Methods for weight loss and preserving skeletal muscle mass

Abstract

The present disclosure provides a method for preserving skeletal muscle mass during weight loss.In one embodiment, the present disclosure provides a method for preserving skeletal muscle mass during weight loss in a subject in need thereof, comprising administering a therapeutically effective amount of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole or its pharma- ceutically acceptable salt to the subject.In another embodiment, the weight loss is caused by fat loss.In another embodiment, the subject suffers from obesity, excess body fat, diabetes, high blood pressure (hypertension), dyslipidemia, hypertriglyceridemia, acquired lipodystrophy, hereditary lipodystrophy, partial lipodystrophy, or metabolic syndrome.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This international PCT application claims priority to and the benefit of U.S. Provisional Application No. 63 / 307,506, filed February 7, 2022, and U.S. Provisional Application No. 63 / 382,456, filed November 4, 2022, the contents of which are incorporated herein by reference in their entireties.

[0002] Technical Field The present disclosure relates to methods for preserving skeletal muscle mass during weight loss. [Background technology]

[0003] background Obesity is a well-known risk factor for the development of many common diseases, such as type 2 diabetes (T2D) and nonalcoholic fatty liver disease (NAFLD). Obesity is best viewed as any degree of excess adiposity that confers health risks. Weight loss is an essential treatment for people with obesity because it can ameliorate the risk of developing complications such as heart, liver, pancreatic, and kidney disease. One of the major challenges to weight loss is the preservation of skeletal muscle mass. The potential health benefits of bariatric surgery or diet-induced weight loss may be undermined by the associated loss of lean body mass. Cava et al., "Preserving healthy Muscle during Weight Loss", 2017 Advances in Nutrition, 8(3): pp. 511-519; Zamboni et al. "Sarcopenic Obesity", 2021 Sarcopnia, pp. 147-156. Low muscle mass and the risk of impaired muscle function can increase the risk of further complications. Therefore, there is a great need for weight loss methods that can also help preserve skeletal muscle mass.

[0004] The administration of mitochondrial chemical uncouplers as a means to reduce fat deposition has been a scientific goal for many years. While there are several small molecules that uncouple mitochondrial oxidative phosphorylation, the best known is 2,4-dinitrophenol (DNP). DNP is known to uncouple with robust efficacy, which is unfortunately associated with an unacceptably high rate of significant adverse effects (J. Med. Toxicol. 2011 Sep; 7(3): 205-212). These adverse effects can include hyperthermia, tachycardia, sweating, and tachypnoea, ultimately resulting in death. Being a small, highly permeable lipophilic acid, DNP is rapidly absorbed in the stomach. High concentrations distribute rapidly, uncouple immediately, and generate high levels of heat in a short period of time. Thus, DNP has a small therapeutic index and is extremely dangerous in overdose. DNP was labeled "exceedingly dangerous and unfit for human consumption" by the Federal Food, Drug, and Cosmetic Act of 1938. Thus, there is a need for uncouplers that can safely treat mitochondrial-related disorders or conditions.

[0005] 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole is a novel small molecule uncoupling agent (compound 1). It acts as a controlled metabolic accelerator (CMA). It is designed to effectively address the root cause of metabolic disease, the accumulation of fat and sugar in the body. CMA works to improve cellular metabolism as well as increase energy expenditure and calorie consumption, reducing fat accumulation. Using a novel controlled and targeted approach, compound 1 can increase mitochondrial proton leak, an ongoing process in the body that dissipates energy and accounts for 20%-40% of daily calories. Compound 1 exploits the mitochondrial uncoupling mechanism to increase substrate utilization. In recent years, the incidence and prevalence of muscle wasting has been observed to increase in obese populations. In patients with obese sarcopenia, the maintenance of muscle mass is crucial, and the loss of muscle mass is not only counterproductive to these patients' recovery of metabolic health, but also directly causes subsequent morbidity and reduced quality of life due to the decline, and increases dependency on daily care. In the future, there is a dire need for pharmaceutical interventions that can tackle excess adiposity without adverse effects on muscle mass. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Cava et al., "Preserving healthy muscle during Weight Loss", 2017 Advances in Nutrition, 8(3): pp. 511-519 [Non-Patent Document 2] Zamboni et al. "Sarcopenic Obesity", 2021 Sarcopnia, pp. 147-156 Summary of the Invention [Means for solving the problem]

[0007] overview In one embodiment, the present disclosure provides a method of preserving skeletal muscle mass during weight loss in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole, or a pharma- ceutically acceptable salt thereof.

[0008] In another embodiment, the weight loss is due to fat reduction.

[0009] In another embodiment, the subject suffers from obesity, excess body fat, diabetes, high blood pressure (hypertension), dyslipidemia, hypertriglyceridemia, acquired lipodystrophy, hereditary lipodystrophy, partial lipodystrophy, or metabolic syndrome.

[0010] In another embodiment, the subject suffers from a disorder selected from non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

[0011] In another embodiment, the subject suffers from reduced muscle mass or obesity sarcopenia.

[0012] In another embodiment, the subject has a body mass index greater than 28 kg / m2.

[0013] In another embodiment, the therapeutically effective amount of Compound 1 is from about 30 mg to about 1400 mg per day, from about 50 mg to about 100 mg per day, from about 150 mg to about 600 mg per day, or from 200 mg to 550 mg orally once daily.

[0014] In another embodiment, the subject experiences greater than 5%, 10%, 20%, 30%, or 40% fat reduction.

[0015] In one embodiment, the method slows the progression of obesity, hypertension, or diabetes. [Brief description of the drawings]

[0016] [Figure 1] Figure 1 shows the Phase 2 study design flow chart.

[0017] [Diagram 2] FIG. 2 shows the body fat mass change in the FAS population.

[0018] [Diagram 3] FIG. 3 shows body fat change in an elevated HbA1c population.

[0019] [Figure 4] FIG. 4 shows the percent reduction in glycated albumin in the overall (FAS) population.

[0020] [Diagram 5] FIG. 5 shows skeletal muscle and fat mass changes in the FAS population.

[0021] [Figure 6] FIG. 6 shows skeletal muscle mass and fat mass changes in the HbA1c population. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] Detailed Description definition While various embodiments and aspects of the invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments and aspects are provided by way of example only. Numerous variations, changes and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein can be used in practicing the invention.

[0023] The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described. All documents or portions of documents cited in this application, including, without limitation, patents, patent applications, articles, books, manuals, and papers, are hereby expressly incorporated by reference in their entirety for any purpose.

[0024] 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole is a novel small molecule uncoupler. It has the following structure: [ka]

[0025] 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole can be prepared by the procedure described in WO2018 / 129258.

[0026] In this disclosure, the terms Compound 1 and CM1 are interchangeable and both refer to 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole.

[0027] The terms "a" or "an" as used herein mean one or more.

[0028] The terms "comprise," "include," and "having," as well as derivatives thereof, are used interchangeably herein as inclusive open-ended terms. For example, the use of "comprising," "including," or "having" means that whatever elements are comprised, possessed, or included are not the only elements encompassed by the subject of the clause containing the verb.

[0029] As used herein, the term "about" refers to a range of values ​​that includes the specified value that one of ordinary skill in the art would consider to be reasonably similar to the specified value. In some embodiments, the term "about" refers to within a standard deviation using measurements generally accepted in the art. In some embodiments, "about" refers to a range that spans + / - 10%, + / - 5%, or + / - 2% of the specified value. In some embodiments, "about" refers to the specified value.

[0030] As used herein, "treatment" or "treating" or "alleviating" or "ameliorating" or "reducing" are used interchangeably herein. These terms refer to an approach to obtain beneficial or desired results, such as, but not limited to, therapeutic benefit. By therapeutic benefit, it is meant eradication or amelioration of the underlying disorder being treated. Moreover, therapeutic benefit is achieved with eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder, such that an improvement is observed in the subject, even though the subject may still be suffering from the underlying disorder. Treatment includes causing the onset of clinical symptoms of the disease to be slowed by administration of the composition; suppressing the disease, i.e., causing a reduction in clinical symptoms of the disease; inhibiting the disease, i.e., stopping the onset of clinical symptoms by administration of the composition after the initial appearance of symptoms; and / or relieving the disease, i.e., causing the regression of clinical symptoms by administration of the composition after their initial appearance.

[0031] "Patient" or "subject" or "subject in need thereof" refers to an organism suffering from or susceptible to a disease or condition that can be treated by using the methods provided herein. The term does not necessarily indicate that the subject has been diagnosed with a particular disease, but typically refers to an individual under medical supervision. Non-limiting examples include humans and other mammals.

[0032] As used herein, "administration" of the disclosed compounds includes delivering a compound as described herein, or a prodrug or other pharma- ceutically acceptable derivative thereof, to a subject using any suitable formulation or route of administration, e.g., as described herein.

[0033] "Pharmaceutically acceptable" refers to compounds, salts, compositions, dosage forms and other materials that are useful in preparing pharmaceutical compositions that are suitable for veterinary or human pharmaceutical use.

[0034] As used herein, the language "pharmacologically acceptable salts" refers to salts of the administered compounds prepared from pharma- ceutically acceptable non-toxic acids and bases, including inorganic acids, inorganic bases, organic acids, inorganic bases, solvates, hydrates, and clathrates thereof.

[0035] An "effective amount" is an amount sufficient to achieve a stated purpose (e.g., to achieve the effect for which it is administered, to treat a disease, to reduce enzyme activity, to reduce one or more symptoms of a disease or condition, to reduce viral replication in cells). An example of an "effective amount" is an amount sufficient to contribute to the treatment of a disease or the reduction of its symptom(s) or symptoms, which may also be referred to as a "therapeutically effective amount". A "reduction" of a symptom(s) or symptoms (and grammatical equivalents of this phrase) refers to a decrease in the severity or frequency of the symptom(s), or the elimination of the symptom(s). Efficacy may also be expressed as a "-fold" increase or decrease. For example, a therapeutically effective amount may have at least 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more efficacy than a control.

[0036] As used herein, the term "elevated body temperature" in a subject refers to an increase in body temperature associated with adverse effects on the subject, including but not limited to illness, physical discomfort or pain, coma, and death. In one non-limiting embodiment, a significant increase in body temperature is an increase of about 0.5°C, about 1°C, about 1.5°C, about 2°C, about 2.5°C, about 3°C, about 3.5°C, about 4°C, about 4.5°C, about 5°C, about 5.5°C, about 6°C or more.

[0037] As used herein, HbA1c refers to hemoglobin A1c; MMRM refers to mixed model repeated measures. A negative value indicates a decreased parameter value.

[0038] Treatment Method

[0039] In one aspect, disclosed herein is a method for preserving skeletal muscle mass during weight loss in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole, or a pharma- ceutically acceptable salt thereof.

[0040] In another aspect, disclosed herein is a method for treating fibrosis, progressive fibrosis, or progressive fibrotic liver disease NASH in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole, or a pharma- ceutically acceptable salt thereof.

[0041] In one embodiment, the weight loss is due to fat loss.

[0042] In another embodiment, the subject suffers from obesity, excess body fat, diabetes, high blood pressure (hypertension), dyslipidemia, hypertriglyceridemia, acquired lipodystrophy, hereditary lipodystrophy, partial lipodystrophy, or metabolic syndrome.

[0043] In another embodiment, the subject suffers from obesity or excess body fat.

[0044] In another embodiment, the diabetes is type 2 diabetes mellitus (T2DM).

[0045] In another embodiment, the subject suffers from a disorder selected from non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

[0046] In another embodiment, the subject suffers from sarcopenia. Sarcopenia is the age-related loss of muscle mass and muscle strength. Increased amounts of adipose tissue are often associated with sarcopenia, a condition called sarcopenic obesity. Symptoms of sarcopenia include, but are not limited to, falls, muscle weakness, slow walking speed, self-reported muscle wasting, or difficulty performing normal daily activities.

[0047] In another embodiment, the subject suffers from reduced muscle mass or sarcopenic obesity.

[0048] In certain embodiments, the subject suffers from at least one symptom selected from reduced exercise tolerance, fatigue, tiredness, increased time to recover after exercise, and ankle swelling.

[0049] In another embodiment, the subject has abnormal HbA1c levels.

[0050] In another embodiment, the subject has an elevated HbA1c level of greater than 5.7.

[0051] In certain embodiments, the subject has a high body mass index (BMI).

[0052] In another embodiment, the subject has a body mass index greater than 28 kg / m2.

[0053] In certain embodiments, the subject's BMI is between 28.0 and 45.0 kg / m2.

[0054] In certain embodiments, the subject is suffering from fibrosis or progressive fibrosis.

[0055] In certain embodiments, the subject has the progressive fibrotic liver disease NASH.

[0056] In certain embodiments, the therapeutically effective amount is from about 30 mg to about 1400 mg per day, from about 100 mg to about 1000 mg per day, from about 150 mg to about 600 mg per day, from 200 mg to 550 mg orally once daily, or from about 50 mg to about 100 mg per day.

[0057] In certain embodiments, the therapeutically effective amount is about 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, or 600 mg per day.

[0058] In certain embodiments, the therapeutically effective amount is about 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, or 95 mg per day.

[0059] In certain embodiments, the therapeutically effective amount is about 150 mg, 300 mg, or 450 mg per day.

[0060] In another embodiment, Compound 1 is administered orally.

[0061] In another embodiment, the subject experiences greater than 5%, 10%, 20%, or 30% fat reduction.

[0062] In another embodiment, subjects with elevated HbA1c levels experience approximately 40% fat reduction.

[0063] In another embodiment, the subject i) lipid reduction of at least 10% or at least 30%; ii) a reduction in blood pressure of at least 5 mmHg; and / or iii) At least 50% reduction in liver fat experience at least one of the following:

[0064] In another embodiment, the subject i) lipid reduction of at least 10% or at least 30%; ii) a reduction in blood pressure of at least 5 mmHg; and / or iii) At least 30% reduction in liver fat experience at least one of the following:

[0065] In another embodiment, the method slows the progression of obesity, hypertension, or diabetes.

[0066] In one embodiment, the method slows the progression of obesity, hypertension, or diabetes.

[0067] Pharmaceutical dosage form

[0068] The present disclosure includes a novel pharmaceutical dosage form of Compound 1 or a pharma- ceutically acceptable salt thereof. The dosage forms described herein are suitable for oral administration to a subject. The dosage form may be any form suitable for oral administration, including, but not limited to, capsules or tablets. In some embodiments, the present disclosure provides a single unit dose capsule or tablet form containing about 30 mg to about 1400 mg, about 100 mg to about 1000 mg, about 150 mg to about 600 mg, or 200 mg to 550 mg of Compound 1 or a pharma- ceutically acceptable salt thereof. In some embodiments, Compound 1 is administered in a hydroxypropyl methylcellulose capsule.

[0069] In some embodiments, the amount of Compound 1 in the unit dosage is about 30mg, 40mg, 50mg, 60mg, 70mg, 75mg, 80mg, 90mg, 100mg, 150mg, 170mg, 200mg, 250mg, 300mg, 340mg, 350mg, 400mg, 450mg, 500mg, 510mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, 850mg, 900mg, 950mg, 1000mg, 1050mg, 1100mg, 1150mg, 1200mg, 1250mg, 1300mg, 1350mg, or 1400mg.In some embodiments, the single unit dosage form is a capsule.In some embodiments, the single unit dosage form is a tablet.

[0070] In some embodiments, the amount of compound 1 in a unit dose is about 30 mg, 100 mg, 200 mg, 500 mg, 600 mg, 1050 mg, or 1400 mg. In some embodiments, the amount of compound 1 in a unit dose is about 200 mg, 400 mg, or 550 mg. In some embodiments, the amount of compound 1 in a unit dose is about 170 mg, 340 mg, or 510 mg. In some embodiments, the amount of compound 1 in a unit dose is about 150 mg, 300 mg, or 450 mg.

[0071] In some embodiments, the amount of Compound 1 in the unit dosage is about 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, or 95 mg per day.

[0072] Route of administration In therapeutic use for controlling or preventing weight gain in a mammal, the compounds of the present disclosure or pharmaceutical compositions thereof can be administered orally or parenterally. EXAMPLES

[0073] Example 1 A Phase 2a Study of Compound 1 in Subjects with Elevated Liver Fat and High Body Mass Index (BMI) This is due to nonalcoholic fatty liver disease (NAFLD), elevated liver fat (>8%), and elevated body mass index (BMI) (>28 kg / m 2 from 45kg / m 2 This was a 61-day, randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of three doses of orally administered Compound 1 compared with placebo in subjects with chronic obstructive pulmonary disease (COPD). Subjects were stratified by glycated hemoglobin (HbA1c ≥ 5.7%). The primary endpoint was the relative change in liver fat content from baseline to day 61 as assessed by magnetic resonance imaging proton density fat fraction (MRI-PDFF); secondary endpoints included safety, changes in body composition, weight, glycemic control, and inflammatory markers.

[0074] 80 subjects were enrolled (placebo n=20, Compound 1 150 mg n=20, 300 mg n=21, 450 mg n=19). At baseline, HbA1c was elevated in 40% of subjects. At day 61, the absolute and relative reductions in liver fat in Compound 1-treated subjects and HbA1c subsets were highly significant (p<0.0001 vs. placebo). Responder analysis using 30% or greater reduction in liver fat by MRI-PDFF showed responses in 40%, 71%, and 72% for the 150 mg, 300 mg, and 450 mg doses of Compound 1, respectively, and 43%, 75%, and 86% in the HbA1c subset vs. 0-5% for placebo (p<0.05 for all comparisons). Compound 1 treatment was associated with significant reductions in total body fat, body weight, inflammatory markers, and glycated albumin. Lean body mass was preserved. No serious adverse events occurred. Six subjects discontinued prematurely, three on Compound 1 (150 mg n=2, 300 n=1) and three on placebo. Diarrhea and flushing, most often mild, occurred in 35% and 25% of Compound 1 subjects, respectively.

[0075] research design

[0076] This was a phase 2, single-center, randomized, parallel-group, double-blind, placebo-controlled study to evaluate the safety and efficacy of Compound 1 in healthy subjects with high BMI and evidence of elevated liver fat. Subjects were screened over a 45-day period, and eligible subjects were randomized to receive a once-daily oral dose of Compound 1 at 150 mg, 300 mg, or 450 mg or matching placebo under fasting conditions for 61 days. Randomization was stratified by glycated hemoglobin A1c (HbA1c), with normal baseline defined as HbA1c of <5.7% and high baseline defined as HbA1c of ≥5.7%. The final follow-up visit occurred within 10 to 14 days after the last dose. See Figure 1.

[0077] Randomization was based on HbA 1c Subjects are stratified into two HbA1c strata: one subgroup of subjects with normal baseline HbA1c, defined as an HbA1c of <5.7%, and the other subgroup of subjects with high baseline HbA1c, defined as an HbA1c between 5.7% and 9.0%, inclusive.

[0078] the purpose The primary efficacy and safety objectives of the study are to: Efficacy: To evaluate the reduction in liver fat content as assessed by magnetic resonance imaging proton density fat fraction (MRI-PDFF) from baseline to day 61 in subjects with elevated BMI treated with Compound 1 compared to placebo. Safety: To evaluate the safety and tolerability of repeated daily dosing of the compound for 61 days in overweight and obese subjects as defined by BMI. The secondary objectives of this study were to: To evaluate the rate and amount of weight loss following 61 days of Compound 1 treatment. To evaluate the change from baseline in whole body adiposity by MRI after 61 days of Compound 1 treatment. To characterize the pharmacokinetic (PK) profiles of Compound 1 and its metabolites, DNP and M1, over 61 days of dosing in subjects with high BMI. To assess and correlate changes from baseline in measures of liver composition with changes in liver fat content following dosing with Compound 1. · To investigate the pharmacodynamic (PD) effects of compound 1 on metabolic and cardiovascular risk factors. To investigate the PD effects of compound 1 on metabolomic, proteomic and lipidomic profiles; · If data permits, characterize the dose / exposure relationship of Compound 1 efficacy and PD effects.

[0079] Inclusion criteria Subjects must meet all of the following inclusion criteria to be eligible: 1.28.0kg / m 2 from 45.0 kg / m 2 Adult men or women, aged 28 to 65 years (inclusive) at the time of informed consent, with a BMI between 0.01 and 0.05 (inclusive). a. Female subjects of childbearing potential must be non-lactating, not pregnant as confirmed by a negative urine pregnancy test at screening, and agree to continue using an effective method of contraception for at least 4 weeks until 30 days after the last dose of study drug or a barrier method for 2 weeks prior to the first study drug administration. b. Female subjects of childbearing potential must not donate eggs during the study and for at least 30 days after the last dose of study drug. c. Non-childbearing female subjects must be surgically sterile (e.g., hysterectomy, bilateral tubal ligation, oophorectomy) or postmenopausal (follicle-stimulating hormone (FSH) >40 U / L at screening and no menses for >1 year). d. Male subjects who have not had a vasectomy and / or subjects who have had a vasectomy but do not have two post-surgical negative tests for sperm, must agree to use an acceptable method of contraception from the time of the first dose of study drug until 30 days after the last dose of study drug, and to not donate sperm during the study and for at least 30 days after the last dose of study drug.

[0080] Exclusion criteria Subjects will be excluded from the study if any of the following criteria are met: 1. Insulin-controlled diabetes. 2. Pregnant, breastfeeding or planning to become pregnant. 3. Intolerance to Magnetic Resonance Imaging (MRI) or having a condition that contraindicates the MRI procedure, including but not limited to incompatibility with MRI scanners or surgical clips / metal implants / shrapnel. Subjects must not be claustrophobic, have a history of claustrophobia, or intolerance of enclosed or small spaces. 4. Weight gain or loss of >5% in the 3 months prior to the study or >10% in the 6 months prior to screening. 5. History of lap banding, intragastric balloon, duodenal jejunal sleeve, or bariatric surgery within 5 years of screening, planned bariatric surgery prior to the end of study participation, or plans to lose weight during this study either through a specialized diet, exercise program, or both. 6. History of malignant hyperthermia. 7. History of chronic severe recurrent skin rash of unknown cause. 8. History of cardiovascular disease or current clinically significant cardiovascular disease, including but not limited to, transient ischemic attack, stroke, arrhythmia, syncope, unstable angina, myocardial infarction, congestive heart failure, or uncontrolled hypertension within 6 months prior to screening (uncontrolled hypertension defined as a systolic blood pressure of ≥ 160 mmHg or a diastolic blood pressure of ≥ 100 mmHg based on the average of three resting determinations in the sitting position with an appropriately sized cuff). 9. Resting heart rate of <45 bpm or >110 bpm. 10. On screening ECG or by history: Marked baseline prolongation of the QT / QTcF interval (e.g., repeated demonstration of a QTcF interval of >450 msec in men and >470 msec in women). b. History of additional risk factors for polymorphic ventricular tachycardia (TdP) (e.g., family history of heart failure, hypokalemia, long QT syndrome) or family history of sudden cardiac death of unknown origin. 11. Renal disease, kidney transplant, or CKD-EPI creatinine equation (NKF 2009; https: / / www.kidney.org / content / ckd-epi-creatinine-equation-2009) <50mL / min / 1.73m 2 Estimated glomerular filtration rate (eGFR). 12. Significant lung disease requiring chronic daily medication, such as chronic obstructive pulmonary disease (COPD), emphysema, pulmonary fibrosis, or asthma. 13. Untreated Obesity Hypoventilation Syndrome (OHS) or Obstructive Sleep Apnea (OSA). 14. History of liver disease or active (acute or chronic) liver disease other than non-alcoholic fatty liver disease (NAFLD) / non-alcoholic steatohepatitis (NASH), including but not limited to autoimmune liver disease, viral hepatitis, hereditary hemochromatosis, primary biliary cirrhosis, Wilson's disease, alpha-1-antitrypsin deficiency, alcoholic liver disease, acute fatty liver of pregnancy or drug-induced (including acetaminophen) liver disease. 15. Clinically significant gastroparesis, history of or treatment for inflammatory bowel disease, or any surgical procedure of the upper gastrointestinal tract except cholecystectomy, or any secondary gastric procedure approved by a medical monitor. 16. History of cirrhosis and / or hepatic decompensation, such as ascites, hepatic encephalopathy, or variceal bleeding. 17. History of acute pancreatitis or chronic pancreatitis of any cause within 1 year of screening. Serum triglyceride concentration greater than 18.500 mg / dL. 19. HbA1C > 9.0% 1c . 20. Family (mother / father / sibling) and / or personal history of retinal detachment at any time in the past. 21. Any history or current diagnosis of glaucoma. 22. Evidence of the following at screening eye exam: a. Peripheral retinal pathology requiring treatment, retinal tears, or lattices requiring treatment. b. Diabetic retinopathy with macular exudates or macular edema if demonstrated by optical coherence tomography (OCT) and examination. c. Any active macular disease affecting vision, such as macular pucker (epiretinal membrane) and macular degeneration. d. Visually significant cataracts as determined by an ophthalmologist. e. Any previous intravitreal injection of an anti-VEGF agent for macular degeneration. f. History of previous vitrectomy. 23. History of malignant neoplasms within 5 years of screening, except for basal or squamous cell skin cancer, cervical intraepithelial carcinoma, or prostate cancer that is not currently or is not expected to require radiation therapy, chemotherapy and / or surgical intervention or to initiate hormonal treatment. 24. History of organ transplantation. 25. Received a COVID-19 vaccine less than 1 week prior to dosing (Visit 2 / Day 1) and / or is scheduled to receive a COVID-19 vaccine during the study period. 26. History of significant substance abuse within 1 year prior to screening, or frequent use of soft drugs (e.g., marijuana) within 3 months prior to the screening visit, or hard drugs (e.g., cocaine, phencyclidine [PCP], opioid derivatives including heroin, and amphetamine derivatives) within 1 year prior to screening. 27. History of alcoholism within the last 2 years or current evidence of excessive alcohol consumption as assessed by a screening assessment using the Alcohol Use Disorders Identification Test (AUDIT, Thompson 2018), and a history of regular alcohol consumption of more than approximately 14 drinks / week for men and 7 drinks / week for women [1 drink = 4 oz (120 mL) of wine or 12 oz (360 mL) of beer or 1 oz (30 mL) of distilled liquor] within 6 months of screening, as determined by the investigator. 28. Positive urine drug screen for drugs of abuse or a positive phosphatidylethanol (PEth) blood test result of >100 ng / mL at screening. In the example of an exclusive PEth value, consideration for enrollment may be provided if the Primary Investigator and Medical Monitor agree that the subject's history is not consistent with alcohol abuse. 29. Current regular vaping or >5 cigarettes or equivalent per week. Use of nicotine patches for smoking cessation is acceptable. 30. Positive test results for hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCVAb), or human immunodeficiency virus (HIV1 / 2) antibody. 31. Neutropenia defined as absolute neutrophil count of ≤1000 / μL. 32. Serum AST or ALT >5 × upper limit of normal (ULN) at screening. (One repeat test may be possible within 7 days at the investigator's discretion). 33. Total bilirubin >ULN unless due to Gilbert's syndrome or considered normal variation in the absence of other clinically relevant liver dysfunction as approved by Medical Monitor. 34. International normalized ratio (INR) ≥ 1.3 at screening if there is other evidence of underlying significant liver dysfunction. 35. Participation in another clinical trial at screening or exposure to any investigational drug, including topical, within 30 days of screening, or within 5 half-lives if half-life is known. 36. No tattoos or body piercings during the course of the study. Any underlying physical or psychological medical condition that, in the opinion of the investigator or sponsor, would make it impossible for the subject to be able to comply with the study requirements or to complete the study. 37. Any condition that the investigator believes may interfere with his / her ability to provide written informed consent, comply with study instructions, or confound interpretation of study results or place the subject at undue risk. 38. Known or potential hypersensitivity to Compound 1 or its excipients. Prohibited medications (current use): 39. Any herbal supplements, over-the-counter, mail order or prescription drugs for weight loss. 40. Prescription or over-the-counter stimulants, such as: dextroamphetamine / Dexedrine, dextroamphetamine / amphetamine combination products / Adderall, or methylphenidate (Ritalin®, Concerta®). 41. Thiazolidinediones (TZDs): Pioglitazone / Actos, Rosiglitazone / Avandia. 42. Glucagon-like peptide 1 (GLP1) agonists: Exenatide / Byetta / Bydureon, lixisenatide / Adlixin, liraglutide / Victoza, dulaglutide / Trulicity, semaglutide / Ozempic. 43. Sodium-glucose cotransporter-2 (SGLT2) inhibitors: canagliflozin / Invokana, dapagliflozin / Forxiga, empagliflozin / Jardiance, ertugliflozin / Steglatro. 44. Vitamin E: Use of ursodiol or high-dose vitamin E >400 IU / day for at least 1 month within the last 6 months or initiation of high-dose vitamin E within the last 3 months prior to screening. 45. Recent (within 3 months of screening) or current use of obeticholic acid / Ocaliva, systemic corticosteroids, methotrexate, tamoxifen, amiodarone, or long-term use of tetracycline. 46. ​​Warfarin, heparin, factor Xa inhibitors (dabigatran betrixaban edoxaban, apixaban, and rivaroxaban). 47. Concomitant medications known to prolong the QT / QTc interval and to be associated with an increased risk of polymorphic ventricular tachycardia as identified in the https: / / crediblemeds.org / website list category of 'Known Risk'. 48. Products containing cannabidiol (CBD).

[0081] Phase 2a study results A Phase 2a metabolism study of Compound 1 was conducted in obese participants (body mass index 28 kg / m2) with elevated liver fat (greater than 8%). 2 from 45kg / m 2 The Phase 2a study was a 61-day randomized, double-blind, placebo-controlled study designed to evaluate the safety and efficacy of three dose levels of Compound 1 (150 mg, 300 mg, and 450 mg) in ... Weight loss was exclusively from fat loss and maintained lean body mass at 8 weeks at all dose levels, with no changes in diet or exercise behavior. Weight and fat loss was greatest at the highest dosage level, with participants losing an average of 6 pounds (p<0.001, high dose vs. placebo). Participants with elevated HbA1c levels experienced greater weight and fat loss, losing an average of 10 pounds (p<0.0001, high dose vs. placebo). Fat loss was observed by MRI in the liver, visceral and subcutaneous compartments. Absolute reductions in liver fat by MRI-PDFF of >30% were observed: 40%, 71%, and 72% at the 150 mg, 300 mg, and 450 mg dose levels for Compound 1, respectively, and 43%, 75%, and 86% in the HbA1c subset at Compound 1 doses versus 0-5% for placebo (P<0.05 for all). The relative reduction in liver fat was 33%, 43%, and 40%, corresponding to responder rates of 40%, 71%, and 72% (>30% relative reduction) at the low, medium, and high doses, respectively, compared with a placebo relative reduction of 2% liver fat and 5% responder rate. Compound 1 was well tolerated at all dose levels with excellent compliance. No serious adverse events or deaths were reported. Diarrhea and transient flushing associated with alcohol intake occurred in 25% and 31.6% of Compound 1 subjects, respectively, and were the most commonly reported treatment-emergent adverse events. The majority of these events were mild; one participant discontinued Compound 1 in the low-dose arm due to diarrhea, but no participants discontinued for any reason at the high dose. -Short-term treatment with Compound 1 was associated with significant improvements across primary and secondary endpoints related to NAFLD and obesity. The safety and tolerability of Compound 1 combined with its ability to reduce hepatic and whole-body steatosis in subjects regardless of HbA1c status suggests that long-term treatment with Compound 1 has the potential to be an effective treatment for NAFLD and other obesity-related metabolic diseases. Compound 1 at 150 mg, 300 mg, and 450 mg demonstrated a significant dose-related positive effect on the primary efficacy endpoint of change from baseline in liver fat content by MRI-PDFF across the entire population and among those with elevated HbA1c, with these changes occurring within 61 days of treatment. Placebo-corrected changes from baseline ranged from 0.6% to -7% for Compound 1, which compares favorably to other short-term Phase 2 studies of drugs for NAFLD (Harrison et al., 2021; Loomba et al., 2020). Approximately 60% of subjects overall and 68% of subjects in subgroups experienced at least a 30% reduction in liver fat based on MRI-PDFF, with placebo-corrected mean percent changes from baseline ranging from -33% to 43% for overall subjects and -42% to -50% for subjects in subgroups. Reductions in liver fat content were accompanied by reductions in body weight accounted for by body fat without reductions in lean body mass. Improvements in liver volume, SAT, and CAP scores occurred with Compound 1 in the overall group and in the subgroup with elevated HbA1c. At the 300 mg and 450 mg doses, Compound 1 demonstrated significant positive effects on several endpoints, such as InBody scale measurements of body weight, fat mass, and percent body fat, without significant effects on skeletal muscle mass, lean body mass, or dry lean mass. Compared to placebo, mean body weight was reduced by 6 pounds in the 450 mg group and 10 pounds in the subgroup of subjects with elevated HbA1c at day 61, while skeletal muscle mass (and lean body mass and dry lean mass) remained unchanged. Significant reductions in inflammation and metabolic markers were observed with Compound 1. In this study, glycated albumin was used to assess metabolic control, rather than HbA1c, because changes in glycated albumin occurred earlier than HbA1c (120 days) and were a better marker of glycemic control in this 61-day study. A 0.5% reduction in HbA1c was observed in parallel with a larger reduction in glycated albumin that was statistically significant. The preferential loss of fat and improved glycemic control in subjects with elevated HbA1c is intriguing and has the potential to improve metabolic and inflammatory health in people with type 2 diabetes and obesity as a longer-term treatment. · The results indicate that treatment with compound 1 improves FAST scores and that this improvement is of a clinically relevant magnitude evident at the lowest dose used (150 mg). The FAST score is a non-invasive test to identify patients with progressive liver fibrosis. Non-alcoholic fatty liver disease has a high prevalence, especially in obese and type 2 diabetes patient populations. Some patients can survive with elevated levels of liver fat without progressive disease, while others progress to develop NASH. Currently, a definitive diagnosis of NASH requires liver biopsy and histological scoring, an invasive and time-consuming diagnostic procedure associated with some risk. The challenge to identifying patients with progressive disease puts them at risk of progressing to later stages of NASH without intervention. Fibroscan is a non-invasive ultrasound-based measurement of liver elasticity and stiffness, providing a measure of fibrosis. Aspartate aminotransferase (AST) is a liver enzyme that can be measured in blood samples, and elevated levels indicate liver damage. In combination, fibroscan and AST levels (FAST score) have been shown to provide a valuable indicator of patients with progressive fibrosis (Woreta et al. PLoS One 2022 April 15; 17(4): e0266859, https: / / doi.org / 10.1371 / journal.pone.0266859). A relatively small reduction in FAST score of 0.2 points has been shown to provide improvement in some clinical measures in patients diagnosed with NASH (Wong et al, J. of Hepatology Vol. 75, pp. S257-S258) 2021; Newsome et al, The N England J of Medicine 2021;384:1113-24). Thus, the present disclosure provides a method for treating a subject having an elevated FAST score, where the subject is experiencing progressive disease. In some embodiments, the method reduces the FAST score in the patient to reduce the risk of progressive disease. In some embodiments, the progressive disease includes progressive fibrosis, progressive NASH, and / or progressive fibrotic liver disease NASH. NASH is a form of NAFLD that has liver inflammation and liver damage in addition to fat in the liver. The inflammation and liver damage of NASH can cause liver fibrosis, or scarring. NASH can lead to cirrhosis, where the liver becomes scarred and permanently damaged. Our data further indicate that Compound 1 is efficacious at lower dose levels to treat patients with HbA1c levels between 5.7% and 9.0%, who have the progressive fibrotic liver disease NASH. Specific efficacy and safety results of Phase 2a are shown in the figures and tables below:

[0082] (1) Treatment outcomes in response across all dose arms (>30% liver fat reduction by MRI-PDFF) as shown in Table 1 below: Table 1 [Table 1]

[0083] (2) Body fat loss in the overall group as shown in Table 2 and Figure 2. Table 2 [Table 2]

[0084] (3) Body fat change (mean ± SEM) in the elevated HbA1c population as shown in Table 3 and Figure 3 below. Table 3 [Table 3]

[0085] (4) Preservation of skeletal muscle mass is shown in Table 4 below: Table 4 [Table 4]

[0086] (5) The change in MRI-proton density fat percentage (%) from baseline to day 61 in all subjects and in the subgroup of subjects with elevated HbA1c is shown in Table 5. Table 5 [Table 5-1] [Table 5-2]

[0087] (6) Percent (%) change in glycated albumin from baseline to day 61, as shown in Table 6 and Figure 4. Table 6 [Table 6]

[0088] (7) MMRM analyses of the changes from baseline to day 61 in fat mass, percent body fat, lean body mass, and in all subjects and in the subgroup of subjects with elevated HbA1c are shown in Figures 5 and 6 and Table 7. Table 7 [Table 7] LS refers to change from baseline and 95% CI of association; LS means differences and 95% CI of association, and two-sided p-values ​​are from MMRM models with treatment as fixed effect, baseline HbA1c stratification as factor, and baseline parameter values ​​as covariates. Weight loss in subjects administered Compound 1 was achieved without a corresponding loss in lean body mass, i.e., the overall weight loss observed was largely due to fat loss, but the treatment effect can be attributed entirely to fat loss. Not only was weight loss more pronounced in participants with elevated HbA1c (all participants had HbA1c>5.7 at baseline, amounting to approximately 40% in all cohorts), but weight loss was more fat-specific, as no loss in muscle mass was observed from baseline and an increase in muscle mass was achieved compared to placebo.

[0089] In addition, the 300mg and 450mg doses of Compound 1 demonstrated significant positive effects on several secondary endpoints, such as InBody scale measurements of body weight, body fat mass, and percent body fat, without effects on skeletal muscle mass, lean body mass, or dry lean mass. Compared to placebo, mean body weight was reduced by 6 pounds in the 450mg group and 10 pounds in the subgroup of subjects with elevated HbA1c at day 61, while skeletal muscle mass (as well as lean body mass and dry lean mass) remained unchanged. Significant reductions in inflammation and metabolic markers were observed with Compound 1. In this study, glycated albumin was used to assess metabolic control, rather than HbA1c, because changes in glycated albumin occurred earlier than HbA1c (120 days) and were a better marker of glycemic control in this 61-day study. A 0.5% reduction in HbA1c was observed in parallel with a larger reduction in glycated albumin that was statistically significant. Preferential loss of fat and improved glycemic control in subjects with elevated HbA1c has the potential to be an interesting, longer-term treatment to improve metabolic and inflammatory health in people with type 2 diabetes and obesity.

Claims

1. 1. A composition for use in a method for preserving skeletal muscle mass during weight loss or weight maintenance in a subject in need thereof, the composition comprising 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole, or a pharmaceutically acceptable salt thereof, the method comprising administering to the subject a therapeutically effective amount of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole, or a pharmaceutically acceptable salt thereof.

2. The composition of claim 1 , wherein the weight loss is due to fat loss.

3. 3. The composition of claim 1 or claim 2, wherein the subject suffers from obesity, excess body fat, diabetes, high blood pressure (hypertension), dyslipidemia, hypertriglyceridemia, acquired lipodystrophy, hereditary lipodystrophy, partial lipodystrophy, or metabolic syndrome.

4. 3. The composition of claim 1 or claim 2, wherein the subject suffers from obesity or excess body fat.

5. The composition of claim 1 or claim 2, wherein the subject suffers from diabetes.

6. The composition of claim 5, wherein the diabetes is type 2 diabetes mellitus (T2DM).

7. 3. The composition of claim 1 or claim 2, wherein the subject suffers from a disorder selected from non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

8. The composition of claim 1 or claim 2, wherein the subject suffers from sarcopenia.

9. The composition of claim 1 or claim 2, wherein the subject suffers from sarcopenic obesity.

10. 3. The composition of claim 1 or claim 2, wherein the subject suffers from reduced muscle mass, muscle loss, muscle weakness, decreased muscle strength, slow walking speed, or difficulty performing normal daily activities.

11. The composition described in claim 1 or claim 2, wherein the method slows the progression of obesity, hypertension, or diabetes.

12. The composition of claim 1 or claim 2, wherein the subject has an abnormal HbA1c level.

13. The composition of claim 12, wherein the abnormal HbA1c level is elevated HbA1c.

14. 3. The composition of claim 1 or claim 2, wherein the subject has a body mass index greater than 28 kg / m2.

15. 3. The composition of claim 1 or claim 2, wherein the therapeutically effective amount is from about 30 mg to about 1400 mg per day, from about 100 mg to about 1000 mg per day, from about 150 mg to about 600 mg per day, from 200 mg to 550 mg per day, or from about 50 mg to about 100 mg per day.

16. 3. The composition of claim 1 or claim 2, wherein the therapeutically effective amount is about 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, or 600 mg per day.

17. 3. The composition of claim 1 or claim 2, wherein the therapeutically effective amount is about 150 mg, 300 mg, or 450 mg per day.

18. 3. The composition of claim 1 or claim 2, wherein the therapeutically effective amount is about 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, or 95 mg per day.

19. The composition described in claim 1 or claim 2, characterized in that the 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole, or a pharmaceutically acceptable salt thereof, is administered orally once a day.

20. 3. The composition of claim 1 or claim 2, wherein the subject experiences greater than 5%, 10%, 20%, 30%, or 40% fat reduction.

21. 21. The composition of claim 20, wherein the subject with elevated HbA1c levels experiences approximately 40% fat reduction.

22. The object is i) lipid reduction of at least 10% or at least 30%; ii) a decrease in blood pressure of at least 5 mmHg; and / or iii) a reduction in liver fat of at least 30% or at least 50% The composition of claim 1 or claim 2, wherein the composition experiences at least one of the following symptoms:

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