least one GLP-1 RA or other NuSH receptor modulator but no AMP kinase inhibitor, the phosphodiesterase inhibitor, and / or the calcium channel inhibitor, compared to glucose tolerance level, or other metabolic improvement, previously achieved by the subject. In some embodiments, the method sustains muscle mass in the subject and / or reduces excess muscle loss in the subject compared to methods that do not comprise administration of an AMP kinase inhibitor, a phosphodiesterase inhibitor, and / or a calcium channel inhibitor (e.g., methods comprising administration of only a GLP-1 RA or other NuSH receptor modulator). In some embodiments, the method does not result in a loss of muscle mass. In some embodiments, the method increases a lean-to-fat mass ratio of the subject.

[0431] In some embodiments, the method further comprises administering a GLP-1 RA or other NuSH receptor agonist. In some embodiments. AMP kinase inhibitor, the phosphodiesterase inhibitor, and / or the calcium channel inhibitor and the GLP-1 RA or other NuSH receptor modulator are administered concurrently. In some embodiments, the AMP kinase inhibitor, the phosphodiesterase inhibitor, and / or the calcium channel inhibitor is administered prior to administration of the GLP-1 RA or other NuSH receptor modulator. In some embodiments, the AMP kinase inhibitor, the phosphodiesterase inhibitor, and / or the calcium channel inhibitor is administered after administration of the GLP-1 RA or other NuSH receptor modulator. In some embodiments, the method allows for a lower dose of the GLP-1 RA or other NuSH receptor agonist to be administered compared to methods that do not comprise administration of a AMP kinase inhibitor, the phosphodiesterase inhibitor, and / or the calcium channel inhibitor (e.g., methods comprising administration of only a GLP-1 RA or other NuSH receptor modulator), thereby reducing side effects from and / or amount of the GLP-1 RA or NuSH receptor agonist. In some embodiments, the method allows for administration of a lower dose of the NuSH receptor modulator than an FDA allowed dose of the NuSH receptor modulator.

[0432] In some embodiments, the NuSH receptor modulator is a human NuSH receptor agonist. In some embodiments, the NuSH receptor modulator is a GLP-1 receptor agonist (GLP-1 RA), a GIP receptor agonist (GIP RA), or a GCG receptor agonist (GCG RA). In some embodiments, the NuSH receptor modulator is a dual agonist for GLP-1 receptor and GIP receptor, GLP-1 receptor and GCG receptor, or GIP receptor and GCG receptor. In some embodiments, the NuSH receptor modulator is an agonist for GLP-1 receptor, GIP receptor, Attorney Docket No. 047162-7543WO1(02791)

[0433] and GCG receptor. In some embodiments, the NuSH receptor modulator comprises one or more of a GLP-1 receptor mono agonist (GLP-1 RA), a GIP receptor mono agonist (GIP RA), a GCG receptor mono agonist (GCG RA), a dual agonist for GLP-1 receptor and GIP receptor, a dual agonist GLP-1 receptor and GCG receptor, or a dual agonist GIP receptor and GCG receptor, or a triple agonist for GLP-1 receptor, GIP receptor, and GCG receptor.

[0434] In some embodiments, the GLP-1 receptor mono agonist is selected from the group consisting of semaglutide (e.g., Ozempic, Wegovy, Rybelsus - an oral semaglutide), exenatide (e.g., Byetta, Bydureon), liraglutide (e.g., Victoza, Saxenda), dulaglutide (e.g., Trulicity), lixisenatide (e.g., Lyxumia, Adlyxin), Orforglipron, and albiglutide (e.g., Eperzan, Tanzeum).

[0435] In some embodiments, the GIP receptor mono agonist includes, but is not limited to, PF-07976016 (Pfizer).

[0436] In some embodiments, the GCG receptor mono agonist includes, but is not limited to, GCG analog HM15136. In some embodiments, the GLP-1 and GIP dual receptor agonist includes, but is not limited to, tirzepatide (e.g., Mounjaro, Zepbound).

[0437] In some embodiments, the GLP-1 and GCG dual receptor agonist includes, but is not limited to, Cotadutide (MEDI0382), Efinopegdutide (MK-6024 / JNJ-64565111), Mazsutide (IBI-362), and Pemyidutide (ALT-801).

[0438] In some embodiments, the GLP-1, GIP, and GCG triple receptor agonist includes, but is not limited to, Retatrutide (LY3437943), Maridebart Cafraglutide (Amgen), and HM15211.

[0439] In some embodiments, the NuSH receptor modulator comprises an agonist of amylin or peptide YY. In some embodiments, the agonist of amylin or peptide YY includes, but is not limited to, pramlintide, Cagrilintide, and amycretin.

[0440] In some embodiments, the method comprises administering an AMP kinase inhibitor and the NuSH receptor modulator liraglutide. In some embodiments, the method comprises administering an AMP kinase inhibitor and the NuSH receptor modulator semaglutide. In some embodiments, the method comprises administering an AMP kinase inhibitor and the NuSH receptor modulator Orforglipron. In some embodiments, the method comprises administering an AMP kinase inhibitor and the NuSH receptor modulator tirzepatide.

[0441] In some embodiments, the method comprises administering a phosphodiesterase inhibitor and the NuSH receptor modulator liraglutide. In some embodiments, the method comprises administering a phosphodiesterase inhibitor and the NuSH receptor modulator semaglutide. In some embodiments, the method comprises administering a phosphodiesterase inhibitor and the NuSH receptor modulator Orforglipron. In some embodiments, the method Attorney Docket No. 047162-7543WO1(02791)

[0442] comprises administering a phosphodiesterase inhibitor and the NuSH receptor modulator tirzepatide.

[0443] In some embodiments, the method comprises administering a calcium channel inhibitor and the NuSH receptor modulator liraglutide. In some embodiments, the method comprises administering a calcium channel inhibitor and the NuSH receptor modulator semaglutide. In some embodiments, the method comprises administering a calcium channel inhibitor and the NuSH receptor modulator Orforglipron. In some embodiments, the method comprises administering a calcium channel inhibitor and the NuSH receptor modulator tirzepatide.

[0444] In some embodiments, the method further comprises administering to the subject at least one additional agent or therapy useful for treating obesity and / or treating or preventing T2D or other obesity-related disease, disorder, or condition in the subject. In some embodiments, the at least one additional agent or therapy useful for treating obesity and / or treating or preventing T2D or other obesity-related disease, disorder, or condition includes, but is not limited to, islet-related therapies and islet transplantation therapies. In some embodiments, the islet-related therapies include, but is not limited to, therapies involving the gene editing of islet cells and transfection of islet cells with vectors to induce gene expression. In some embodiments, the additional agent or therapy includes, but is not limited, to leptin, ghrelin, MC4RA, myostatin inhibitors, activin inhibitors, myostatin / activin A inhibitors, NRLP3, and metformin.

[0445] In some embodiments, administration of the GLP-1 RA or other NuSH receptor agonist is discontinued after a desired weight and or glucose tolerance level is achieved, or if there is a desire or need to discontinue the GLP-1 RA or other NuSH receptor modulator, and administration of the PK activator is continued to achieve or to maintain the desired weight and / or glucose tolerance level of the subject. In some embodiments, an amount of the NuSH receptor modulator is decreased or discontinued. In some embodiments, the amount of the NuSH receptor modulator is decreased or discontinued after the subject reaches a desired weight or is no longer losing weight. In some embodiment, the amount of the NuSH receptor modulator is decreased or discontinued after the subject reaches a desired glucose tolerance level. In some embodiments, wherein the amount of the NuSH receptor modulator is decreased or discontinued if the subject experiences a negative side effect associated with the NuSH receptor modulator. In some embodiments, the desire or need to discontinue the GLP-1 RA or other NuSH receptor modulator includes, but is not limited to, side effects associated with the GLP-1 RA or other NuSH receptor modulator. In some embodiments, the desire or need to Attorney Docket No. 047162-7543WO1(02791)

[0446] discontinue the GLP-1 RA or other NuSH receptor modulator includes, but is not limited to, pricing of the GLP-1 RA or other NuSH receptor modulator.

[0447] In some embodiments, the desired weight of the subject was achieved by any one or more of the following mechanism(s): lifestyle of the subject, bariatric surgery, the GLP-1 RA or other NuSH receptor modulator administered to the subject, and / or other anti-obesity medication (e.g.. phentermine, bupropion, naltrexone, topiramate, orlistat) administered to the subject.

[0448] In some embodiments, the subject previously experienced loss of lean body mass, unsatisfactory control of metabolic homeostasis, resolution hepatic steatosis, and / or loss of bone density by a prior GLP-1 RA or other NuSH receptor modulator therapy or a prior non-NuSH therapy.

[0449] In some embodiments, the subject is a mammal. In some embodiments, the subject is a companion animal. In some embodiments, the subject is a dog. In some embodiments, the subject is a cat. In some embodiments, the subject is a livestock animal. In some embodiments, the subject is a horse. In some embodiments, the subject is a sheep. In some embodiments, the subject is a pig. In some embodiments, the subject is a cow. In some embodiments, the subject is a goat. In some embodiments, the subject is a non-human primate. In some embodiments, the subj ect is a human.

[0450] In some embodiments of any of the above aspects, obesity is determined by methods including, but not limited to, weight, waist circumference, waist-to-height ratio, body mass index (BMI), body fat percentage, android-to-gynoid fat ratio, and waist-to-hip ratio. In some embodiments of any of the above aspects, the other obesity-related disease, disorder, or condition or the obesity-related disease, disorder, or condition or the disease, disorder, or condition is a metabolic disease, disorder, or condition (e.g., CVD [primary or secondary prevention], HFpEF, CKD, CKM syndrome, hypertension, hyperlipidemia, MAFLD / MASH, PCOS, infertility, cancer, etc.) or a functional disease, disorder, or condition (e.g., OA, OSA, back pain, incontinence, etc.). In some embodiments, the other obesity-related disease, disorder, or condition or the obesity-related disease, disorder, or condition or the disease, disorder, or condition includes, but is not limited to, an orthopedic disease, disorder, or condition; an obstetric disease, disorder, or condition; a dermatological disease, disorder, or condition; an ear, nose, and throat (ENT) disease, disorder, or condition; a hematological disease, disorder, or condition; an infectious disease, disorder, or condition; a disease, disorder, or condition associated with a subject’s offspring; an oral and maxillofacial disease, disorder, Attorney Docket No. 047162-7543WO1(02791)

[0451] or condition; a rheumatological disease, disorder, or condition; a urogenital disease, disorder, or condition; an endocrine disease, disorder, or condition; a geriatric disease, disorder, or condition; a neurological disease, disorder, or condition; a vascular disease, disorder, or condition; a psychiatric disease, disorder, or condition; a gastrointestinal or hepatological disease, disorder, or condition; a cardiovascular disease, disorder, or condition; a gynecological disease, disorder, or condition: a micronutrient-related disease, disorder, or condition; a respiratory disease, disorder, or condition; a transplant-related disease, disorder, or condition; a cancer-related disease, disorder, or condition; a renal disease, disorder, or condition; an ophthalmological disease, disorder, or condition; a urological disease, disorder, or condition; a reproductive disease, disorder, or condition; a traumatological disease, disorder, or condition; or any combination thereof. In some embodiments, the orthopedic disease, disorder, or condition includes, but is not limited to, chronic leg pain, a fracture (e.g., of a clavicle, a hip, a lower extremity, a spine, an upper extremity), lower back pain, osteoarthritis (e.g., of a hip, a knee, a hand), osteoporosis, tendonitis (e.g., of a rotator cuff, of an upper extremity), intervertebral disc disorder, osteoporotic fracture, or a combination thereof. In some embodiments, the obstetric disease, disorder, or condition includes, but is not limited to, abruptio placentae, disordered childbirth, genital tract infection, maternal deep-vein thrombosis (DVT), maternal pulmonary embolism (PE), maternal sepsis, maternal thrombosis, gestational diabetes mellitus, preterm delivery, preterm premature rupture of membranes (PPROM), gestational hypertension, eclampsia, preeclampsia, peripheral edema, postepidural hypotension, postpartum hemorrhage, postterm birth, spontaneous abortion, cervical incompetence, polyhydramnios, or any combination thereof. In some embodiments, the dermatological disease, disorder, or condition includes, but is not limited to, alopecia, atopic dermatitis, dermatophytes, hidradenitis suppurativa, psoriasis, pyoderma gangrenosum, acrochordons, acanthosis nigricans, lichen sclerosus, cellulitis, elephantiasis nostras verrucosa, intertrigo, keratosis pilaris, lymphedema, plantar hyperkeratosis, striae distensae, hyperhidrosis, erysipelas, folliculitis, onychomycosis, tinea cruris, or any combination thereof. In some embodiments, the ENT disease, disorder, or condition includes, but is not limited to, allergic rhinitis, chronic rhinosinusitis, nasal obstruction, otitis media (eosinophilic), temporomandibular joint (TMJ) disorder, primary cerebrospinal fluid (CSF) rhinorrhea, temporal bone encephalocele, Meniere’s disease, or any combination thereof. In some embodiments, the hematological disease, disorder, or condition includes, but is not limited to, anti-phospholipid syndrome, deep vein thrombosis, leukemia, venous thromboembolism, monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma, Non- Attorney Docket No. 047162-7543WO1(02791)

[0452] Hodgkin’s lymphoma, Waldenstrom macroglobulinemia. plasmacytoma, or any combination thereof. In some embodiments, the infectious disease, disorder, or condition includes, but is not limited to, bladder infections (e.g., multiple bladder infections), tonsillitis, upper respiratory tract infection, yeast infections (e.g., multiple yeast infections), or any combination thereof. In some embodiments, the disease, disorder, or condition associated with a subject’s offspring includes, but is not limited to, offspring asthma, offspring autism, offspring epilepsy, offspring obesity, neonatal complications, or any combination thereof. In some embodiments, the oral and maxillofacial disease, disorder, or condition includes, but is not limited to, edentulism, gingivitis, periodontitis, or any combination thereof. In some embodiments, the rheumatological disease, disorder, or condition includes, but is not limited to, fibromyalgia, rheumatoid arthritis, gout, hyperuricemia, psoriatic arthritis, or any combination thereof. In some embodiments, the urogenital disease, disorder, or condition includes, but is not limited to, benign prostatic hypertrophy, lower urinary tract symptoms, urinary tract infections, nocturia, overactive bladder, stress urinary incontinence, urge urinary’ incontinence, kidney stones, or any combination thereof. In some embodiments, the endocrine disease, disorder, or condition includes, but is not limited to, insulin resistance, hypothyroidism, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, prediabetes, thyroid nodule, type 2 diabetes mellitus, osteoporosis, or any combination thereof. In some embodiments, the geriatric disease, disorder, or condition includes, but is not limited to, cerebral atrophy, cognitive impairment, frailty, pressure ulcer, or any combination thereof. In some embodiments, the neurological disease, disorder, or condition includes, but is not limited to, chronic pain syndrome, multiple sclerosis, peripheral neuropathy, meralgia paresthetica, ulnar nerve compression, carpal tunnel syndrome, idiopathic headache, migraine headache, pseudotumor cerebri, or any combination thereof. In some embodiments, the vascular disease, disorder, or condition includes, but is not limited to, abdominal aortic aneurysm, thrombophlebitis, venous insufficiency, or any combination thereof. In some embodiments, the psychiatric disease, disorder, or condition includes, but is not limited to. depression, manic episodes, stress, anti-social personality disorder, anxiety, attention-deficit / hyperactivity disorder (ADHD), avoidant personality disorder, panic disorder, or any combination thereof. In some embodiments, the gastrointestinal or hepatological disease, disorder, or condition includes, but is not limited to, colonic diverticulosis, pancreatitis, gallstone disease, nonalcoholic steatohepatitis (NASH), NASH-associated cirrhosis, erosive esophagitis, gastroesophageal reflux disease (GERD), GERD-associated asthma, hiatal hernia, Barrett’s esophagus, non-alcoholic fatty liver disease (NAFLD), gallbladder polyps, colorectal adenoma, or any combination thereof. In some Attorney Docket No. 047162-7543WO1(02791)

[0453] embodiments, the cardiovascular disease, disorder, or condition includes, but is not limited to, carotid atherosclerosis, heart failure, acute myocardial infarction, coronary artery disease, stable angina, unstable angina, periphery artery disease, atrial fibrillation, diastolic dysfunction, left atrial enlargement, stroke (e.g., hemorrhagic stroke, ischemic stroke, mixed stroke), hypertension, left ventricular hypertrophy, sudden cardiac death, or any combination thereof. In some embodiments, the gynecological disease, disorder, or condition includes, but is not limited to, uterine leiomyomata, menstrual irregularities, premenstrual syndrome, dyspareunia, fecal incontinence, or any combination thereof. In some embodiments, the micronutrient-related disease, disorder, or condition includes, but is not limited to, iron deficiency, vitamin D deficiency, thiamine deficiency, or any combination thereof. In some embodiments, the respiratory disease, disorder, or condition includes, but is not limited to, chronic bronchitis, asthma, atelectasis, exercise-induced bronchoconstriction (EIB), obstructive sleep apnea, or any combinations thereof. In some embodiments, the transplant-related disease, disorder, or condition includes, but is not limited to, solid organ graft dysfunction. In some embodiments, the oncological disease, disorder, or condition includes, but is not limited to, appendix carcinoid tumor, pancreatic neuroendocrine tumor, peritoneal cancer, transitional cell carcinoma, anaplastic thyroid carcinoma, cholangiocarcinoma, colorectal adenocarcinoma, endometrial cancer, cutaneous melanoma, epithelial ovarian cancer, esophageal squamous cell carcinoma (SqCC), extrahepatic bile duct cancer, gallbladder cancer, gastric cardia adenocarcinoma, glioma, inflammatory breast cancer, invasive ductal carcinoma of a breast, meningioma, pancreatic adenocarcinoma, papillary thyroid carcinoma, prostatic adenocarcinoma, renal cell carcinoma, T1 endometrioid cancer, T2 invasive endometrial cancer, urothelial cell carcinoma, follicular thyroid carcinoma, esophageal adenocarcinoma, gastric high-grade dysplasia, hepatocellular carcinoma, or any combination thereof. In some embodiments, the renal disease, disorder, or condition comprises albuminuria, chronic kidney disease, diabetic nephropathy, end-stage renal failure, glomerulonephritis, nephrosclerosis, proteinuria, or any combination thereof. In some embodiments, the ophthalmological disease, disorder, or condition includes, but is not limited to, cataracts, glaucoma, macular degeneration or any combination thereof. In some embodiments, the urological disease, disorder, or condition comprises kidney stones. In some embodiments, the reproductive disease, disorder, or condition comprises secondary hypogonadism, sexual dysfunction, poor semen quality, subfertility, erectile dysfunction, or any combination thereof. In some embodiments, the traumatological disease, disorder, or condition includes, but is not limited to, ventral hernia, fall-related injuries, increased risk of injuries, or any combination Attorney Docket No. 047162-7543WO1(02791)

[0454] thereof. In some embodiments, the obesity-related disease, disorder, or condition includes, but is not limited to, a metabolic disease, disorder, or condition selected from the group consisting of cardiovascular disease, Heart Failure with Preserved Ejection Fraction, Heart Failure with Reduced Ejection Fraction (HFrEF), Chronic Kidney Disease (CKD), Cardiovascular-Kidney-Metabolic (CKM) Syndrome, hypertension, hyperlipidemia, Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD), Metabolic-Associated Steatohepatitis (MASH), infertility’. Polycystic Ovary Syndrome (PCOS), and cancer. In some embodiments, the obesity-related disease, disorder, or condition includes, but is not limited to, obesity, Type I diabetes, Type II diabetes mellitus, idiopathic Type I diabetes (Type lb), latent autoimmune diabetes in adults (LADA), early-onset Type 2 diabetes (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, coronary heart disease, ischemic stroke, restenosis after angioplasty, peripheral vascular disease, intermittent claudication, myocardial infarction, dyslipidemia, post-prandial lipemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, diabetic retinopathy, macular degeneration, cataract, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X, hyperglycemia, hyperinsulinemia, hypertriglyceridemia, insulin resistance, impaired glucose metabolism, skin and connective tissue disorders, foot ulcerations and ulcerative colitis, endothelial dysfunction and impaired vascular compliance, hyper apo B lipoprotein emi a, and maple syrup urine disease.

[0455] In some aspects, provided herein are methods of increasing mitochondrial membrane potential in a subject in need thereof. In some embodiments, the method comprises administering a pyruvate kinase (PK) activator (PKa). In some embodiments, the PKa is administered as a monotherapy. In some embodiments, increasing mitochondrial membrane potential in a cell contacted with the PKa comprises increasing a mitochondrial membrane potential by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% as compared to a mitochondrial membrane potential measured in a control cell not contacted with PKa. In some embodiments, increasing mitochondrial membrane potential in a cell contacted with the PKa comprises increasing a mitochondrial membrane potential by 10%, 20%. 30%, 40%, 50%, 60%, 70%, 80%. 90%, or 100% as compared to a mitochondrial membrane potential measured in a control cell not contacted with PKa. In some embodiments, increasing mitochondrial membrane potential in a cell contacted with the PKa comprises increasing a mitochondrial membrane Attorney Docket No. 047162-7543WO1(02791)

[0456] potential by at most 10%, at most 20%, at most 30%, at most 40%, at most 50%, at most 60%, at most 70%, at most 80%, at most 90%, or at most 100% as compared to a mitochondrial membrane potential measured in a control cell not contacted with PKa. In some embodiments, increasing mitochondrial membrane potential in a cell contacted with the PKa comprises increasing a mitochondrial membrane potential by between 10% and 100%, between 20% and 100%, between 30% and 100%. between 40% and 100%, between 50% and 100%. between 60% and 100%, between 70% and 100%, between 80% and 100%, and between 90% and 100% as compared to a mitochondrial membrane potential measured in a control cell not contacted with PKa. In some embodiments, the PKa is TEPP-46. In some embodiments, the PKa is mitapivat. In some embodiments, the PKa is etavopivat. In some embodiments, the PKa is a compound represented by Formula A as described above.

[0457] In some aspects, provided herein are methods of increasing mitochondrial membrane potential in a subject in need thereof. In some embodiments, the method comprises administering to the subject a PK activator and a NuSH receptor modulator. In some embodiments, the method comprises administering to the subject a PKa, wherein the subject has been previously administered a NuSH receptor modulator. In some embodiments, the method comprises administering to the subject a NuSH receptor modulator, wherein the subject has been previously administered a PKa. In some embodiments, the method comprises administering an AMP kinase inhibitor, a phosphodiesterase (e.g., a PDE4B inhibitor), or a calcium channel inhibitor and a NuSH receptor modulator. In some embodiments, the method comprises administering to the subject an AMP kinase inhibitor, a phosphodiesterase inhibitor, or a calcium channel inhibitor, wherein the subject has been previously administered a NuSH receptor modulator. In some embodiments, the method comprises administering to the subject a NuSH receptor modulator, wherein the subject has been previously administered an AMP kinase inhibitor, a phosphodiesterase inhibitor, or a calcium channel inhibitor. In some embodiments, increasing mitochondrial membrane potential in a cell contacted with the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator comprises increasing a mitochondrial membrane potential in a cell contacted with the combination of the PKa and NuSH receptor modulator or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and NuSH receptor modulator by at least 10%, at least 20%, at least 30%. at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% as compared to a mitochondrial membrane potential measured in a cell not contacted with the combination of Attorney Docket No. 047162-7543WO1(02791)

[0458] the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator. In some embodiments, increasing mitochondrial membrane potential in a cell contacted with the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator comprises increasing a mitochondrial membrane potential by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% as compared to a mitochondrial membrane potential measured in a cell not contacted with the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator. In some embodiments, increasing mitochondrial membrane potential in a cell contacted with the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator comprises increasing a mitochondrial membrane potential by at most 10%, at most 20%, at most 30%. at most 40%, at most 50%, at most 60%, at most 70%, at most 80%, at most 90%, or at most 100% as compared to a mitochondrial membrane potential measured in a cell not contacted with the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator. In some embodiments, increasing mitochondrial membrane potential in a cell contacted with the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator comprises increasing a mitochondrial membrane potential by between 10% and 100%, between 20% and 100%, between 30% and 100%, between 40% and 100%, between 50% and 100%, between 60% and 100%, between 70% and 100%, between 80% and 100%, and between 90% and 100% as compared to a mitochondrial membrane potential measured in a cell not contacted with the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is tirzepatide. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is liraglutide. In some embodiments, the Attorney Docket No. 047162-7543WO1(02791)

[0459] PKa is a compound of Formula A as described above and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is tirzepatide. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is tirzepatide. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is tirzepatide. In some embodiments, the method comprises administering an AMP kinase inhibitor and the NuSH receptor modulator liraglutide. In some embodiments, the method comprises administering an AMP kinase inhibitor and the NuSH receptor modulator semaglutide. In some embodiments, the method comprises administering an AMP kinase inhibitor and the NuSH receptor modulator Orforglipron. In some embodiments, the method comprises administering an AMP kinase inhibitor and the NuSH receptor modulator tirzepatide. In some embodiments, the method comprises administering a phosphodiesterase inhibitor and the NuSH receptor modulator liraglutide. In some embodiments, the method comprises administering a phosphodiesterase inhibitor and the NuSH receptor modulator semaglutide. In some embodiments, the method comprises administering a phosphodiesterase inhibitor and the NuSH receptor modulator Orforglipron. In some embodiments, the method comprises administering a phosphodiesterase inhibitor and the NuSH receptor modulator tirzepatide. In some embodiments, the phosphodiesterase inhibitor is a PDE4B inhibitor. In some embodiments, the method comprises administering a calcium channel inhibitor and the NuSH receptor modulator liraglutide. In some embodiments, the method comprises administering a calcium channel inhibitor and the NuSH receptor modulator semaglutide. In some embodiments, the method comprises administering a calcium channel inhibitor and the NuSH receptor modulator Orforglipron. In some embodiments, the method comprises administering a calcium channel inhibitor and the NuSH receptor modulator tirzepatide.

[0460] In some aspects, provided herein are methods of improving pancreatic islet function in a subject in need thereof. In some embodiments, the method comprises administering to the Attorney Docket No. 047162-7543WO1(02791)

[0461] subject a pyruvate kinase (PK) activator (PKa). In some embodiments, the PKa is administered as a monotherapy. In some embodiments, improving pancreatic islet function comprises increasing insulin release from pancreatic islet cells. In some embodiments, increasing insulin release from pancreatic islet cells administered the PKa comprises increasing a level of insulin release by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% as compared to a level of insulin release from a control cell not administered the PKa. In some embodiments, increasing insulin release from pancreatic islet cells administered the PKa comprises increasing a level of insulin release by 10%, 20%, 30%, 40%. 50%, 60%, 70%, 80%, 90%, or 100% as compared to a level of insulin release from a control cell not administered the PKa. In some embodiments, increasing insulin release from pancreatic islet cells administered the PKa comprises increasing a level of insulin release by at most 10%, at most 20%, at most 30%, at most 40%, at most 50%, at most 60%, at most 70%, at most 80%, at most 90%, or at most 100% as compared to a level of insulin release from a control cell not administered the PKa. In some embodiments, increasing insulin release from pancreatic islet cells administered the PKa comprises increasing a level of insulin release by between 10% and 100%, between 20% and 100%, between 30% and 100%, between 40% and 100%, between 50% and 100%, between 60% and 100%, between 70% and 100%, between 80% and 100%, and between 90% and 100% as compared to a level of insulin release from a control cell not administered the PKa. In some embodiments, the PKa is TEPP-46. In some embodiments, the PKa is mitapivat. In some embodiments, the PKa is etavopivat. In some embodiments, the PKa is a compound represented by Formula A as described above.

[0462] In some aspects, provided herein are methods of improving pancreatic islet function in a subject in need thereof. In some embodiments, the method comprises administering to the subject a PK activator and a NuSH receptor modulator. In some embodiments, the method comprises administering to the subject a PKa, wherein the subject has been previously administered a NuSH receptor modulator. In some embodiments, the method comprises administering to the subject a NuSH receptor modulator, wherein the subject has been previously administered a PKa. In some embodiments, the method comprises administering an AMP kinase inhibitor, a phosphodiesterase (e.g., a PDE4B inhibitor), or a calcium channel inhibitor and a NuSH receptor modulator. In some embodiments, the method comprises administering to the subject an AMP kinase inhibitor, a phosphodiesterase inhibitor, or a calcium channel inhibitor, wherein the subject has been previously administered a NuSH receptor modulator. In some embodiments, the method comprises administering to the subject a NuSH receptor modulator, wherein the subject has been previously administered an AMP Attorney Docket No. 047162-7543WO1(02791)

[0463] kinase inhibitor, a phosphodiesterase inhibitor, or a calcium channel inhibitor. In some embodiments, improving pancreatic islet function comprises increasing insulin release from pancreatic islet cells. In some embodiments, increasing insulin release from pancreatic islet cells administered the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator comprises increasing a level of insulin release from pancreatic islet cells administered the combination of the PKa and NuSH receptor modulator or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and NuSH receptor modulator by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% as compared to a level of insulin release from a control cell not administered the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator. In some embodiments, increasing insulin release from pancreatic islet cells administered the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the, NuSH receptor modulator comprises increasing a level of insulin release by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% as compared to a level of insulin release from a control cell not administered the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator. In some embodiments, increasing insulin release from pancreatic islet cells administered the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator comprises increasing a level of insulin release by at most 10%, at most 20%, at most 30%, at most 40%, at most 50%, at most 60%, at most 70%, at most 80%, at most 90%, or at most 100% as compared to a level of insulin release from a control cell not administered the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator. In some embodiments, increasing insulin release from pancreatic islet cells administered the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator comprises increasing a level of insulin release by between 10% and 100%, between 20% and 100%, between 30% and 100%, between 40% and 100%, between 50% and Attorney Docket No. 047162-7543WO1(02791)

[0464] 100%, between 60% and 100%, between 70% and 100%, between 80% and 100%. and between 90% and 100% as compared to a level of insulin release from a control cell not administered the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is tirzepatide. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is tirzepatide. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is tirzepatide. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is tirzepatide. In some embodiments, the method comprises administering an AMP kinase inhibitor and the NuSH receptor modulator liraglutide. In some embodiments, the method comprises administering an AMP kinase inhibitor and the NuSH receptor modulator semaglutide. In some embodiments, the method comprises administering an AMP kinase inhibitor and the NuSH receptor modulator Orforglipron. In some embodiments, the method comprises administering an AMP kinase inhibitor and the NuSH receptor modulator tirzepatide. In some embodiments, the method comprises administering a phosphodiesterase inhibitor and the NuSH receptor modulator liraglutide. In some embodiments, the method comprises administering a phosphodiesterase inhibitor and the NuSH receptor modulator semaglutide. In some embodiments, the method comprises administering a phosphodiesterase inhibitor and the NuSH receptor modulator Orforglipron. In some embodiments, the method comprises administering a phosphodiesterase inhibitor and the NuSH receptor modulator tirzepatide. In Attorney Docket No. 047162-7543WO1(02791)

[0465] some embodiments, the method comprises administering a calcium channel inhibitor and the NuSH receptor modulator liraglutide. In some embodiments, the method comprises administering a calcium channel inhibitor and the NuSH receptor modulator semaglutide. In some embodiments, the method comprises administering a calcium channel inhibitor and the NuSH receptor modulator Orforglipron. In some embodiments, the method comprises administering a calcium channel inhibitor and the NuSH receptor modulator tirzepatide.

[0466] In some aspects, provided herein are methods of increasing insulin release in a subj ect in need thereof. In some embodiments, the method comprises administering to the subject a pyruvate kinase (PK) activator. In some embodiments, the PKa is administered as a monotherapy. In some embodiments, increasing insulin release when a subject is administered the PKa comprises increasing a level of insulin release by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% as compared to a level of insulin release when the subject is not administered the PKa. In some embodiments, increasing insulin release when a subject is administered the PKa comprises increasing a level of insulin release by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% as compared to a level of insulin release when the subject is not administered the PKa. In some embodiments, increasing insulin release when a subject is administered the PKa comprises increasing a level of insulin release by at most 10%, at most 20%, at most 30%, at most 40%, at most 50%, at most 60%, at most 70%, at most 80%, at most 90%, or at most 100% as compared to a level of insulin release when the subject is not administered the PKa. In some embodiments, increasing insulin release when a subject is administered the PKa comprises increasing a level of insulin release by between 10% and 100%, between 20% and 100%, between 30% and 100%, between 40% and 100%, between 50% and 100%, between 60% and 100%, between 70% and 100%, between 80% and 100%, and between 90% and 100% as compared to a level of insulin release when the subject is not administered the PKa. In some embodiments, the PKa is TEPP-46. In some embodiments, the PKa is mitapivat. In some embodiments, the PKa is etavopivat. In some embodiments, the PKa is a compound represented by Formula A as described above.

[0467] In some aspects, provided herein are methods of increasing insulin release in a subj ect in need thereof. In some embodiments, the method comprises administering to the subject a PK activator and a NuSH receptor modulator. In some embodiments, the method comprises administering to the subject a PKa, wherein the subject has been previously administered a NuSH receptor modulator. In some embodiments, the method comprises administering to the Attorney Docket No. 047162-7543WO1(02791)

[0468] subject a NuSH receptor modulator, wherein the subject has been previously administered a PKa. In some embodiments, the method comprises administering an AMP kinase inhibitor, a phosphodiesterase (e.g., a PDE4B inhibitor), or a calcium channel inhibitor and a NuSH receptor modulator. In some embodiments, the method comprises administering to the subject an AMP kinase inhibitor, a phosphodiesterase inhibitor, or a calcium channel inhibitor, wherein the subject has been previously administered a NuSH receptor modulator. In some embodiments, the method comprises administering to the subject a NuSH receptor modulator, wherein the subject has been previously administered an AMP kinase inhibitor, a phosphodiesterase inhibitor, or a calcium channel inhibitor. In some embodiments, increasing insulin release when a subject is administered the combination of the PKa and NuSH receptor modulator or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator comprises increasing a level of insulin release by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% as compared to a level of insulin release when the subject is not administered the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator. In some embodiments, increasing insulin release when a subj ect is administered the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator comprises increasing a level of insulin release by at most 10%, at most 20%, at most 30%, at most 40%, at most 50%, at most 60%, at most 70%, at most 80%, at most 90%, or at most 100% as compared to a level of insulin release when the subject is not administered the combination of the PKa and NuSH receptor modulator, or the combination of AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator. In some embodiments, increasing insulin release when a subject is administered the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator comprises increasing a level of insulin release by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% as compared to a level of insulin release when the subject is not administered the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator. In some embodiments, increasing insulin release when a subject is administered the combination of the PKa and NuSH receptor Attorney Docket No. 047162-7543WO1(02791)

[0469] modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator comprises increasing a level of insulin release by at between 10% and 100%, between 20% and 100%, between 30% and 100%, between 40% and 100%, between 50% and 100%, between 60% and 100%, between 70% and 100%, between 80% and 100%, or between 90% and 100% as compared to a level of insulin release when the subject is not administered the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is tirzepatide. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is tirzepatide. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is tirzepatide. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is tirzepatide. In some embodiments, the method comprises administering an AMP kinase inhibitor and the NuSH receptor modulator liraglutide. In some embodiments, the method comprises administering an AMP kinase inhibitor and the NuSH receptor modulator semaglutide. In some embodiments, the method comprises administering an AMP kinase inhibitor and the NuSH receptor modulator Orforglipron. In some embodiments, the method comprises administering an AMP kinase inhibitor and the NuSH receptor modulator tirzepatide. In some embodiments, the method comprises administering a phosphodiesterase inhibitor and the NuSH receptor modulator liraglutide. In some embodiments, the method comprises administering a phosphodiesterase inhibitor and the Attorney Docket No. 047162-7543WO1(02791)

[0470] NuSH receptor modulator semaglutide. In some embodiments, the method comprises administering a phosphodiesterase inhibitor and the NuSH receptor modulator Orforglipron. In some embodiments, the method comprises administering a phosphodiesterase inhibitor and the NuSH receptor modulator tirzepatide. In some embodiments, the method comprises administering a calcium channel inhibitor and the NuSH receptor modulator liraglutide. In some embodiments, the method comprises administering a calcium channel inhibitor and the NuSH receptor modulator semaglutide. In some embodiments, the method comprises administering a calcium channel inhibitor and the NuSH receptor modulator Orforglipron. In some embodiments, the method comprises administering a calcium channel inhibitor and the NuSH receptor modulator tirzepatide.

[0471] In some aspects, provided herein are methods of reducing insulin resistance in a subject in need thereof. In some embodiments, the method comprises administering to the subject a pyruvate kinase (PK) activator. In some embodiments, the PKa is administered as a monotherapy. In some embodiments, reducing insulin resistance when a subject is administered the PKa comprises reducing a level of insulin resistance by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% as compared to a level of insulin resistance when the subject is not administered the PKa. In some embodiments, reducing insulin resistance when a subject is administered the PKa comprises reducing a level of insulin resistance by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% as compared to a level of insulin resistance when the subject is not administered the PKa. In some embodiments, reducing insulin resistance when a subject is administered the PKa comprises reducing a level of insulin resistance by at most 10%, at most 20%, at most 30%, at most 40%, at most 50%, at most 60%, at most 70%, at most 80%, at most 90%, or at most 100% as compared to a level of insulin resistance when the subject is not administered the PKa. In some embodiments, reducing insulin resistance when a subject is administered the PKa comprises reducing a level of insulin resistance by between 10% and 100%, between 20% and 100%, between 30% and 100%, between 40% and 100%, between 50% and 100%, between 60% and 100%, between 70% and 100%, between 80% and 100%, and between 90% and 100% as compared to a level of insulin resistance when the subject is not administered the PKa. In some embodiments, the PKa is TEPP-46. In some embodiments, the PKa is mitapivat. In some embodiments, the PKa is etavopivat. In some embodiments, the PKa is a compound represented by Formula A as described above. Attorney Docket No. 047162-7543WO1(02791)

[0472] In some aspects, provided herein are methods of reducing insulin resistance in a subject in need thereof. In some embodiments, the method comprises administering to the subject a PK activator and a NuSH receptor modulator. In some embodiments, the method comprises administering to the subject a PKa, wherein the subject has been previously administered a NuSH receptor modulator. In some embodiments, the method comprises administering to the subject a NuSH receptor modulator, wherein the subject has been previously administered a PKa. In some embodiments, the method comprises administering an AMP kinase inhibitor, a phosphodiesterase (e.g., a PDE4B inhibitor), or a calcium channel inhibitor and a NuSH receptor modulator. In some embodiments, the method comprises administering to the subject an AMP kinase inhibitor, a phosphodiesterase inhibitor, or a calcium channel inhibitor, wherein the subject has been previously administered a NuSH receptor modulator. In some embodiments, the method comprises administering to the subject a NuSH receptor modulator, wherein the subject has been previously administered an AMP kinase inhibitor, a phosphodiesterase inhibitor, or a calcium channel inhibitor. In some embodiments, reducing insulin resistance when a subject is administered the combination of the PKa and NuSH receptor modulator or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator comprises reducing a level of insulin resistance by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%. at least 90%, or at least 100% as compared to a level of insulin resistance when the subject is not administered the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator. In some embodiments, reducing insulin resistance when a subject is administered the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator comprises reducing a level of insulin resistance by at most 10%, at most 20%, at most 30%, at most 40%. at most 50%, at most 60%, at most 70%, at most 80%, at most 90%, or at most 100% as compared to a level of insulin resistance when the subject is not administered the combination of the PKa and NuSH receptor modulator, or the combination of AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator. In some embodiments, reducing insulin resistance when a subject is administered the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator comprises reducing a level of insulin Attorney Docket No. 047162-7543WO1(02791)

[0473] resistance by 10%. 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% as compared to a level of insulin resistance when the subject is not administered the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator. In some embodiments, reducing insulin resistance when a subject is administered the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator comprises reducing a level of insulin resistance by at between 10% and 100%, between 20% and 100%, between 30% and 100%, between 40% and 100%, between 50% and 100%, between 60% and 100%. between 70% and 100%, between 80% and 100%, or between 90% and 100% as compared to a level of insulin resistance when the subject is not administered the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is tirzepatide. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is tirzepatide. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is tirzepatide. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is tirzepatide. In some embodiments, the method comprises administering an AMP kinase inhibitor and the NuSH receptor modulator liraglutide. In some embodiments, the method comprises administering an AMP kinase inhibitor and the NuSH receptor modulator semaglutide. In some Attorney Docket No. 047162-7543WO1(02791)

[0474] embodiments, the method comprises administering an AMP kinase inhibitor and the NuSH receptor modulator Orforglipron. In some embodiments, the method comprises administering an AMP kinase inhibitor and the NuSH receptor modulator tirzepatide. In some embodiments, the method comprises administering a phosphodiesterase inhibitor and the NuSH receptor modulator liraglutide. In some embodiments, the method comprises administering a phosphodiesterase inhibitor and the NuSH receptor modulator semaglutide. In some embodiments, the method comprises administering a phosphodiesterase inhibitor and the NuSH receptor modulator Orforglipron. In some embodiments, the method comprises administering a phosphodiesterase inhibitor and the NuSH receptor modulator tirzepatide. In some embodiments, the method comprises administering a calcium channel inhibitor and the NuSH receptor modulator liraglutide. In some embodiments, the method comprises administering a calcium channel inhibitor and the NuSH receptor modulator semaglutide. In some embodiments, the method comprises administering a calcium channel inhibitor and the NuSH receptor modulator Orforglipron. In some embodiments, the method comprises administering a calcium channel inhibitor and the NuSH receptor modulator tirzepatide.

[0475] In some aspects, provided herein are methods of improving glucose tolerance in a subject in need thereof by administering a monotherapy. In some embodiments, the method comprises administering to the subject a pyruvate kinase (PK) activator. In some embodiments, the PKa is administered as a monotherapy. In some embodiments, improving glucose tolerance comprises reducing glucose levels to a baseline level when the PKa is administered within 240 minutes, within 180 minutes, within 120 minutes, within 90 minutes, within 60 minutes, or within 30 minutes. In some embodiments, the baseline level is substantially similar to a level of glucose measured in the subject following a six -hour fast. In some embodiments, the PKa is TEPP-46. In some embodiments, the PKa is mitapivat. In some embodiments, the PKa is etavopivat. In some embodiments, the PKa is a compound represented by Formula A as described above.

[0476] In some aspects, provided herein are methods of improving glucose tolerance in a subject in need thereof. In some embodiments, the method comprises administering a PKa and a NuSH receptor modulator. In some embodiments, the method comprises administering to the subject a PKa, wherein the subject has been previously administered a NuSH receptor modulator. In some embodiments, the method comprises administering to the subject a NuSH receptor modulator, wherein the subject has been previously administered a PKa. In some embodiments, the method comprises administering an AMP kinase inhibitor, a Attorney Docket No. 047162-7543WO1(02791)

[0477] phosphodiesterase (e.g., a PDE4B inhibitor), or a calcium channel inhibitor and a NuSH receptor modulator. In some embodiments, the method comprises administering to the subject an AMP kinase inhibitor, a phosphodiesterase inhibitor, or a calcium channel inhibitor, wherein the subject has been previously administered a NuSH receptor modulator. In some embodiments, the method comprises administering to the subject a NuSH receptor modulator, wherein the subject has been previously administered an AMP kinase inhibitor, a phosphodiesterase inhibitor, or a calcium channel inhibitor. In some embodiments, improving glucose tolerance comprises reducing glucose levels to a baseline level when the combination of the PKa and NuSH receptor modulator or the combination of the AMP kinase inhibitor, phosphodiesterase inhibitor, or calcium channel inhibitor and NuSH receptor modulator within 240 minutes, within 180 minutes, within 120 minutes, within 90 minutes, within 60 minutes, or within 30 minutes. In some embodiments, the baseline level is substantially similar to a level of glucose measured in the subject following a six-hour fast. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is tirzepatide. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is tirzepatide. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is tirzepatide. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is tirzepatide. In some embodiments, the method comprises administering an AMP kinase inhibitor and the NuSH receptor modulator liraglutide. In some embodiments, the method comprises administering an AMP kinase inhibitor and the NuSH receptor modulator semaglutide. In some embodiments, the method comprises administering an AMP kinase Attorney Docket No. 047162-7543WO1(02791)

[0478] inhibitor and the NuSH receptor modulator Orforglipron. In some embodiments, the method comprises administering an AMP kinase inhibitor and the NuSH receptor modulator tirzepatide. In some embodiments, the method comprises administering a phosphodiesterase inhibitor and the NuSH receptor modulator liraglutide. In some embodiments, the method comprises administering a phosphodiesterase inhibitor and the NuSH receptor modulator semaglutide. In some embodiments, the method comprises administering a phosphodiesterase inhibitor and the NuSH receptor modulator Orforglipron. In some embodiments, the method comprises administering a phosphodiesterase inhibitor and the NuSH receptor modulator tirzepatide. In some embodiments, the method comprises administering a calcium channel inhibitor and the NuSH receptor modulator liraglutide. In some embodiments, the method comprises administering a calcium channel inhibitor and the NuSH receptor modulator semaglutide. In some embodiments, the method comprises administering a calcium channel inhibitor and the NuSH receptor modulator Orforglipron. In some embodiments, the method comprises administering a calcium channel inhibitor and the NuSH receptor modulator tirzepatide.

[0479] In some aspects, provided herein are methods of reducing blood glucose levels and / or blood lipid levels in a subject in need thereof. In some embodiments, the method comprises administering to the subject a pyruvate kinase (PK) activator. In some embodiments, reducing blood glucose levels comprises reducing a level of blood glucose when the PKa is administered by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% as compared to a control level of blood glucose measured when the PKa is not administered. In some embodiments, reducing blood glucose levels comprises reducing a level of blood glucose when the PKa is administered by at most 10%, at most 20%, at most 30%, at most 40%, at most 50%, at most 60%, at most 70%, at most 80%, at most 90%, or at most 100% as compared to a control level of blood glucose measured when the PKa is not administered. In some embodiments, reducing blood glucose levels comprises reducing a level of blood glucose when the PKa is administered by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% as compared to a control level of blood glucose measured when the PKa is not administered. In some embodiments, reducing blood glucose levels comprises reducing a level of blood glucose when the PKa is administered by between 10% and 100%. between 20% and 100%, between 30% and 100%, between 40% and 100%, between 50% and 100%, between 60% and 100%, between 70% and 100%, between 80% and 100%, and between 90% and 100% as compared to a control level of blood glucose Attorney Docket No. 047162-7543WO1(02791)

[0480] measured when the PKa is not administered. In some embodiments, reducing blood lipid levels comprises reducing a level of blood lipids when the PKa is administered by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% as compared to a control level of blood lipids measured when the PKa is not administered measured. In some embodiments, reducing blood lipid levels comprises reducing a level of blood lipids when the PKa is administered by at most 10%, at most 20%, at most 30%, at most 40%, at most 50%, at most 60%, at most 70%, at most 80%, at most 90%, or at most 100% as compared to a control level of blood lipids measured when the PKa is not administered. In some embodiments, reducing blood lipid levels comprises reducing a level of blood lipids when PKa is administered by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% as compared to a control level of blood lipids measured when the PKa is not administered. In some embodiments, reducing blood lipid levels comprises reducing a level of blood lipids when PKa is administered by between 10% and 100%, between 20% and 100%, between 30% and 100%. between 40% and 100%, between 50% and 100%, between 60% and 100%, between 70% and 100%, between 80% and 100%, and between 90% and 100% as compared to a control level of blood lipids measured when the PKa is not administered. In some embodiments, the PKa is TEPP-46. In some embodiments, the PKa is mitapivat. In some embodiments, the PKa is etavopivat. In some embodiments, the PKa is a compound represented by Formula A as described above.

[0481] In some aspects, provided herein are methods of reducing blood glucose levels and / or blood lipid levels in a subject in need thereof. In some embodiments, the method comprises administering to the subject a PK activator and a NuSH receptor modulator. In some embodiments, the method comprises administering to the subject a PKa, wherein the subject has been previously administered a NuSH receptor modulator. In some embodiments, the method comprises administering to the subject a NuSH receptor modulator, wherein the subject has been previously administered a PKa. In some embodiments, the method comprises administering an AMP kinase inhibitor, a phosphodiesterase (e.g., a PDE4B inhibitor), or a calcium channel inhibitor and a NuSH receptor modulator. In some embodiments, the method comprises administering to the subject an AMP kinase inhibitor, a phosphodiesterase inhibitor, or a calcium channel inhibitor, wherein the subject has been previously administered a NuSH receptor modulator. In some embodiments, the method comprises administering to the subject a NuSH receptor modulator, wherein the subject has been previously administered an AMP kinase inhibitor, a phosphodiesterase inhibitor, or a calcium channel inhibitor. In some embodiments, reducing blood glucose levels comprises reducing a level of blood glucose when Attorney Docket No. 047162-7543WO1(02791)

[0482] the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator is administered by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% as compared to a control level of blood glucose measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator is not administered. In some embodiments, reducing blood glucose levels comprises reducing a level of blood glucose when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator is administered by at most 10%, at most 20%, at most 30%, at most 40%, at most 50%, at most 60%, at most 70%, at most 80%, at most 90%, or at most 100% as compared to a control level of blood glucose measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator is not administered. In some embodiments, reducing blood glucose levels comprises reducing a level of blood glucose when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator is administered by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% as compared to a control level of blood glucose measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator is not administered. In some embodiments, reducing blood glucose levels comprises reducing a level of blood glucose when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator is administered by between 10% and 100%, between 20% and 100%, between 30% and 100%, between 40% and 100%, between 50% and 100%, between 60% and 100%, between 70% and 100%, between 80% and 100%, and between 90% and 100% as compared to a control level of blood glucose measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator is not administered. In some embodiments, reducing blood lipid levels comprises reducing a level of blood lipids when the combination of the PKa and NuSH receptor modulator, or the Attorney Docket No. 047162-7543WO1(02791)

[0483] combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator is administered by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% as compared to a control level of blood lipids measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator is not administered measured. In some embodiments, reducing blood lipid levels comprises reducing a level of blood lipids when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator is administered by at most 10%, at most 20%, at most 30%, at most 40%, at most 50%, at most 60%, at most 70%, at most 80%, at most 90%, or at most 100% as compared to a control level of blood lipids measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator is not administered. In some embodiments, reducing blood lipid levels comprises reducing a level of blood lipids when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator is administered by 10%, 20%, 30%. 40%. 50%. 60%. 70%. 80%. 90%. or 100% as compared to a control level of blood lipids measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator is not administered. In some embodiments, reducing blood lipid levels comprises reducing a level of blood lipids when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator is administered by between 10% and 100%, between 20% and 100%, between 30% and 100%. between 40% and 100%, between 50% and 100%, between 60% and 100%, between 70% and 100%, between 80% and 100%, and between 90% and 100% as compared to a control level of blood lipids measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator is not administered. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is TEPP-46 and the NuSH receptor Attorney Docket No. 047162-7543WO1(02791)

[0484] modulator is Orforglipron. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is tirzepatide. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is tirzepatide. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is tirzepatide. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is tirzepatide. In some embodiments, the method comprises administering an AMP kinase inhibitor and the NuSH receptor modulator liraglutide. In some embodiments, the method comprises administering an AMP kinase inhibitor and the NuSH receptor modulator semaglutide. In some embodiments, the method comprises administering an AMP kinase inhibitor and the NuSH receptor modulator Orforglipron. In some embodiments, the method comprises administering an AMP kinase inhibitor and the NuSH receptor modulator tirzepatide. In some embodiments, the method comprises administering a phosphodiesterase inhibitor and the NuSH receptor modulator liraglutide. In some embodiments, the method comprises administering a phosphodiesterase inhibitor and the NuSH receptor modulator semaglutide. In some embodiments, the method comprises administering a phosphodiesterase inhibitor and the NuSH receptor modulator Orforglipron. In some embodiments, the method comprises administering a phosphodiesterase inhibitor and the NuSH receptor modulator tirzepatide. In some embodiments, the method comprises administering a calcium channel inhibitor and the NuSH receptor modulator liraglutide. In some embodiments, the method comprises administering a calcium channel inhibitor and the NuSH receptor modulator semaglutide. In some embodiments, the method comprises administering a calcium channel inhibitor and the NuSH receptor modulator Orforglipron. In some embodiments, the method comprises administering a calcium channel inhibitor and the NuSH receptor modulator tirzepatide. Attorney Docket No. 047162-7543WO1(02791)

[0485] In some aspects, provided herein are methods of reducing hepatic lipid levels in a subject in need thereof. In some embodiments, the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa). In some embodiments, reducing hepatic lipid levels comprises reducing a level of hepatic lipids when the PKa is administered by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%. at least 90%. or at least 100% as compared to a control level of hepatic lipids measured when the PKa is not administered. In some embodiments, reducing hepatic lipid levels comprises reducing a level of hepatic lipids when the PKa is administered by at most 10%, at most 20%, at most 30%, at most 40%, at most 50%, at most 60%, at most 70%, at most 80%, at most 90%. or at most 100% as compared to a control level of hepatic lipids measured when the PKa is not administered. In some embodiments, reducing hepatic lipid levels comprises reducing a level of hepatic lipids when the PKa is administered by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% as compared to a control level of hepatic lipids measured when the PKa is not administered. In some embodiments, reducing hepatic lipid levels comprises reducing a level of hepatic lipids when the PKa is administered by between 10% and 100%, between 20% and 100%, between 30% and 100%, between 40% and 100%, between 50% and 100%, between 60% and 100%, between 70% and 100%, between 80% and 100%, or between 90%, and 100% as compared to a control level of hepatic lipids measured when the PKa is not administered. In some embodiments, the PKa is TEPP-46. In some embodiments, the PKa is mitapivat. In some embodiments, the PKa is etavopivat. In some embodiments, the PKa is a compound represented by Formula A as described above.

[0486] In some aspects, provided herein are methods of reducing hepatic lipid levels in a subject in need thereof. In some embodiments, the method comprises administering to the subject a PK activator and a NuSH receptor modulator. In some embodiments, the method comprises administering to the subject a PKa, wherein the subject has been previously administered a NuSH receptor modulator. In some embodiments, the method comprises administering to the subject a NuSH receptor modulator, wherein the subject has been previously administered a PKa. In some embodiments, the method comprises administering an AMP kinase inhibitor, a phosphodiesterase (e.g., a PDE4B inhibitor), or a calcium channel inhibitor and a NuSH receptor modulator. In some embodiments, the method comprises administering to the subject an AMP kinase inhibitor, a phosphodiesterase inhibitor, or a calcium channel inhibitor, wherein the subject has been previously administered a NuSH receptor modulator. In some embodiments, the method comprises administering to the subject a NuSH receptor modulator, wherein the subject has been previously administered an AMP Attorney Docket No. 047162-7543WO1(02791)

[0487] kinase inhibitor, a phosphodiesterase inhibitor, or a calcium channel inhibitor.. In some embodiments, reducing hepatic lipid levels comprises reducing a level of hepatic lipids when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator is administered by at least 10%, at least 20%, at least 30%, at least 40%. at least 50%. at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% as compared to a control level of hepatic lipids measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator is not administered. In some embodiments, reducing hepatic lipid levels comprises reducing a level of hepatic lipids when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator is administered by at most 10%, at most 20%, at most 30%, at most 40%, at most 50%, at most 60%, at most 70%, at most 80%, at most 90%, or at most 100% as compared to a control level of hepatic lipids measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator is not administered. In some embodiments, reducing hepatic lipid levels comprises reducing a level of hepatic lipids when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator is administered by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% as compared to a control level of hepatic lipids measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator is not administered. In some embodiments, reducing hepatic lipid levels comprises reducing a level of hepatic lipids when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator is administered by between 10% and 100%, between 20% and 100%, between 30% and 100%, between 40% and 100%, between 50% and 100%, between 60% and 100%, between 70% and 100%, between 80% and 100%, or between 90%, and 100% as compared to a control level of hepatic lipids measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator is not administered. In some embodiments, Attorney Docket No. 047162-7543WO1(02791)

[0488] the PKa is TEPP-46 and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is tirzepatide. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is tirzepatide. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is tirzepatide. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is tirzepatide. In some embodiments, the method comprises administering an AMP kinase inhibitor and the NuSH receptor modulator liraglutide. In some embodiments, the method comprises administering an AMP kinase inhibitor and the NuSH receptor modulator semaglutide. In some embodiments, the method comprises administering an AMP kinase inhibitor and the NuSH receptor modulator Orforglipron. In some embodiments, the method comprises administering an AMP kinase inhibitor and the NuSH receptor modulator tirzepatide. In some embodiments, the method comprises administering a phosphodiesterase inhibitor and the NuSH receptor modulator liraglutide. In some embodiments, the method comprises administering a phosphodiesterase inhibitor and the NuSH receptor modulator semaglutide. In some embodiments, the method comprises administering a phosphodiesterase inhibitor and the NuSH receptor modulator Orforglipron. In some embodiments, the method comprises administering a phosphodiesterase inhibitor and the NuSH receptor modulator tirzepatide. In some embodiments, the method comprises administering a calcium channel inhibitor and the NuSH receptor modulator liraglutide. In some embodiments, the method comprises administering a calcium channel inhibitor and the NuSH receptor modulator semaglutide. In some embodiments, the method comprises administering a calcium channel inhibitor and the NuSH receptor modulator Orforglipron. In some embodiments, the method Attorney Docket No. 047162-7543WO1(02791)

[0489] comprises administering a calcium channel inhibitor and the NuSH receptor modulator tirzepatide.

[0490] In some aspects, provided herein are methods of reducing fat mass in a subject in need thereof. In some embodiments, the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa). In some embodiments, the PKa is administered as a monotherapy. In some embodiments, reducing fat mass comprises reducing a level of fat mass measured when the PKa is administered by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%. at least 65%, at least 70%, at least 75%, or at least 80% as compared to a level of fat mass measured when the PKa is not administered. In some embodiments, reducing fat mass comprises reducing a level of fat mass measured when the PKa is administered by at most 5%, at most 10%, at most 15%, at most 20%, at most 25%, at most 30%, at most 35%, at most 40%, at most 45%, at most 50%, at most 55%, at most 60%, at most 65%, at most 70%, at most 75%, or at most 80% as compared to a level of fat mass measured when the PKa is not administered. In some embodiments, reducing fat mass comprises reducing a level of fat mass measured when the PKa is administered by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%. or 80% as compared to a level of fat mass measured when the PKa is not administered. In some embodiments, reducing fat mass comprises reducing a level of fat mass measured when the PKa is administered by between 5% and 80%, between 10% and 80%, between 15% and 80%, between 20% and 80%, between 25% and 80%, between 30% and 80%, between 35% and 80%, between 40 % and 80%, between 45% and 80%, between 50% and 80%, between 55% and 80%. between 60 % and 80%, between 65% and 80%. between 70% and 80%, or between 75% and 80% as compared to a level of fat mass measured when the PKa is administered. In some embodiments, the PKa is TEPP-46. In some embodiments, the PKa is mitapivat. In some embodiments, the PKa is etavopivat. In some embodiments, the PKa is a compound represented by Formula A as described above.

[0491] In some aspects, provided herein are methods of reducing fat mass in a subject in need thereof. In some embodiments, the method comprises administering to the subject a PK activator and a NuSH receptor modulator. In some embodiments, the method comprises administering to the subject a PKa, wherein the subject has been previously administered a NuSH receptor modulator. In some embodiments, the method comprises administering to the subject a NuSH receptor modulator, wherein the subject has been previously administered a PKa. In some embodiments, the method comprises administering an AMP kinase inhibitor, a Attorney Docket No. 047162-7543WO1(02791)

[0492] phosphodiesterase (e.g., a PDE4B inhibitor), or a calcium channel inhibitor and a NuSH receptor modulator. In some embodiments, the method comprises administering to the subject an AMP kinase inhibitor, a phosphodiesterase inhibitor, or a calcium channel inhibitor, wherein the subject has been previously administered a NuSH receptor modulator. In some embodiments, the method comprises administering to the subject a NuSH receptor modulator, wherein the subject has been previously administered an AMP kinase inhibitor, a phosphodiesterase inhibitor, or a calcium channel inhibitor. In some embodiments, reducing fat mass comprises reducing a level of fat mass measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator are administered by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, or at least 80% as compared to a level of fat mass measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator are not administered. In some embodiments, reducing fat mass comprises reducing a level of fat mass measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator are administered by at most 5%, at most 10%, at most 15%, at most 20%, at most 25%, at most 30%, at most 35%, at most 40%, at most 45%, at most 50%, at most 55%, at most 60%, at most 65%, at most 70%, at most 75%, or at most 80% as compared to a level of fat mass measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator are not administered. In some embodiments, reducing fat mass comprises reducing a level of fat mass measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator are administered by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% as compared to a level of fat mass measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator are not administered. In some embodiments, reducing fat mass comprises reducing a level of fat mass measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase Attorney Docket No. 047162-7543WO1(02791)

[0493] inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator are administered by between 5% and 80%, between 10% and 80%, between 15% and 80%, between 20% and 80%, between 25% and 80%, between 30% and 80%, between 35% and 80%, between 40 % and 80%, between 45% and 80%, between 50% and 80%, between 55% and 80%, between 60 % and 80%. between 65% and 80%, between 70% and 80%. or between 75% and 80% as compared to a level of fat mass measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator are not administered. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is tirzepatide. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is tirzepatide. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is tirzepatide. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is tirzepatide. In some embodiments, the method comprises administering an AMP kinase inhibitor and the NuSH receptor modulator liraglutide. In some embodiments, the method comprises administering an AMP kinase inhibitor and the NuSH receptor modulator semaglutide. In some embodiments, the method comprises administering an AMP kinase inhibitor and the NuSH receptor modulator Orforglipron. In some embodiments, the method comprises administering an AMP kinase inhibitor and the NuSH receptor modulator tirzepatide. In some embodiments, the method comprises administering a phosphodiesterase inhibitor and the NuSH receptor modulator liraglutide. In some embodiments, the method Attorney Docket No. 047162-7543WO1(02791)

[0494] comprises administering a phosphodiesterase inhibitor and the NuSH receptor modulator semaglutide. In some embodiments, the method comprises administering a phosphodiesterase inhibitor and the NuSH receptor modulator Orforglipron. In some embodiments, the method comprises administering a phosphodiesterase inhibitor and the NuSH receptor modulator tirzepatide. In some embodiments, the method comprises administering a calcium channel inhibitor and the NuSH receptor modulator liraglutide. In some embodiments, the method comprises administering a calcium channel inhibitor and the NuSH receptor modulator semaglutide. In some embodiments, the method comprises administering a calcium channel inhibitor and the NuSH receptor modulator Orforglipron. In some embodiments, the method comprises administering a calcium channel inhibitor and the NuSH receptor modulator tirzepatide.

[0495] In some aspects, provided herein are methods of increasing muscle mass in a subject in need thereof. In some embodiments, the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa). In some embodiments, the PKa is administered as a monotherapy. In some embodiments, increasing muscle comprises increasing a level of muscle mass measured when the PKa is administered by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%. at least 60%. at least 65%. at least 70%. at least 75%. at least 80%. at least 85%, at least 90%, at least 95%, or at least 100% as compared to a level of muscle mass measured when the PKa is not administered. In some embodiments, increasing muscle comprises increasing a level of muscle mass measured when the PKa administered by at most 5%, at most 10%, at most 15%, at most 20%. at most 25%. at most 30%, at most 35%, at most 40%, at most 45%, at most 50%, at most 55%, at most 60%, at most 65%, at most 70%, at most 75%, at most 80%, at most 85%, at most 90%, at most 95%, or at most 100% as compared to a level of muscle mass measured when the PKa is not administered. In some embodiments, increasing muscle comprises increasing a level of muscle mass measured when the PKa is administered by 5%, 10%. 15%. 20%. 25%. 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%.

[0496] 90%, 95%, or 100% as compared to a level of muscle mass measured when the PKa is not administered. In some embodiments, increasing muscle comprises increasing a level of muscle mass measured when the PKa is administered by between 5% and 100%, between 10% and 100%, between 15% and 100%. between 20% and 100%, between 25% and 100%. between 30% and 100%, between 35% and 100%, between 40% and 100%, between 45% and 100%, between 50% and 100%, between 55% and 100%, between 60% and 100%, between 65% and Attorney Docket No. 047162-7543WO1(02791)

[0497] 100%, between 70% and 100%. between 75% and 100%, between 80% and 100%. between 85% and 100%, between 90% and 100%, or between 95% and 100% as compared to a level of muscle mass measured when the PKa is not administered. In some embodiments, the PKa is TEPP-46. In some embodiments, the PKa is mitapivat. In some embodiments, the PKa is etavopivat. In some embodiments, the PKa is a compound represented by Formula A as described above. In some embodiments, increasing muscle mass may be used to address a disease or a condition, wherein the disease or condition is selected from age-related sarcopenia, frailty syndrome, cachexia associated with cancer, cachexia associated with other conditions such as heart failure, chronic kidney disease, chronic obstructive pulmonary disease, AIDS-related wasting, neuromuscular disorders such as muscular dystrophies, glucocorticoid-induced muscle atrophy, disuse atrophy following immobilization, osteoporosis with associated muscle weakness, recovery following major surgery or trauma, metabolic disorders characterized by loss of lean mass such as sarcopenic obesity, bariatric procedures such as gastric bypass surgery, muscle atrophy associated with hypothyroidism or hypogonadism, muscle atrophy induced by chemotherapy or radiation therapy, neuromuscular disorders such as motor neuron disease (ALS) and muscular dystrophy, gastrointestinal disorders of malabsorption such as inflammatory bowel disease, disorders associated with excess loss of nutrients such as Fanconi syndrome and SGLT2 deficiency, critical illness myopathy, and conditions requiring improved physical function including rehabilitation following orthopedic injury or prolonged hospitalization.

[0498] In some aspects, provided herein are methods of increasing muscle mass in a subject in need thereof. In some embodiments, the method comprises administering to the subject a PK activator and a NuSH receptor modulator. In some embodiments, the method comprises administering to the subject a PKa, wherein the subject has been previously administered a NuSH receptor modulator. In some embodiments, the method comprises administering to the subject a NuSH receptor modulator, wherein the subject has been previously administered a PKa. In some embodiments, the method comprises administering an AMP kinase inhibitor, a phosphodiesterase (e.g., a PDE4B inhibitor), or a calcium channel inhibitor and a NuSH receptor modulator. In some embodiments, the method comprises administering to the subject an AMP kinase inhibitor, a phosphodiesterase inhibitor, or a calcium channel inhibitor, wherein the subject has been previously administered a NuSH receptor modulator. In some embodiments, the method comprises administering to the subject a NuSH receptor modulator, wherein the subject has been previously administered an AMP kinase inhibitor, a phosphodiesterase inhibitor, or a calcium channel inhibitor. In some embodiments, increasing Attorney Docket No. 047162-7543WO1(02791)

[0499] muscle comprises increasing a level of muscle mass measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator are administered by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%. at least 70%. at least 75%, at least 80%, at least 85%, at least 90%, at least 95%. or at least 100% as compared to a level of muscle mass measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator are not administered. In some embodiments, increasing muscle comprises increasing a level of muscle mass measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and NuSH receptor modulator are administered by at most 5%, at most 10%, at most 15%, at most 20%, at most 25%, at most 30%, at most 35%, at most 40%, at most 45%, at most 50%, at most 55%, at most 60%, at most 65%, at most 70%, at most 75%, at most 80%, at most 85%, at most 90%, at most 95%, or at most 100% as compared to a level of muscle mass measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and NuSH receptor modulator are not administered. In some embodiments, increasing muscle comprises increasing a level of muscle mass measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and NuSH receptor modulator are administered by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% as compared to a level of muscle mass measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and NuSH receptor modulator are not administered. In some embodiments, increasing muscle comprises increasing a level of muscle mass measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and NuSH receptor modulator are administered by between 5% and 100%, between 10% and 100%, between 15% and 100%, between 20% and 100%. between 25% and 100%, between 30% and 100%, between 35% and 100%, between 40% and 100%, between 45% and 100%, between 50% and 100%, between 55% and 100%, between 60% and 100%, between 65% and 100%, between 70% and 100%, Attorney Docket No. 047162-7543WO1(02791)

[0500] between 75% and 100%. between 80% and 100%, between 85% and 100%, between 90% and 100%, or between 95% and 100% as compared to a level of muscle mass measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and NuSH receptor modulator are not administered. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is tirzepatide. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is tirzepatide. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is tirzepatide. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is tirzepatide. In some embodiments, the method comprises administering an AMP kinase inhibitor and the NuSH receptor modulator liraglutide. In some embodiments, the method comprises administering an AMP kinase inhibitor and the NuSH receptor modulator semaglutide. In some embodiments, the method comprises administering an AMP kinase inhibitor and the NuSH receptor modulator Orforglipron. In some embodiments, the method comprises administering an AMP kinase inhibitor and the NuSH receptor modulator tirzepatide. In some embodiments, the method comprises administering a phosphodiesterase inhibitor and the NuSH receptor modulator liraglutide. In some embodiments, the method comprises administering a phosphodiesterase inhibitor and the NuSH receptor modulator semaglutide. In some embodiments, the method comprises administering a phosphodiesterase inhibitor and the NuSH receptor modulator Orforglipron. In some embodiments, the method comprises administering a phosphodiesterase inhibitor and the NuSH receptor modulator tirzepatide. In Attorney Docket No. 047162-7543WO1(02791)

[0501] some embodiments, the method comprises administering a calcium channel inhibitor and the NuSH receptor modulator liraglutide. In some embodiments, the method comprises administering a calcium channel inhibitor and the NuSH receptor modulator semaglutide. In some embodiments, the method comprises administering a calcium channel inhibitor and the NuSH receptor modulator Orforglipron. In some embodiments, the method comprises administering a calcium channel inhibitor and the NuSH receptor modulator tirzepatide. In some embodiments, increasing muscle mass may be used to address a disease or a condition, wherein the disease or condition is selected from age-related sarcopenia, frailty syndrome, cachexia associated with cancer, cachexia associated with other conditions such as heart failure, chronic kidney disease, chronic obstructive pulmonary disease, AIDS-related wasting, neuromuscular disorders such as muscular dystrophies, glucocorticoid-induced muscle atrophy, disuse atrophy following immobilization, osteoporosis with associated muscle weakness, recovery following major surgery or trauma, metabolic disorders characterized by loss of lean mass such as sarcopenic obesity, bariatric procedures such as gastric bypass surgery, muscle atrophy associated with hypothyroidism or hypogonadism, muscle atrophy induced by chemotherapy or radiation therapy, neuromuscular disorders such as motor neuron disease (ALS) and muscular dystrophy, gastrointestinal disorders of malabsorption such as inflammatory bowel disease, disorders associated with excess loss of nutrients such as Fanconi syndrome and SGLT2 deficiency, critical illness myopathy, and conditions requiring improved physical function including rehabilitation following orthopedic injury or prolonged hospitalization.

[0502] In some aspects, provided herein are methods of improving muscle function in a subject in need thereof. In some embodiments, the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa). In some embodiments, the PKa is administered as a monotherapy. In some embodiments, improving muscle function comprises increasing a level of muscle function measured when the PKa is administered by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100% as compared to a level of muscle function measured when the PKa is not administered. In some embodiments, improving muscle function comprises increasing a level of muscle function measured when the PKa administered by at most 5%, at most 10%, at most 15%, at most 20%, at most 25%, at most 30%, at most 35%, at most 40%, at most 45%, at most 50%, at most 55%, at most 60%, at most 65%, at most Attorney Docket No. 047162-7543WO1(02791)

[0503] 70%, at most 75%. at most 80%, at most 85%, at most 90%, at most 95%, or at most 100% as compared to a level of muscle function measured when the PKa is not administered. In some embodiments, improving muscle function comprises increasing a level of muscle function measured when the PKa is administered by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%. 65%. 70%. 75%, 80%, 85%, 90%, 95%, or 100% as compared to a level of muscle function measured when the PKa is not administered. In some embodiments, improving muscle function comprises increasing a level of muscle function measured when the PKa is administered by between 5% and 100%, between 10% and 100%, between 15% and 100%, between 20% and 100%, between 25% and 100%, between 30% and 100%, between 35% and 100%, between 40% and 100%. between 45% and 100%, between 50% and 100%. between 55% and 100%, between 60% and 100%, between 65% and 100%, between 70% and 100%, between 75% and 100%, between 80% and 100%, between 85% and 100%, between 90% and 100%, or between 95% and 100% as compared to a level of muscle function measured when the PKa is not administered. In some embodiments, muscle function is measured by the manual muscle testing (MMT) scale, dynamometry, tensiomyography (TMG), magnetic resonance imaging (MRI), computed tomography (CT), bioimpedance analysis (BIA), diagnostic ultrasound, handgrip strength, gait speed test, chair-rise test, or other assays known in the art. In some embodiments, the PKa is TEPP-46. In some embodiments, the PKa is mitapivat. In some embodiments, the PKa is etavopivat. In some embodiments, the PKa is a compound represented by Formula A as described above. In some embodiments, increasing muscle function may be used to address a disease or a condition, wherein the disease or condition is selected from age-related sarcopenia, frailty syndrome, cachexia associated with cancer, cachexia associated with other conditions such as heart failure, chronic kidney disease, chronic obstructive pulmonary disease, AIDS-related wasting, neuromuscular disorders such as muscular dystrophies, glucocorticoid-induced muscle atrophy, disuse atrophy following immobilization, osteoporosis with associated muscle weakness, recovery following major surgery or trauma, metabolic disorders characterized by loss of lean mass such as sarcopenic obesity, bariatric procedures such as gastnc bypass surgery, muscle atrophy associated with hypothyroidism or hypogonadism, muscle atrophy induced by chemotherapy or radiation therapy, neuromuscular disorders such as motor neuron disease (ALS) and muscular dystrophy, gastrointestinal disorders of malabsorption such as inflammatory bowel disease, disorders associated with excess loss of nutrients such as Fanconi syndrome and SGLT2 deficiency, critical illness myopathy, and conditions requiring improved physical function including rehabilitation following orthopedic injury or prolonged hospitalization. Attorney Docket No. 047162-7543WO1(02791)

[0504] In some aspects, provided herein are methods of improving muscle function in a subject in need thereof. In some embodiments, the method comprises administering to the subject a PK activator and a NuSH receptor modulator. In some embodiments, the method comprises administering to the subject a PKa, wherein the subject has been previously administered a NuSH receptor modulator. In some embodiments, the method comprises administering to the subject a NuSH receptor modulator, wherein the subject has been previously administered a PKa. In some embodiments, the method comprises administering an AMP kinase inhibitor, a phosphodiesterase (e.g., a PDE4B inhibitor), or a calcium channel inhibitor and a NuSH receptor modulator. In some embodiments, the method comprises administering to the subject an AMP kinase inhibitor, a phosphodiesterase inhibitor, or a calcium channel inhibitor, wherein the subject has been previously administered a NuSH receptor modulator. In some embodiments, the method comprises administering to the subject a NuSH receptor modulator, wherein the subject has been previously administered an AMP kinase inhibitor, a phosphodiesterase inhibitor, or a calcium channel inhibitor. In some embodiments, improving muscle function comprises increasing a level of muscle function measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator are administered by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100% as compared to a level of muscle function measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator are not administered. In some embodiments, improving muscle function comprises increasing a level of muscle function measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and NuSH receptor modulator are administered by at most 5%, at most 10%, at most 15%, at most 20%, at most 25%, at most 30%, at most 35%, at most 40%, at most 45%, at most 50%, at most 55%, at most 60%, at most 65%, at most 70%, at most 75%, at most 80%, at most 85%, at most 90%, at most 95%, or at most 100% as compared to a level of muscle function measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and NuSH receptor modulator are not administered. In some embodiments, improving muscle function comprises increasing a Attorney Docket No. 047162-7543WO1(02791)

[0505] level of muscle function measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and NuSH receptor modulator are administered by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% as compared to a level of muscle function measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and NuSH receptor modulator are not administered. In some embodiments, improving muscle function comprises increasing a level of muscle function measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and NuSH receptor modulator are administered by between 5% and 100%, between 10% and 100%, between 15% and 100%, between 20% and 100%, between 25% and 100%, between 30% and 100%, between 35% and 100%, between 40% and 100%, between 45% and 100%. between 50% and 100%, between 55% and 100%, between 60% and 100%, between 65% and 100%, between 70% and 100%, between 75% and 100%, between 80% and 100%, between 85% and 100%, between 90% and 100%, or between 95% and 100% as compared to a level of muscle function measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and NuSH receptor modulator are not administered. In some embodiments, muscle function is measured by the manual muscle testing (MMT) scale, dynamometry,, tensiomyography (TMG), magnetic resonance imaging (MRI), computed tomography (CT), bioimpedance analysis (BIA), diagnostic ultrasound, handgrip strength, gait speed test, chair-rise test, or other assays known in the art. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is tirzepatide. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is tirzepatide. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is mitapivat Attorney Docket No. 047162-7543WO1(02791)

[0506] and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is tirzepatide. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is tirzepatide. In some embodiments, the method comprises administering an AMP kinase inhibitor and the NuSH receptor modulator liraglutide. In some embodiments, the method comprises administering an AMP kinase inhibitor and the NuSH receptor modulator semaglutide. In some embodiments, the method comprises administering an AMP kinase inhibitor and the NuSH receptor modulator Orforglipron. In some embodiments, the method comprises administering an AMP kinase inhibitor and the NuSH receptor modulator tirzepatide. In some embodiments, the method comprises administering a phosphodiesterase inhibitor and the NuSH receptor modulator liraglutide. In some embodiments, the method comprises administering a phosphodiesterase inhibitor and the NuSH receptor modulator semaglutide. In some embodiments, the method comprises administering a phosphodiesterase inhibitor and the NuSH receptor modulator Orforglipron. In some embodiments, the method comprises administering a phosphodiesterase inhibitor and the NuSH receptor modulator tirzepatide. In some embodiments, the method comprises administering a calcium channel inhibitor and the NuSH receptor modulator liraglutide. In some embodiments, the method comprises administering a calcium channel inhibitor and the NuSH receptor modulator semaglutide. In some embodiments, the method comprises administering a calcium channel inhibitor and the NuSH receptor modulator Orforglipron. In some embodiments, the method comprises administering a calcium channel inhibitor and the NuSH receptor modulator tirzepatide. In some embodiments, increasing muscle mass may be used to address a disease or a condition, wherein the disease or condition is selected from age-related sarcopenia, frailty syndrome, cachexia associated with cancer, cachexia associated with other conditions such as heart failure, chronic kidney disease, chronic obstructive pulmonary disease, AIDS-related wasting, neuromuscular disorders such as muscular dystrophies, glucocorticoid-induced muscle atrophy, disuse atrophy following immobilization, osteoporosis with associated muscle weakness, recovery following major surgery or trauma, metabolic disorders characterized by loss of lean mass such as sarcopenic obesity, bariatric procedures such as gastric bypass surgery,, muscle atrophy associated with hypothyroidism or hypogonadism, muscle atrophy induced by chemotherapy or radiation therapy, neuromuscular Attorney Docket No. 047162-7543WO1(02791)

[0507] disorders such as motor neuron disease (ALS) and muscular dystrophy, gastrointestinal disorders of malabsorption such as inflammatory bowel disease, disorders associated with excess loss off nutrients such as Fanconi syndrome and SGLT2 deficiency, critical illness myopathy, and conditions requiring improved physical function including rehabilitation following orthopedic injury or prolonged hospitalization.

[0508] In some aspects, provided herein are methods of reducing fat mass and maintaining or increasing muscle mass in a subject in need thereof. In some embodiments, the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa). In some embodiments, the PKa is administered as a monotherapy. In some embodiments, reducing fat mass comprises reducing a level of fat mass measured when the PKa is administered by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, or at least 80% as compared to a level of fat mass measured when the PKa is not administered, while maintaining or increasing muscle mass comprises at least between a decrease in muscle mass when the PKa is administered of less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%; less than 4%, less than 3%, less than 2%, less than 1%, or 0% as compared to a level of muscle mass measured when the PKa is not administered and an increase in muscle mass when the PKa is administered of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100% as compared to a level of muscle mass measured when the PKa is not administered. In some embodiments, reducing fat mass comprises reducing a level of fat mass measured when the PKa is administered by at most 5%, at most 10%, at most 15%, at most 20%, at most 25%, at most 30%, at most 35%, at most 40%, at most 45%, at most 50%, at most 55%, at most 60%, at most 65%, at most 70%, at most 75%, or at most 80% as compared to a level of fat mass measured when the PKa is not administered, while maintaining or increasing muscle mass comprises between a decrease in muscle mass when the PKa is administered of at least between less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%; less than 4%, less than 3%, less than 2%, less than 1%, or 0% as compared to a level of muscle mass measured when the PKa is not administered and an increase in muscle mass when the PKa is administered of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at Attorney Docket No. 047162-7543WO1(02791)

[0509] least 80%, at least 85%, at least 90%, at least 95%, or at least 100% as compared to a level of muscle mass measured when the PKa is not administered. In some embodiments, reducing fat mass comprises reducing a level of fat mass measured when the PKa is administered by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% as compared to a level of fat mass measured when the PKa is not administered, while maintaining or increasing muscle mass comprises between a decrease in muscle mass when the PKa is administered of at least between less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%; less than 4%, less than 3%, less than 2%, less than 1%, or 0% as compared to a level of muscle mass measured when the PKa is not administered and an increase in muscle mass when the PKa is administered of at least 5%, at least 10%. at least 15%. at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100% as compared to a level of muscle mass measured when the PKa is not administered.. In some embodiments, reducing fat mass comprises reducing a level of fat mass measured when the PKa is administered by between 5% and 80%, between 10% and 80%, between 15% and 80%, between 20% and 80%, between 25% and 80%, between 30% and 80%, between 35% and 80%, between 40 % and 80%, between 45% and 80%, between 50% and 80%, between 55% and 80%, between 60 % and 80%, between 65% and 80%. between 70% and 80%. or between 75% and 80% as compared to a level of fat mass measured when the PKa is administered, while maintaining or increasing muscle mass comprises between a decrease in muscle mass when the PKa is administered of at least between less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%; less than 4%, less than 3%, less than 2%. less than 1%, or 0% as compared to a level of muscle mass measured when the PKa is not administered and an increase in muscle mass when the PKa is administered of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100% as compared to a level of muscle mass measured when the PKa is not administered. In some embodiments, the PKa is TEPP-46. In some embodiments, the PKa is mitapivat. In some embodiments, the PKa is etavopivat. In some embodiments, the PKa is a compound represented by Formula A as described above.

[0510] In some aspects, provided herein are methods of reducing fat mass and maintaining or increasing muscle mass in a subject in need thereof. In some embodiments, the method comprises administering to the subj ect a PK activator and a NuSH receptor modulator. In some Attorney Docket No. 047162-7543WO1(02791)

[0511] embodiments, the method comprises administering to the subject a PK activator and a NuSH receptor modulator. In some embodiments, the method comprises administering to the subject a PKa, wherein the subject has been previously administered a NuSH receptor modulator. In some embodiments, the method comprises administering to the subject a NuSH receptor modulator, wherein the subject has been previously administered a PKa. In some embodiments, the method comprises administering an AMP kinase inhibitor, a phosphodiesterase (e.g., a PDE4B inhibitor), or a calcium channel inhibitor and a NuSH receptor modulator. In some embodiments, the method comprises administering to the subject an AMP kinase inhibitor, a phosphodiesterase inhibitor, or a calcium channel inhibitor, wherein the subject has been previously administered a NuSH receptor modulator. In some embodiments, the method comprises administering to the subject a NuSH receptor modulator, wherein the subject has been previously administered an AMP kinase inhibitor, a phosphodiesterase inhibitor, or a calcium channel inhibitor. In some embodiments, reducing fat mass comprises reducing a level of fat mass measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator are administered by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%. at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, or at least 80% as compared to a level of fat mass measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator are not administered. In some embodiments, reducing fat mass comprises reducing a level of fat mass measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator are administered by at most 5%, at most 10%, at most 15%, at most 20%, at most 25%, at most 30%, at most 35%, at most 40%, at most 45%, at most 50%. at most 55%, at most 60%, at most 65%, at most 70%, at most 75%. or at most 80% as compared to a level of fat mass measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator are not administered, while maintaining or increasing muscle mass comprises a decrease in muscle mass when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator are administered of at least between less Attorney Docket No. 047162-7543WO1(02791)

[0512] than 10%, less than 9%, less than 8%, less than 7%. less than 6%, less than 5%; less than 4%, less than 3%, less than 2%, less than 1 %, or 0% as compared to a level of muscle mass measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator are not administered or an increase in muscle mass when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator are administered of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100% as compared to a level of muscle mass measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator are not administered. In some embodiments, reducing fat mass comprises reducing a level of fat mass measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator are administered by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% as compared to a level of fat mass measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator are not administered, while maintaining or increasing muscle mass comprises a decrease in muscle mass when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator are administered of at least between less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%; less than 4%, less than 3%, less than 2%, less than 1%, or 0% as compared to a level of muscle mass measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator are not administered or an increase in muscle mass when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator are administered of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, Attorney Docket No. 047162-7543WO1(02791)

[0513] at least 75%, at least 80%, at least 85%, at least 90%. at least 95%, or at least 100% as compared to a level of muscle mass measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator are not administered. In some embodiments, reducing fat mass comprises reducing a level of fat mass measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator are administered by between 5% and 80%, between 10% and 80%, between 15% and 80%, between 20% and 80%, between 25% and 80%, between 30% and 80%, between 35% and 80%, between 40 % and 80%. between 45% and 80%, between 50% and 80%, between 55% and 80%, between 60 % and 80%, between 65% and 80%, between 70% and 80%, or between 75% and 80% as compared to a level of fat mass measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator are not administered, while maintaining or increasing muscle mass comprises a decrease in muscle mass when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator are administered of at least between less than 10%, less than 9%, less than 8%. less than 7%, less than 6%, less than 5%; less than 4%, less than 3%, less than 2%, less than 1%, or 0% as compared to a level of muscle mass measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator are not administered or an increase in muscle mass when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator are administered of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100% as compared to a level of muscle mass measured when the combination of the PKa and NuSH receptor modulator, or the combination of the AMP kinase inhibitor, the phosphodiesterase inhibitor, or the calcium channel inhibitor and the NuSH receptor modulator are not administered. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is semaglutide. In some Attorney Docket No. 047162-7543WO1(02791)

[0514] embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is TEPP-46 and the NuSH receptor modulator is tirzepatide. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is a compound of Formula A as described above and the NuSH receptor modulator is tirzepatide. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is mitapivat and the NuSH receptor modulator is tirzepatide. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is liraglutide. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is semaglutide. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is Orforglipron. In some embodiments, the PKa is etavopivat and the NuSH receptor modulator is tirzepatide. In some embodiments, the method comprises administering an AMP kinase inhibitor and the NuSH receptor modulator liraglutide. In some embodiments, the method comprises administering an AMP kinase inhibitor and the NuSH receptor modulator semaglutide. In some embodiments, the method comprises administering an AMP kinase inhibitor and the NuSH receptor modulator Orforglipron. In some embodiments, the method comprises administering an AMP kinase inhibitor and the NuSH receptor modulator tirzepatide. In some embodiments, the method comprises administering a phosphodiesterase inhibitor and the NuSH receptor modulator liraglutide. In some embodiments, the method comprises administering a phosphodiesterase inhibitor and the NuSH receptor modulator semaglutide. In some embodiments, the met...

Claims

Attorney Docket No. 047162-7543WO1(02791)CLAIMSWhat is claimed is:

1. A method comprising administering a pyruvate kinase (PK) activator (PKa), wherein the method results in a reduction in fat mass and a maintenance or increase in muscle mass.

2. A method of treating obesity in a subj ect in need thereof, wherein the method comprises administering to the subject in need thereof a pyruvate kinase (PK) activator.

3. The method of claim 2, wherein the method comprises maintaining or increasing muscle mass.

4. A method of reducing fat mass and maintaining or increasing muscle mass in a subject in need thereof, wherein the method comprises administering a pyruvate kinase (PK) activator (PKa) to the subject, wherein the method results in a reduction in fat mass in the subject and a maintenance or increase in muscle mass in the subject.

5. The method of claim 4. wherein the reducing fat mass comprises reducing a level of fat mass measured when the PKa is administered by at least 5% as compared to a level of fat mass measured when the PKa is not administered.

6. The method of claim 4 or 5, wherein the maintaining or increasing muscle mass comprises between a decrease in muscle mass when the PKa is administered of less than 10% as compared to a level of muscle mass measured when the PKa is not administered.

7. A method of increasing mitochondrial membrane potential in a subject in need thereof, wherein the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa).

8. A method of treating an obesity-related disease, disorder, or condition in a subject in need thereof, wherein the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa).

9. The method of claim 8, wherein the obesity-related disease, disorder, or condition is Type 2 diabetes mellitus (T2D).

10. A method of treating a disease, disorder, or condition in a subject in need thereof, wherein the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa).Attorney Docket No. 047162-7543WO1(02791)11. The method of claim 10, wherein the disease, disorder, or condition is Type 2 diabetes mellitus (T2D).

12. A method of modulating pyruvate kinase (PK) activity and modulating NuSH receptor activity, wherein the method comprises administering a pyruvate kinase (PK) activator (PKa).

13. A method of improving pancreatic islet function in a subject in need thereof, wherein the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa).

14. A method of improving glucose tolerance in a subject in need thereof, wherein the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa).

15. A method of reducing insulin resistance in a subj ect in need thereof, wherein the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa).

16. A method of increasing insulin release in a subject in need thereof, wherein the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa).

17. A method of reducing blood glucose levels and / or blood lipid levels in a subject in need thereof, wherein the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa).

18. A method of reducing hepatic lipids in a subject in need thereof, wherein the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa).

19. A method of reducing fat mass in a subject in need thereof, wherein the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa).

20. The method of claim 19. wherein the reducing fat mass comprises reducing a level of fat mass measured when the PKa is administered by at least 5% as compared to a level of fat mass measured when the PKa is not administered.

21. A method of increasing muscle mass in a subject in need thereof, wherein the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa).

22. The method of claim 21, wherein the increasing muscle mass comprises an increase in muscle mass of at least 5% as compared to a level of muscle mass measured when the PKa is not administered.Attorney Docket No. 047162-7543WO1(02791)23. A method of increasing muscle function in a subject in need thereof, wherein the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa).

24. The method of claim 23, wherein the increasing muscle function comprises an increase in muscle function of at least 5% as compared to a level of muscle function measured when the PKa is not administered.

25. A method of increasing lean-to-fat mass ratio in a subject in need thereof, wherein the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa).

26. A method of reducing body mass index (BMI) in a subject in need thereof, wherein the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa).

27. The method of any one of claims 1-25, wherein the method comprising administering the PKa as a monotherapy.

28. The method of any one of claims 1-26, wherein the method further comprises administering to the subject a nutrient stimulated hormone (NuSH) receptor modulator.

29. The method of any one of claims 1-26 and 28, wherein the method further comprises administering to the subject at least one additional agent or therapy useful for treating obesity and / or T2D and / or other obesity-related disease, disorder, or condition.

30. The method of claim 29, wherein the at least one additional agent or therapy comprises leptin, ghrelin, mc4RA, myostatin inhibitors, activin inhibitors, NRLP3, and metformin.

31. A method of treating obesity in a subj ect in need thereof, wherein the method comprises administering to the subject in need thereof a pyruvate kinase (PK) activator and a nutrient stimulated hormone (NuSH) receptor modulator.

32. A method of treating obesity in a subj ect in need thereof, wherein the method comprises administering to the subject in need thereof a pyruvate kinase (PK) activator (PKa), wherein the subject has been previously administered a nutrient stimulated hormone (NuSH) receptor modulator.

33. A method of treating obesity in a subject in need thereof, wherein the method comprises administering to the subj ect in need thereof a nutrient stimulated hormone (NuSH) receptor modulator, wherein the subject has been previously administered a pyruvate kinase (PK) activator (PKa).Attorney Docket No. 047162-7543WO1(02791)34. The method of any one of claims 31-33, wherein the method does not result in a loss of muscle mass.

35. The method of any one of claims 31-34, wherein the method increases a lean-to-fat mass ratio of the subject.

36. A method of treating an obesity-related disease, disorder, or condition in a subject in need thereof, wherein the method comprises administering to the subject a pyruvate kinase (PK) activator and a nutrient stimulated hormone (NuSH) receptor modulator.

37. A method of treating an obesity-related disease, disorder, or condition in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a pyruvate kinase (PK) activator (PKa), wherein the subject has been previously administered a nutrient stimulated hormone (NuSH) receptor modulator.

38. A method of treating an obesity-related disease, disorder, or condition in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a nutrient stimulated hormone (NuSH) receptor modulator, wherein the subject has been previously administered a pyruvate kinase (PK) activator (PKa).

39. The method of any one of claims 8 or 36-38, wherein the obesity-related disease, disorder, or condition is a metabolic disease, disorder, or condition selected from the group consisting of cardiovascular disease, Heart Failure with Preserved Ejection Fraction, Heart Failure with Reduced Ejection Fraction (HFrEF), Chronic Kidney Disease (CKD), Cardiovascular-Kidney-Metabolic (CKM) Syndrome, hypertension, hyperlipidemia, Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD), Metabolic-Associated Steatohepatitis (MASH), infertility', Polycystic Ovary Syndrome (PCOS), and cancer.

40. The method of any one of claims 8 or 36-38, wherein the obesity-related disease, disorder, or condition is a functional disease, disorder, or condition selected from the group consisting of osteoarthritis (OA), Obstructive sleep apnea (OSA), back pain, and incontinence.

41. A method of treating or preventing a disease, disorder, or condition in a subj ect in need thereof, the method comprises administering to the subject a pyruvate kinase (PK) activator and nutrient stimulated hormone (NuSH) receptor modulator.

42. A method of treating a disease, disorder, or condition in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a pyruvate kinaseAttorney Docket No. 047162-7543WO1(02791)(PK) activator (PKa). wherein the subject has been previously administered a nutrient stimulated hormone (NuSH) receptor modulator.

43. A method of treating a disease, disorder, or condition in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a nutrient stimulated hormone (NuSH) receptor modulator, wherein the subject has been previously administered a pyruvate kinase (PK) activator (PKa).

44. The method of any one of claims 41-43, wherein the disease, disorder or condition is Type 2 diabetes mellitus (T2D).

45. A method of modulating pyruvate kinase (PK) activity and modulating NUSH-R activity in a cell, wherein the method comprises contacting the cell with a pyruvate kinase (PK) activator (PKa) and a nutrient stimulated hormone (NuSH) receptor modulator.

46. A method of modulating pyruvate kinase (PK) activity and modulating NUSH-R activity in a cell, wherein the method comprises contacting the cell with a pyruvate kinase (PK) activator (PKa), wherein the cell has been previously contacted with a nutrient stimulated hormone (NuSH) receptor modulator.

47. A method of modulating pyruvate kinase (PK) activity and modulating NUSH-R activity in a cell, wherein the method comprises contacting the cell with a nutrient stimulated hormone (NuSH) receptor modulator, wherein the cell has been previously contacted with a pyruvate kinase (PK) activator (PKa).

48. A method of improving pancreatic islet function in a subject in need thereof, wherein the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa) and a nutrient stimulated hormone (NuSH) receptor modulator.

49. A method of improving pancreatic islet function in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a pyruvate kinase (PK) activator (PKa), wherein the subject has been previously administered a nutrient stimulated hormone (NuSH) receptor modulator.

50. A method of improving pancreatic islet function in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a nutrient stimulated hormone (NuSH) receptor modulator, wherein the subject has been previously administered a pyruvate kinase (PK) activator (PKa).Attorney Docket No. 047162-7543WO1(02791)51. The method of any one of claims 48-50, wherein the improving pancreatic islet function comprises increasing insulin release from pancreatic islet cells.

52. A method of improving glucose tolerance in a subject in need thereof, wherein the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa) and a nutrient stimulated hormone (NuSH) receptor modulator.

53. A method of improving glucose tolerance a subject in need thereof, wherein the method comprises administering to the subject in need thereof a pyruvate kinase (PK ) activator (PKa), wherein the subject has been previously administered a nutrient stimulated hormone (NuSH) receptor modulator.

54. A method of improving glucose tolerance in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a nutrient stimulated hormone (NuSH) receptor modulator, wherein the subject has been previously administered a pyruvate kinase (PK) activator (PKa).

55. The method of any one of claims 52-54, wherein the improving glucose tolerance comprises reducing glucose levels to a baseline level within 60 minutes.

56. The method of claim 55, wherein the baseline level is substantially similar to a level of glucose measured in the subject following a six-hour fast.

57. A method of increasing insulin release in a subject in need thereof, wherein the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa) and a nutrient stimulated hormone (NuSH) receptor modulator.

58. A method of increasing insulin release in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a pyruvate kinase (PK) activator (PKa), wherein the subject has been previously administered a nutrient stimulated hormone (NuSH) receptor modulator.

59. A method of increasing insulin release in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a nutrient stimulated hormone (NuSH) receptor modulator, wherein the subject has been previously administered a pyruvate kinase (PK) activator (PKa).Attorney Docket No. 047162-7543WO1(02791)60. The method of any one of claims 57-59, wherein the increasing insulin release comprises at least 10% increase in insulin release as compared to a subject not administered the PKa.

61. A method of reducing blood glucose levels and / or blood lipid levels in a subj ect in need thereof, wherein the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa) and a nutrient stimulated hormone (NuSH) receptor modulator.

62. A method of reducing blood glucose levels and / or blood lipid levels in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a pyruvate kinase (PK) activator (PKa). wherein the subject has been previously administered a nutrient stimulated hormone (NuSH) receptor modulator.

63. A method of reducing blood glucose levels and / or blood lipid levels in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a nutrient stimulated hormone (NuSH) receptor modulator, wherein the subject has been previously administered a pyruvate kinase (PK) activator (PKa).

64. A method of reducing hepatic lipids in a subject in need thereof, wherein the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa) and a nutrient stimulated hormone (NuSH) receptor modulator.

65. A method of reducing hepatic lipids in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a pyruvate kinase (PK) activator (PKa), wherein the subject has been previously administered a nutrient stimulated hormone (NuSH) receptor modulator.

66. A method of reducing hepatic lipids in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a nutrient stimulated hormone (NuSH) receptor modulator, wherein the subject has been previously administered a pyruvate kinase (PK) activator (PKa).

67. A method of reducing fat mass in a subject in need thereof, wherein the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa) and a nutrient stimulated hormone (NuSH) receptor modulator.

68. A method of reducing fat mass in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a pyruvate kinase (PK) activator (PKa),Attorney Docket No. 047162-7543WO1(02791)wherein the subject has been previously administered a nutrient stimulated hormone (NuSH) receptor modulator.

69. A method of reducing fat mass in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a nutrient stimulated hormone (NuSH) receptor modulator, wherein the subject has been previously administered a pyruvate kinase (PK) activator (PKa).

70. A method of increasing muscle mass in a subject in need thereof, wherein the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa) and a nutrient stimulated hormone (NuSH) receptor modulator.

71. A method of increasing muscle mass in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a pyruvate kinase (PK) activator (PKa), wherein the subject has been previously administered a nutrient stimulated hormone (NuSH) receptor modulator.

72. A method of increasing muscle mass in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a nutrient stimulated hormone (NuSH) receptor modulator, wherein the subject has been previously administered a pyruvate kinase (PK) activator (PKa).

73. A method of increasing lean-to-fat mass ratio in a subject in need thereof, wherein the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa) and a nutrient stimulated hormone (NuSH) receptor modulator.

74. A method of increasing lean-to-fat mass ratio in a subject in need thereof, wherein the method comprises administering to the subj ect in need thereof a pyruvate kinase (PK) activator (PKa), wherein the subject has been previously administered a nutrient stimulated hormone (NuSH) receptor modulator.

75. A method of increasing lean-to-fat mass ratio in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a nutrient stimulated hormone (NuSH) receptor modulator, wherein the subject has been previously administered a pyruvate kinase (PK) activator (PKa).Attorney Docket No. 047162-7543WO1(02791)76. A method of reducing body mass index (BMI) in a subject in need thereof, wherein the method comprises administering to the subject a pyruvate kinase (PK) activator (PKa) and a nutrient stimulated hormone (NuSH) receptor modulator.

77. A method of reducing body mass index (BMI) in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a pyruvate kinase (PK) activator (PKa), wherein the subject has been previously administered a nutrient stimulated hormone (NuSH) receptor modulator.

78. A method of reducing body mass index (BMI) a subject in need thereof, wherein the method comprises administering to the subject in need thereof a nutrient stimulated hormone (NuSH) receptor modulator, wherein the subject has been previously administered a pyruvate kinase (PK) activator (PKa).

79. The method of any one of claims 1-78, wherein the pyruvate kinase activator (PKa) is red blood cell pyruvate kinase activator (PKR) (e.g., mitapivat, etavopivat, or tebapivat) or an activator of a pyruvate kinase M2 (PKM2) isoform (e.g., TEPP-46, DASA-58, or ML-265).

80. The method of any one of claims 1-79, wherein the PKa is TEPP-46, mitapivat, etavopivat, or a compound represented by the following structural formula Formula A:(Formula A),or a pharmaceutically acceptable salt thereof, wherein:U1, U2, and U3 are each independently N, O, S, C, or CR1, as valency permits;U4, U6, and U7are each independently N or C, as valency permits;U5 is N, NR3, or CR4, as valency permits;m is 1 or 2;Attorney Docket No. 047162-7543WO1(02791)Ring A is phenyl,U8 is N or CR1;each instance of Ri is independently hydrogen or Ci— Ce alkyl;Li is -S-, — S— CH2—. CH2S S(=O)2, S(=O), -S(=O)2O- -OS(=O)2-. -S( O)O- -OS(-O)-. -S( O)CH2- -CH2S(-O)- -S(-O)2CH2- -CH2S(-O)2--S(-O)2NR5- -NR5S(=O)2, ~S(=O)NR5~. ~NR5S(=O)~ — NRsSf— O)2O—. -OS(=O)2NR5- — NRsS(=O)O—. -OS(=O)NR5- -S(=O)(=NR5)- -C(=O)- -C(=O)O- -0C(=0)-. -C(=O)NRs- -N(R5)C(=O)-, -NRA4=0)0- -OC(=O)N S- -NR5C(=O)NR5- -NR5, -C(=S)NR5, N(R5)C(=S)-, or ~(CRjRk)q~;R₂ is C₁─C₆ alkyl, C₃─C₁₂ cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 14-membered aryl, or 5- to 14-membered heteroaryl, wherein the alkyl is optionally substituted with 0 to 3 groups each independently selected from halogen, OH, CN, and NR5R5, and wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted at each substitutable ring carbon atom with Rpand optionally substituted at each substitutable ring nitrogen atom by Rnc; or─L₁─R₂ is ─H, ─CN, ─CH₃, ─OH, Br, C₁─C₆ haloalkyl, C₂─C₆ alkenyl, C₁─C₆ alkyl, C₃─C₁₂ cycloalkyl, 3- to 8─membered heterocyclyl, 6- to 14-membered aryl, or 5- to 14-membered heteroaryl; wherein each alkyl and alkenyl is optionally substituted with 0 to 3 groups each independently selected from halogen, OH, CN, and NR5R5, and wherein each cycloalkyl, heterocyclyl. aryl, and heteroaryl is optionally substituted at each substitutable ring carbon atom with Rpand optionally substituted at each substitutable ring nitrogen atom by Rnc;each instance of Rᵖ is independently hydrogen, halogen, ─CN,─NO₂,─N₃, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, ─ORc3, ─SRc3, ─N(Rc3)₂, ─C(=O)N(Rc3)₂, ─N(Rc3)C(=O)Rc3, ─C(=O)Rc3, ─C(=O)ORc3, ─OC(=O)Rc3, ─S(=O)Rc3, ─S(=O)₂Rc3, ─S(=O)ORc3, ─OS(=O)Rc3, ─S(=O)₂ORc3, ─OS(=O)₂Rc3,─S(=O)N(Rc3)₂, ─S(=O)₂N(Rc3)₂, ─N(Rc3)S(=O)Rc3, ─N(Rc3)S(=O)₂Rc3, ─N(Rc3)C(=O)ORc3, ─OC(=O)N(Rc3)₂, ─N(Rc3)C(=O)N(Rc3)₂, ─N(Rc3)S(=O)N(Rc3)₂, ─N(Rc3)S(=O)₂N(Rc3)₂, ─N(Rc3)S(=O)ORc3, -─N(Rc3)S(=O)₂ORc3, ─OS(=O)N(Rc3)₂, ─OS(=O)₂N(Rc3)₂; or alternativelyAttorney Docket No. 047162-7543WO1(02791)two instances of Rpattached to the adjacent ring carbon atoms, can be taken together with the carbon atoms to which they are attached to form 3- to 8-membered cycloalkyl, 5- to 6-membered saturated or partially saturated monocyclic heterocyclyl, or 5- to 6-membered monocyclic heteroaryl; wherein:each instance of Rc3 is independently hydrogen or C₁─C₆ alkyl;L₂ is ─S─, ─S─CH₂─, ─CH₂─S─, S(=O)₂, ─S(=O)─, S(=O)₂O─, ─OS(=O)₂─, ─S(=O)O─, ─OS(=O)─, ─S(=O)CH₂─, ─CH₂S(=O)─, ─S(=O)₂CH₂─, ─CH₂S(=O)₂─, ─S(=O)₂NR₅─, ─NR₅S(=O)₂─, ─S(=O)NR₅─, ─NR₅S(=O)─, ─NR₅S(=O)₂O─, ─OS(=O)₂NR₅─, ─NR₅S(=O)O─, ─OS(=O)NR₅─, ─S(=O)(=NR₅)─, ─C(=O)─, C(=O)O─, ─OC(=O)─, ─C(=O)NR₅─, ─N(R₅)C(=O)─, ─NR₅C(=O)O─, ─OC(=O)NR₅─, ─NR₅C(=O)NR₅─, ─NR₅─, ─C(=S)NR₅─, ─N(R₅)C(=S)─, or ─(CRaRb)r─;each instance of Raand Rbare independently hydrogen, halogen, CN, OH, NO2, N3, or Ci— Co alkyl; wherein the Ci— Ce alkyl represented by Raor Rbare each optionally substituted with 0 to 3 groups each independently selected from halogen, OH, CN. and NR5R5;each instance of Rʲ and Rᵏ are independently hydrogen, halogen, CN, OH, NO₂, N₃, or C₁─C₆ alkyl; wherein the C₁─C₆ alkyl represented by Rᵃ or Rᵇ are each optionally substituted with 0 to 3 groups each independently selected from halogen, OH, CN, and NR₅R₅;q is 1 or 2;r is 1 or 2;Q is C₃─C₁₂ cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 14-membered aryl, or 5- to 14-membered heteroaryl, each of which is optionally substituted at each substitutable ring carbon atom with Rnand optionally substituted at each substitutable ring nitrogen atom by Rna; or─L₂─Q is ─H, ─CN, ─CH₃, ─OH, Br, C₁─C₆ haloalkyl, C₂─C₆ alkenyl, C₁─C₆ alkyl, C₃─C₁₂ cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 14-membered aryl, or 5- to 14-membered heteroaryl; wherein each alkyl and alkenyl is optionally substituted with 0 to 3 groups each independently selected from halogen, OH, CN, and NR5R5, and wherein each cycloalkyl, heterocyclyl, aryl. and heteroaryl is optionally substituted at each substitutable ring carbon atom with Rnand optionally substituted at each substitutable ring nitrogen atom by Rna;each instance of Rⁿ is independently hydrogen, halogen, ─CN,─NO₂, ─N₃, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, ─ORc4, ─SRc4, ─N(Rc4)₂, ─C(=O)N(Rc4)₂, ─N(Rc4)C(=O)Rc4, ─C(=O)Rc4, ─C(=O)ORc4, ─OC(=O)Rc4,Attorney Docket No. 047162-7543WO1(02791)─S(=O)Rc4, ─S(=O)₂Rc4, ─S(=O)ORc4, ─OS(=O)Rc4, ─S(=O)₂ORc4, ─OS(=O)₂Rc4, ─S(=O)N(Rc4)₂, ─S(=O)₂N(Rc4)₂, ─N(Rc4)S(=O)Rc4, ─N(Rc4)S(=O)₂Rc4, ─N(Rc4)C(=O)ORc4, ─OC(=O)N(Rc4)₂, ─N(Rc4)C(=O)N(Rc4)₂, ─N(Rc4)S(=O)N(Rc4)₂, ─N(Rc4)S(=O)₂N(Rc4)₂, ─N(Rc4)S(=O)ORc4, ─N(Rc4)S(=O)₂ORc4, ─OS(=O)N(Rc4)₂, or ─OS(=O)₂N(Rc4)₂; or alternativelytwo instances of Rnattached to the adjacent ring carbon atoms, can be taken together with the carbon atoms to which they are attached to form an optionally substituted 3— to 8— membered cycloalkyl, 5— to 6— membered saturated or partially saturated monocyclic heterocyclyl, or 5— to 6— membered monocyclic heteroaryl; wherein:each instance of Rc4 is independently hydrogen or C₁─C₆ alkyl;R3 is hydrogen or C1—C6 alkyl;R₄ is hydrogen, C₁─C₆ alkyl, C₁─C₆ haloalkyl, C₁─C₆ alkynyl, halogen, CN, ─C(=O)NR₅R₅, or C≡C(CH₂)wOH, wherein w is 1, 2, 3, 4, 5, or 6, and wherein each alkyl, haloalkyl, and alkynyl is independently optionally substituted with 1─3 instances of C₁─C₄ alkyl or halogen;each instance of Rⁿᵃ and Rⁿᶜ is independently hydrogen, C₁─C₆ alkyl, or C₁─C₆ haloalkyl; andeach instance of R₅ is independently hydrogen or C₁─C₆ alkyl;Attorney Docket No. 047162-7543WO1(02791)R3’ L2 is "(CRaRb),— and Q is phenyl optionally substituted with Rnand Rna, then Li is — (CRjRk)q— and R2 is cycloalkyl, heterocyclyl. aryl, or heteroaryl optionally substituted with Rpand Rnc.

81. The method of claim 80, w herein the PKa is TEPP-46.

82. The method of claim 80, wherein the PKa is mitapivat.

83. The method of claim 80. wherein the PKa is etavopivat.

84. The method of claim 80, wherein the PKa is a compound represented by the following structural formula:or a pharmaceutically acceptable salt thereof, wherein:Ui, U2, and U3 are each independently N, O, S, C, or CRi, as valency permits;U4, Ue, and U7 are each independently N or C. as valency permits;U5 is N, NR3, or CR4, as valency permits;m is 1 or 2;Ring A is phenyl,Attorney Docket No. 047162-7543WO1(02791)U8 is N or CR1;each instance of R1 is independently hydrogen or C1—C6 alkyl;Li is -S-, — S— CH2—. CH2S S(=O)2- S(=O), -S(=O)2O-. -OSt=O)2-. -S( O)O- -OS(-O)-. -S(-O)CH2“ -CH2S(-O)- -S(-O)2CH2- -CH2S(-O)2--S(-O)2NR5- -NR5S(=O)2, ~S(=O)NR5~. ~NR5S(=O)~ — NRsSf— O)2O—. -OS(=O)2NR5- -NR5S(=O)O- -OS(=O)NR5- -S(=O)(=NR5), C(=O), -C(=O)O- -OC(=O)-. -C(=O)NR5- -N(R5)C(=O -NR;C(=O)O- -OC(=O)NR5- -NR5C(=O)NR5“. -NR5, C(=S)NRS, N(R5)C(=S)-, or ~(CRjRk)q~;R2 is C1-C6alkyl, C3-C12 cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 14-membered aryl, or 5- to 14-membered heteroaryl, wherein the alkyl is optionally substituted with 0 to 3 groups each independently selected from halogen, OH, CN, and NR5R5, and wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted at each substitutable ring carbon atom with Rpand optionally substituted at each substitutable ring nitrogen atom by Rnc; or-L1-R2 is H, -CN, -CH3, -OH, Br, C1-C6haloalkyl, C2-C6 alkenyl, C1—C6 alkyl, C3— C12 cycloalkyl, 3- to 8— membered heterocyclyl, 6- to 14-membered aryl, or 5- to 14-membered heteroaryl; wherein each alkyl and alkenyl is optionally substituted with 0 to 3 groups each independently selected from halogen, OH, CN, and NR5R5, and wherein each cycloalkyl, heterocyclyl. aryl, and heteroaryl is optionally substituted at each substitutable ring carbon atom with Rpand optionally substituted at each substitutable ring nitrogen atom by Rnc;each instance of Rpis independently hydrogen, halogen, —CN.-NO2.-N3. C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -ORc3. -SRc3. -N(Rc3)2. -C(=O)N(RC3)2. -N(RC3)C(=O)RC3. -C(=O)RC3. -C(=O)ORc3. — OC(=O)RC3. -S(=O)Rc3. -S(=O)2Rc3, -S(=O)ORC3. -OS(=O)RC3. -S(=O)2ORC3. -OS(=O)2RC3.-S(=O)N(RC3)2. S(=O)2N (RC3)2, -N(RC3)S(=O)RC3, — N(RC3)S(=O)2RC3. -N(RC3)C(=O)ORC3. -OC(=O)N(RC3)2, -N(RC3)C(=O)N(RC3)2. -N(RC3)S(=O)N(RC3)2, -N(RC3)S(=O)2N(RC3)2, -N(RC3)S(=O)ORC3. — N(RC3)S(=O)2ORC3. — OS(=O)N(RC3)2, — OS(=O)2N(RC3)2; or alternativelytwo instances of Rpattached to the adjacent ring carbon atoms, can be taken together with the carbon atoms to which they are attached to form 3- to 8-membered cycloalkyl, 5- to 6-membered saturated or partially saturated monocyclic heterocyclyl, or 5- to 6-membered monocyclic heteroaryl; wherein:each instance of Rc3is independently hydrogen or C1—C6 alkyl;Attorney Docket No. 047162-7543WO1(02791)L2is -S-, -S-CH2-. — CH2— S—. -S(=O)2, ~S(=Oh S(=O)2O- -OS(=O)2- -S(=O)O- -OS(=O)- -S(=O)CH2- -CH2S(=O)- -S(=O)2CH2- -CH2S(=O)2-. S(=O)2NR5, NR5S(=O)2M, -S(=O)NR5- ~NR5S(=O)~ -NR5S(=0)20- — OS(~ O)2NRS—. — NR? S(— 0)0—. -OS( O)NR5- -S(-O)(-NR5)- -C( O)-. ~C(=O)O~, OC(=O)-, -C(=O)NR5, ~N(R5)C(=O)~ NR5C(=O)O- — OC(— O)NRS—. -NR5C(=O)NR5- — NRs—. -C(=S)NR5- — N( R5)C( =S )—. or -(CRaRb),-:each instance of Raand Rbare independently hydrogen, halogen, CN, OH, NO2, N3, or Ci— CV> alkyl; wherein the Ci— Ce alkyl represented by Raor Rbare each optionally substituted with 0 to 3 groups each independently selected from halogen, OH, CN, and NR5R5;each instance of Rjand Rkare independently hydrogen, halogen, CN, OH, NO2, N3, or Ci— Ce alkyl; wherein the Ci— Ce alkyl represented by Raor Rbare each optionally substituted with 0 to 3 groups each independently selected from halogen, OH, CN, and NR5R5;q is 1 or 2;r is 1 or 2;Q is C3—C12 cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 14-membered aryl, or 5-to 14-membered heteroaryl, each of which is optionally substituted at each substitutable ring carbon atom with Rnand optionally substituted at each substitutable ring nitrogen atom by Rna; or—L2—Q is —H, —CN, —CH3, —OH, Br, C1—C6 haloalkyl, C2— Ce alkenyl, Ci— Ce alkyl, C3—C12 cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 14-membered aryl, or 5- to 14-membered heteroaryl; wherein each alkyl and alkenyl is optionally substituted with 0 to 3 groups each independently selected from halogen, OH, CN, and NR5R5, and wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted at each substitutable ring carbon atom with Rnand optionally substituted at each substitutable ring nitrogen atom by Rna;each instance of Rnis independently hydrogen, halogen, — CN.— NO2. — N3. C1-C6 alkyl. C2-C6 alkenyl, C2-C6 alkynyl, -ORc4. -SRc4. -N(RC4)2. -C(=O)N(Rc4)2. -N(RC4)C(=O)RC4. -C(=O)RC4. -C(=O)ORC4. -OC(=O)RC4. -S(=O)Rc4. -S(=O)2RC4. -S(=O)ORC4. -OS(=O)RC4. -S(=O)2ORC4. -OS(=O)2RC4. —S(=O)N(RC4)2, —S(=O)2N(RC4)2, -N(RC4)S(=O)RC4. -N(RC4)S(=O)2RC4, -N(RC4)C(=O)ORC4, -OC(=O)N(RC4)2. -N(RC4)C(=O)N(RC4)2. -N(RC4)S(=O)N(RC4)2. -N(RC4)S(=O)2N(RC4)2. -N(RC4)S(=O)ORC4. -N(RC4)S(=O)2ORC4. -OS(=O)N(RC4)2. or -OS(=O)2N(RC4)2: or alternativelyAttorney Docket No. 047162-7543WO1(02791)two instances of Rnattached to the adjacent ring carbon atoms, can be taken together with the carbon atoms to which they are attached to form an optionally substituted 3- to 8— membered cycloalkyl, 5- to 6— membered saturated or partially saturated monocyclic heterocyclyl, or 5— to 6— membered monocyclic heteroaryl; wherein:each instance of Rc4is independently hydrogen or C1—C6 alkyl;R3 is hydrogen or C1—C6 alkyl;R4 is hydrogen, Ci— Ce alkyl, Ci— Ce haloalkyl, C2— Ce alkynyl, halogen, CN, — C(=O)NRsRs, or C=C(CH2)wOH, wherein w is 1, 2, 3, 4, 5, or 6, and wherein each alkyl, haloalkyl, and alkynyl is independently optionally substituted with 1—3 instances of Ci— C-i alkyl or halogen;each instance of Rnaand Rncis independently hydrogen, Ci— Ce alkyl, or Ci— Ce haloalkyl; andeach instance of R5 is independently hydrogen or C1—C6 alkyl;’ L2 is — (CRaRb)r— and Q is phenyl optionally substituted with Rnand Rna, then Li is — (CRjRk)q— and R2 is cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted with Rpand Rnc.Attorney Docket No. 047162-7543WO1(02791)85. The method of any one of claims 28 and 31-84, wherein the NuSH receptor modulator is a human NuSH receptor modulator.

86. The method of any one of claims 28 and 31-85, wherein the NuSH receptor modulator is a NuSH receptor agonist.

87. The method of any one of claims 28 and 31-86, wherein the NuSH receptor modulator is a GLP-1 receptor agonist.

88. The method of claim 87, wherein the GLP-1 receptor agonist is liraglutide, semaglutide, exenatide, dulaglutide, lixisenatide, Orforglipron, or albiglutide.

89. The method of any one of claims 28 and 31-86, wherein the NuSH receptor modulator is a GTP receptor agonist.

90. The method of any one of claims 28 and 31-86, wherein the NuSH receptor modulator is a dual agonist for GLP-1 receptor and GIP receptor.

91. The method of claim 90, wherein the dual agonist for GLP-1 receptor and GIP receptor is tirzepatide.

92. The method of any one of claims 28 and 31-86, wherein the NuSH receptor modulator is a GCG receptor agonist.

93. The method of any one of claims 28 and 31-86, wherein the NuSH receptor modulator is a triple agonist for GLP-1 receptor, GIP receptor, and GCG receptor.

94. The method of claim 93, wherein the triple agonist for GLP-1 receptor, GIP receptor, and GCG receptor is retatrutide, mazdutide, or survodutide.

95. The method of claim 81, wherein the method comprises administering TEPP-46 and liraglutide.

96. The method of claim 81, wherein the method comprises administering TEPP-46 and semaglutide.

97. The method of claim 81, wherein the method comprises administering TEPP-46 and tirzepatide.Attorney Docket No. 047162-7543WO1(02791)98. The method of claim 81, wherein the method comprises administering TEPP-46 and Orforglipron.

99. The method of claim 82, wherein the method comprises administering mitapivat and liraglutide.

100. The method of claim 82, wherein the method comprises administering mitapivat and semaglutide.

101. The method of claim 82, wherein the method comprises administering mitapivat and tirzepatide.

102. The method of claim 82, wherein the method comprises administering mitapivat and Orforglipron.

103. The method of claim 83, wherein the method comprises administering etavopivat and liraglutide.

104. The method of claim 83, wherein the method comprises administering etavopivat and semaglutide.

105. The method of claim 83, wherein the method comprises administering etavopivat and tirzepatide.

106. The method of claim 83, wherein the method comprises administering etavopivat and Orforglipron.

107. The method of claim 84, wherein the method comprises administering the compound and liraglutide.

108. The method of claim 84, wherein the method comprises administering the compound and semaglutide.

109. The method of claim 84, wherein the method comprises administering the compound and tirzepatide.

110. The method of claim 84, wherein the method comprises administering the compound and Orforglipron.Attorney Docket No. 047162-7543WO1(02791)111. The method of any one of claims 1-110, wherein the method further comprises administering at least one additional agent or therapy useful for treating obesity and / or T2D and / or other obesity-related disease, disorder, or condition.

112. The method of claim 111, wherein the at least one additional agent or therapy comprises leptin, ghrelin, mc4RA, myostatin inhibitors, activin inhibitors, NRLP3, and metformin.

113. The method of any one of claims 1-112, wherein the subject is an animal.

114. The method of any one of claims 1-113, wherein the subject is a non-human primate.

115. The method of any one of claims 1-113, wherein the subject is a livestock animal.

116. The method of claim 115, wherein the livestock animal is a cow, a sheep, a goat, a horse, or a pig.

117. The method of any one of claims 1-113, wherein the subject is a companion animal.

118. The method of claim 117, wherein the companion animal is a dog or a cat.

119. The method of any one of claims 1-112, wherein the subject is a human.

120. The method of any one of claims 28 and 31-119, wherein the PKa is administered concurrently with the NuSH receptor modulator.

121. The method of any one of claims 28 and 31-119, wherein the PKa is administered prior to administration of the NuSH receptor modulator.

122. The method of any one of claims 28 and 31-119, wherein the PKa is administered after to administration of the NuSH receptor modulator.

123. The method of any one of claims 28 and 31-122, wherein the NuSH receptor modulator is administered at a lower dosage when administered with the PKa than when the NuSH receptor modulator is administered without the PKa.

124. The method of any one of claims 28 and 31-123, wherein the NuSH receptor modulator is administered at a lower dosage when administered with the PKa than an FDA approved dose of the NuSH receptor modulator.Attorney Docket No. 047162-7543WO1(02791)125. The method of any one of claims 28 and 31-124. wherein the method further comprises terminating administration of the NuSH receptor modulator following administration of the PKa.

126. The method of any one of claims 28 and 31-124, wherein an amount of the NuSH receptor modulator is decreased or discontinued.

127. The method of claim 126, wherein the amount of the NuSH receptor modulator is decreased or discontinued after the subject reaches a desired weight or is no longer losing weight.

128. The method of claim 126, wherein the amount of the NuSH receptor modulator is decreased or discontinued after the subject reaches a desired glucose tolerance level.

129. The method of claim 126, wherein the amount of the NuSH receptor modulator is decreased or discontinued if the subject experiences a negative side effect associated with the NuSH receptor modulator.

130. The method of claim 126, wherein the amount of the NuSH receptor modulator is decreased or discontinued due to pricing of the NuSH receptor modulator.

131. A method of treating obesity in a subj ect in need thereof, wherein the method comprises administering to the subject in need thereof a nutrient stimulated hormone (NuSH) receptor modulator and an AMP kinase inhibitor, a phosphodiesterase inhibitor, or a calcium channel inhibitor.

132. A method of reducing fat mass in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a nutrient stimulated hormone (NuSH) receptor modulator and an AMP kinase inhibitor, a phosphodiesterase inhibitor, or a calcium channel inhibitor.

133. A method of increasing muscle mass in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a nutrient stimulated hormone (NuSH) receptor modulator and an AMP kinase inhibitor, a phosphodiesterase inhibitor, or a calcium channel inhibitor.

134. A method of increasing a lean-to-fat mass ratio a subject in need thereof, wherein the method comprises administering to the subject in need thereof a nutrient stimulated hormoneAttorney Docket No. 047162-7543WO1(02791)(NuSH) receptor modulator and an AMP kinase inhibitor, a phosphodiesterase inhibitor, or a calcium channel inhibitor.

135. A method of improving insulin release a subject in need thereof, wherein the method comprises administering to the subject in need thereof a nutrient stimulated hormone (NuSH) receptor modulator and an AMP kinase inhibitor, a phosphodiesterase inhibitor, or a calcium channel inhibitor.

136. A method of improving glucose tolerance mass ratio a subject in need thereof, wherein the method comprises administering to the subject in need thereof a nutrient stimulated hormone (NuSH) receptor modulator and an AMP kinase inhibitor, a phosphodiesterase inhibitor, or a calcium channel inhibitor.

137. The method of any one of claims 131-136, wherein the method comprises administering a phosphodiesterase inhibitor, wherein the phosphodiesterase inhibitor is a PDE4B inhibitor.

138. A pharmaceutical combination comprising a pyruvate kinase (PK) activator and a nutrient stimulated hormone (NuSH) receptor modulator.

139. A pharmaceutical composition comprising a pyruvate kinase (PK) activator, a nutrient stimulated hormone (NuSH) receptor modulator, and a pharmaceutically acceptable excipient.

140. The pharmaceutical combination or composition of claim 138 or 139. wherein the pyruvate kinase activator (PKa) is red blood cell pyruvate kinase activator (PKR) or an activator of a pyruvate kinase M2 (PKM2) isoform.

141. The pharmaceutical combination or composition of claim 138 or 139, wherein the PKa is mitapivat, etavopivat, or tebapivat.

142. The pharmaceutical combination or composition of claim 138 or 139, wherein the PKa is TEPP-46, DASA-58, orML-265.

143. The pharmaceutical combination or composition of claim 138 or 139. wherein the PKa is a compound represented by the following structural formula Formula A:Attorney Docket No. 047162-7543WO1(02791)(Formula A),or a pharmaceutically acceptable salt thereof, wherein:U1, U2, and U3 are each independently N, O, S, C, or CR1, as valency permits;U4, U6, and U7are each independently N or C, as valency permits;U5 is N, NR3, or CR4, as valency permits;m is 1 or 2;Ring A is phenyl,U8 is N or CR1;each instance of R1 is independently hydrogen or C1—C6 alkyl;Li is -S-, -S-CH2-. CH2 S, -S(=O)2- -S(=O)-, -S(=O)2O-. -OS(=O)2- -S( O)O- -OS(-O)-. -S( O)CH2 -CH2S(=O)-. -S(=O)2CH2- -CH2S(=O)2- -S(=O)2NR5, -NR5S(=O)2, -S(=O)NR5. ~NR5S(=O)~ -NR5S(=O)2O- -OS(=O)2NR5- -NR5S(=O)O- -OS(=O)NR5- -S(=O)(=NR5)- C(=O), -C(=O)O- -OC(=O)-. -C(=O)NR5- -N(R5)C(=O)- -NR;C(=O)O- -OC(=O)NR5- -NR5C(=O)NR5“. -NRS, C(=S)NR5, N(R5)C(=S)-, or ~(CRjRk)q~;R2 is C1—C6 alkyl, C3—C12 cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 14-membered aryl, or 5- to 14-membered heteroaryl, wherein the alkyl is optionally substituted with 0 to 3 groups each independently selected from halogen, OH, CN, and NR5R5, and wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted at each substitutableAttorney Docket No. 047162-7543WO1(02791)ring carbon atom with Rpand optionally substituted at each substitutable ring nitrogen atom by Rnc; or—L1—R2 is —H, —CN, —CH3, —OH, Br, C1—C6 haloalkyl, C2—C6 alkenyl, C1—C6 alkyl, C3—C12 cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 14-membered aryl, or 5- to 14-membered heteroaryl; wherein each alkyl and alkenyl is optionally substituted with 0 to 3 groups each independently selected from halogen, OH, CN, and NR5R5, and wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted at each substitutable ring carbon atom with Rp and optionally substituted at each substitutable ring nitrogen atom by Rnc;each instance of Rp is independently hydrogen, halogen, —CN, —NO2, —N3, C1—C6 alkyl, C2—C6 alkenyl, C2—C6 alkynyl, —ORc3, —SRc3, —N(Rc3)2, —C(=O)N(Rc3)2, —N(Rc3)C(=O)Rc3, —C(=O)Rc3, —C(=O)ORc3, —OC(=O)Rc3, —S(=O)Rc3, —S(=O)2Rc3, —S(=O)ORc3, —OS(=O)Rc3, —S(=O)2ORc3, —OS(=O)2Rc3,—S(=O)N(Rc3)2, —S(=O)2N(Rc3)2, —N(Rc3)S(=O)Rc3, —N(Rc3)S(=O)2Rc3, —N(Rc3)C(=O)ORc3, —OC(=O)N(Rc3)2, —N(Rc3)C(=O)N(Rc3)2, —N(Rc3)S(=O)N(Rc3)2, —N(Rc3)S(=O)2N(Rc3)2, —N(Rc3)S(=O)ORc3, —N(Rc3)S(=O)2ORc3, —OS(=O)N(Rc3)2, —OS(=O)2N(Rc3)2; or alternativelytwo instances of Rpattached to the adjacent ring carbon atoms, can be taken together with the carbon atoms to which they are attached to form 3- to 8-membered cycloalkyl, 5- to 6-membered saturated or partially saturated monocyclic heterocyclyl, or 5- to 6-membered monocyclic heteroaryk wherein:each instance of Rc3 is independently hydrogen or C1—C6 alkyl;L2 is —S—, —S—CH2—, —CH2—S—, —S(=O)2—, —S(=O)—, —S(=O)2O—, —OS(=O)2—, —S(=O)O—, —OS(=O)—, —S(=O)CH2—, —CH2S(=O)—, —S(=O)2CH2—, —CH2S(=O)2—, —S(=O)2NR5—, —NR5S(=O)2—, —S(=O)NR5—, —NR5S(=O)—, —NR5S(=O)2O—, —OS(=O)2NR5—, —NR5S(=O)O—, —OS(=O)NR5—, —S(=O)(=NR5)—, —C(=O)—, —C(=O)O—, —OC(=O)—, —C(=O)NR5—, —N(R5)C(=O)—, —NR5C(=O)O—, —OC(=O)NR5—, —NR5C(=O)NR5—, —NR5—, —C(=S)NR5—, —N(R5)C(=S)—, or —(CRaRb)r—;each instance of Raand Rbare independently hydrogen, halogen, CN, OH, NO2, N3, or Ci— Ci, alkyl; wherein the Ci— Ci, alkyl represented by Raor Rbare each optionally substituted with 0 to 3 groups each independently selected from halogen, OH, CN, and NR5R5;each instance of Rj and Rk are independently hydrogen, halogen, CN, OH, NO2, N3, or C1—C6 alkyl; wherein the C1—C6 alkyl represented by Ra or Rb are eachAttorney Docket No. 047162-7543WO1(02791)optionally substituted with 0 to 3 groups each independently selected from halogen, OH, CN, and NR5R5;q is 1 or 2;r is 1 or 2;Q is C3—C12 cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 14-membered aryl, or 5- to 14-membered heteroaryl, each of which is optionally substituted at each substitutable ring carbon atom with Rn and optionally substituted at each substitutable ring nitrogen atom by Rna; or—L2—Q is —H, —CN, —CH3, —OH, Br, C1—C6 haloalkyl, C2—C6 alkenyl, C1—C6 alkyl, C3—C12 cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 14-membered aryl, or 5- to 14-membered heteroaryl; wherein each alkyl and alkenyl is optionally substituted with 0 to 3 groups each independently selected from halogen, OH, CN, and NR5R5, and wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted at each substitutable ring carbon atom with Rn and optionally substituted at each substitutable ring nitrogen atom by Rna;each instance of Rn is independently hydrogen, halogen, —CN, —NO2, —N3, C1—C6 alkyl, C2—C6 alkenyl, C2—C6 alkynyl, —ORc4, —SRc4, —N(Rc4)2, —C(=O)N(Rc4)2, —N(Rc4)C(=O)Rc4, —C(=O)Rc4, —C(=O)ORc4, —OC(=O)Rc4, —S(=O)Rc4, —S(=O)2Rc4, —S(=O)ORc4, —OS(=O)Rc4, —S(=O)2ORc4, —OS(=O)2Rc4, —S(=O)N(Rc4)2, —S(=O)2N(Rc4)2, —N(Rc4)S(=O)Rc4, —N(Rc4)S(=O)2Rc4, —N(Rc4)C(=O)ORc4, —OC(=O)N(Rc4)2, —N(Rc4)C(=O)N(Rc4)2, —N(Rc4)S(=O)N(Rc4)2, —N(Rc4)S(=O)2N(Rc4)2, —N(Rc4)S(=O)ORc4, —N(Rc4)S(=O)2ORc4, —OS(=O)N(Rc4)2, or —OS(=O)2N(Rc4)2; or alternatively two instances of Rnattached to the adjacent ring carbon atoms, can be taken together with the carbon atoms to which they are attached to form an optionally substituted 3- to 8—membered cycloalkyl, 5- to 6—membered saturated or partially saturated monocyclic heterocyclyl, or 5— to 6—membered monocyclic heteroaryl; wherein:each instance of Rc4 is independently hydrogen or C1—C6 alkyl;R3 is hydrogen or C1—C6 alkyl;R4 is hydrogen, C1—C6 alkyl, C1—C6 haloalkyl, C2—C6 alkynyl, halogen, CN, —C(=O)NR5R5, or C≡C(CH2)wOH, wherein w is 1, 2, 3, 4, 5, or 6, and wherein each alkyl, haloalkyl, and alkynyl is independently optionally substituted with 1—3 instances of C1—C4 alkyl or halogen;Attorney Docket No. 047162-7543WO1(02791)each instance of Rnaand Rncis independently hydrogen, C1—C6alkyl, or C1—C6haloalkyl; andeach instance of R5 is independently hydrogen or C1—C6 alkyl;’ L2 is — (CRaRb)r— and Q is phenyl optionally substituted with Rnand Rna, then Li is — (CRjRk)qMand R2 is cycloalkyl, heterocyclyl. aryl, or heteroaryl optionally substituted with Rpand Rnc.

144. The pharmaceutical combination or composition of any one of claims 138-143, wherein the NuSH receptor modulator is a human NuSH receptor modulator.

145. The pharmaceutical combination or composition of any one of claims 138-144, wherein the NuSH receptor modulator is a NuSH receptor agonist.

146. The pharmaceutical combination or composition of any one of claims 138-145, wherein the NuSH receptor modulator is a GLP-1 receptor agonist.

147. The pharmaceutical combination or composition of claim 146. wherein the GLP-1 receptor agonist is liraglutide, semaglutide, exenatide, dulaglutide, lixisenatide, or albiglutide.Attorney Docket No. 047162-7543WO1(02791)148. The pharmaceutical combination or composition of any one of claims 138-145, wherein the NuSH receptor modulator is a GIP receptor agonist.

149. The pharmaceutical combination or composition of any one of claims 138-145, wherein the NuSH receptor modulator is a dual agonist for GLP-1 receptor and GIP receptor.

150. The pharmaceutical combination or composition of claim 149. wherein the GLP-1 receptor and GIP receptor dual agonist is tirzepatide.

151. The pharmaceutical combination or composition of any one of claims 138-145, wherein the NuSH receptor modulator is a GCG receptor agonist.

152. The pharmaceutical combination or composition of any one of claims 138-145, wherein the NuSH receptor modulator is a triple agonist for GLP-1 receptor, GIP receptor, and GCG receptor.

153. The pharmaceutical combination or composition of claim 152, wherein the GLP-1 receptor, GIP receptor, and GCG receptor triple agonist is retatrutide, mazdutide. or survodutide.

154. The pharmaceutical combination or composition of any one of claims 138-153, wherein the combination or composition is formulated with a lower dose of the NuSH receptor modulator than a composition not comprising the PKa.

155. The pharmaceutical combination or composition of any one of claims 138-139 and 142, wherein the pharmaceutical combination or composition comprises TEPP-46 and liraglutide.

156. The pharmaceutical combination or composition of any one of claims 138-139 and 142, wherein the pharmaceutical combination or composition comprises TEPP-46 and semaglutide.

157. The pharmaceutical combination or composition of any one of claims 138-139 and 142, wherein the pharmaceutical combination or composition comprises TEPP-46 and tirzepatide.

158. The pharmaceutical combination or composition of any one of claims 138-139 and 142, wherein the pharmaceutical combination or composition comprises TEPP-46 and Orforglipron.

159. The pharmaceutical combination or composition of any one of claims 138-139 and 141 wherein the pharmaceutical combination or composition comprises mitapivat and liraglutide.Attorney Docket No. 047162-7543WO1(02791)160. The pharmaceutical combination or composition of any one of claims 138-139 and 141, wherein the pharmaceutical combination or composition comprises mitapivat and semaglutide.

161. The pharmaceutical combination or composition of any one of claims 138-139 and 141, wherein the pharmaceutical combination or composition comprises mitapivat and tirzepatide.

162. The pharmaceutical combination or composition of any one of claims 138-139 and 141, wherein the pharmaceutical combination or composition comprises mitapivat and Orforglipron.

163. The pharmaceutical combination or composition of any one of claims 138-139 and 141, wherein the pharmaceutical combination or composition comprises etavopivat and liraglutide.

164. The pharmaceutical combination or composition of any one of claims 138-139 and 141, wherein the pharmaceutical combination or composition comprises etavopivat and semaglutide.

165. The pharmaceutical combination or composition of any one of claims 138-139 and 141, wherein the pharmaceutical combination or composition comprises etavopivat and tirzepatide.

166. The pharmaceutical combination or composition of any one of claims 138-139 and 141, wherein the pharmaceutical combination or composition comprises etavopivat and Orforglipron.

167. The pharmaceutical combination or composition of any one of claims 138-139 and 143, wherein the pharmaceutical combination or composition comprises the compound and liraglutide.

168. The pharmaceutical combination or composition of any one of claims 138-139 and 143, wherein the pharmaceutical combination or composition comprises the compound and semaglutide.

169. The pharmaceutical combination or composition of any one of claims 138-139 and 143, wherein the pharmaceutical combination or composition comprises the compound and tirzepatide.

170. The pharmaceutical combination or composition of any one of claims 138-139 and 143, wherein the pharmaceutical combination or composition comprises the compound and Orforglipron.Attorney Docket No. 047162-7543WO1(02791)171. A pharmaceutical combination comprising a nutrient stimulated hormone (NuSH) receptor modulator and an AMP kinase inhibitor, a phosphodiesterase inhibitor, or a calcium channel inhibitor.

172. A pharmaceutical composition comprising a nutrient stimulated hormone (NuSH) receptor modulator; an AMP kinase inhibitor, a phosphodiesterase inhibitor, or a calcium channel inhibitor; and a pharmaceutically acceptable excipient.

173. The pharmaceutical combination or composition of claim 171 or 172, wherein the pharmaceutical combination or composition comprises the phosphodiesterase inhibitor, wherein the phosphodiesterase inhibitor is a PDE4B inhibitor.

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