Methods of treating obesity and obesity-related conditions

Abstract

The present invention relates to methods of reducing weight, HbA1c levels, high-sensitivity C-reactive protein, and systolic blood pressure in human patients comprising administering to the patient maridebart cafraglutide with the result being treatment of obesity, type II diabetes, and other obesity related conditions such as atherosclerotic cardiovascular disease and heart failure.

Description

METHODS OF TREATING OBESITY AND OBESITY-RELATED CONDITIONS CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U. S. Provisional Patent Application No.63 / 724,866 filed November 25, 2024, and U. S. Provisional Patent Application No. 63 / 825,240 filed June 17, 2025, which are incorporated herein by reference in their entirety.SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on October 10, 2025, is named 11060-W001-PCT_Seqlisting. XML and is 11,833 bytes in size.FIELD OF THE INVENTION

[0003] The present invention relates to treatment of obesity and obesity-related conditions using maridebart cafraglutide, an antibody-peptide conjugate that selectively inhibits the glucosedependent insulinotropic polypeptide receptor (GIPR) while agonizing glucagon-like peptide- 1 receptor (GLP-1R).BACKGROUND OF THE INVENTION

[0004] As a multifactorial chronic disease, obesity has been an increasingly prevalent health problem worldwide (World Health Organ. 2016. Obesity and overweight: fact sheet 311). The obesity-associated comorbidities further add burden to the healthcare system (Apovian CM, 2016). The current unmet expectations of anti-obesity therapeutics support the need for developing safe and effective novel agents (Wright SM, Aronne LJ. 2011; Valsamakis et al, 2017).

[0005] Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide- 1 (GLP-1) are gut-derived incretin hormones, well known for their ability to augment glucose stimulated insulin secretion. In addition to the incretin effects, GLP-1 promotes satiety via the GLP-1 receptor (GLP-1R) (Turton et al, 1996) while GIP promotes adiposity via the GIP receptor (GIPR) (Yip et al, 1998; Beck and Max, 1987; Hauner et al, 1988; Knapper et al, 1995). Several GLP-1 receptor agonists have been approved to treat type 2 diabetes and have demonstratedbenefits in controlling obesity (Prasad-Reddy and Isaacs, 2015). Genome-wide association studies in human and mouse show that the GIPR locus contributes to body weight and GIPR knockout mice are protected from diet induced obesity (Berndt et al., 2013; Saxena et al., 2010; Speliotes et al., 2010; Althage et al., 2008; Miyawaki et al., 2002; Nasteska et al., 2014).Pharmacological inhibition of GIPR with anti-GIPR antibodies prevented body weight gain in diet-induced obese (DIO) mice and obese cynomolgus monkeys (Killion et al, 2018). In addition, GIPR antagonism in combination with GLP-1R agonism synergistically reduced body weight in DIO mice and obese cynomolgus monkeys (Killion et al, 2018), suggesting the potential for a GIPR / GLP-1R bispecific molecule for the treatment of obesity.

[0006] As an anti-GIPR / GLP-1R bispecific molecule, maridebart cafraglutide (also known as “AMG-133”) is engineered by conjugating a GLP-1 analog agonist peptide to a fully human monoclonal anti-human GIPR antagonist antibody using natural amino acid linkers. Here we report clinical trial results of maridebart cafraglutide in patients with obesity.SUMMARY OF THE INVENTION

[0007] The present invention is based, in part, on the identification of a therapeutic regimen for effectively promoting weight loss, reducing HbAlc levels, reducing high-sensitivity C reactive protein, and reducing systolic blood pressure in a human patient. In an embodiment, the patient has type II diabetes. In an embodiment, the patient does not have type II diabetes.

[0008] Accordingly, in one aspect, the present invention is directed to a method for treating obesity or promoting weight loss in a human patient comprising administering to the patient a pharmaceutical composition comprising maridebart cafraglutide at an amount of about 70 mg, about 140 mg, about 210 mg, about 280 mg, about 350 mg, or about 420 mg; wherein after the pharmaceutical composition is administered about every four weeks for one year the patient’s weight is reduced by at least 16%. In another aspect, the present invention is directed to use of maridebart cafraglutide for preparation of a medicament for treating obesity or promoting weight loss in a human patient in need thereof, wherein the medicament is formulated for administration at a dose of about 70 mg, about 140 mg, about 210 mg, about 280 mg, about 350 mg, or about 420 mg; and wherein after the pharmaceutical composition is administered about every four weeks for one year the patient’ s weight is reduced by at least 16%. In an embodiment, the patient’s high-sensitivity C-reactive protein (“hs-CRP”) level is reduced by at least 50%. In anembodiment, the patient’s systolic blood pressure (“SBP”) is reduced by at least 8 mmHg. In an embodiment, the amount of maridebart cafraglutide is about 280 mg and the patient’s weight is reduced by at least 19%, the patient’s hs-CRP is reduced by at least 60%, or the patient’s SBP is reduced by at least 12 mmHg. In an embodiment, the amount of maridebart cafraglutide is about 420 mg and the patient’s weight is reduced by at least 18%, the patient’s hs-CRP is reduced by at least 55%, or the patient’s SBP is reduced by at least 11 mmHg.

[0009] In another aspect, the present invention is directed to a method for treating type II diabetes or reducing HbAlc levels in a human patient comprising administering to the patient a pharmaceutical composition comprising maridebart cafraglutide at an amount of about 70 mg, about 140 mg, about 210 mg, about 280 mg, about 350 mg, or about 420 mg; wherein after the pharmaceutical composition is administered about every four weeks for one year the patient’s weight is reduced by at least 12%, and HbAlc level is reduced by at least 1.8%. In another aspect, the present invention is directed to use of maridebart cafraglutide for preparation of a medicament for treating type II diabetes or reducing HbAlc in a human patient in need thereof, wherein the medicament is formulated for administration at a dose of about 70 mg, about 140 mg, about 210 mg, about 280 mg, about 350 mg, or about 420 mg; wherein after the pharmaceutical composition is administered about every four weeks for one year the patient’s weight is reduced by at least 12%, and HbAlc level is reduced by at least 1.8%. In an embodiment, the patient’s high-sensitivity C-reactive protein (“hs-CRP”) level is reduced by at least 40%. In an embodiment, the patient’s systolic blood pressure (“SBP”) is reduced by at least 8 mmHg. In an embodiment, the amount of maridebart cafraglutide is about 280 mg and the patient’s weight is reduced by at least 12% or the patient’s SBP is reduced by at least 12 mmHg. In an embodiment, the amount of maridebart cafraglutide is about 420 mg and the patient’s weight is reduced by at least 16%, the patient’s SBP is reduced by at least 11 mmHg, or the patient’s hs-CRP is reduced by at least 60%.

[0010] In another aspect, the present invention is directed to a method for treating atherosclerotic cardiovascular disease or reducing high-sensitivity C-reactive protein (“hs-CRP”) in a human patient comprising administering to the patient a pharmaceutical composition comprising maridebart cafraglutide at an amount of about 70 mg, about 140 mg, about 210 mg, about 280 mg, about 350 mg, or about 420 mg; wherein after the pharmaceutical composition is administered about every four weeks for one year the patient’s weight is reduced by at least 16%,and hs-CRP level is reduced by at least 50%. In another aspect, the present invention is directed to use of maridebart cafraglutide for preparation of a medicament for treating atherosclerotic cardiovascular disease or reducing high-sensitivity C-reactive protein (“hs-CRP”) in a human patient in need thereof, wherein the medicament is formulated for administration at a dose of about 70 mg, about 140 mg, about 210 mg, about 280 mg, about 350 mg, or about 420 mg; wherein after the pharmaceutical composition is administered about every four weeks for one year the patient’s weight is reduced by at least 16%, and hs-CRP level is reduced by at least 50%. In an embodiment, the amount of maridebart cafraglutide is about 280 mg and the patient’s weight is reduced by at least 19%, the patient’s hs-CRP is reduced by at least 60%, or the patient’s SBP is reduced by at least 12 mmHg. In an embodiment, the amount of maridebart cafraglutide is about 420 mg and the patient’s weight is reduced by at least 18%, the patient’s hs-CRP is reduced by at least 55%, or the patient’s SBP is reduced by at least 11 mmHg.

[0011] In another aspect, the present invention is directed to a method for treating heart failure or reducing systolic blood pressure in a human patient comprising administering to the patient a pharmaceutical composition comprising maridebart cafraglutide at an amount of about 70 mg, about 140 mg, about 210 mg, about 280 mg, about 350 mg, or about 420 mg; wherein after the pharmaceutical composition is administered about every four weeks for one year the patient’s weight is reduced by at least 16%, and systolic blood pressure (“SBP”) is reduced by at least 8 mmHg. In another aspect, the present invention is directed to use of maridebart cafraglutide for preparation of a medicament for treating heart failure or reducing systolic blood pressure in a human patient in need thereof, wherein the medicament is formulated for administration at a dose of about 70 mg, about 140 mg, about 210 mg, about 280 mg, about 350 mg, or about 420 mg; wherein after the pharmaceutical composition is administered about every four weeks for one year the patient’s weight is reduced by at least 16%, and systolic blood pressure (“SBP”) is reduced by at least 8 mmHg. In an embodiment, the amount of maridebart cafraglutide is about 280 mg and the patient’s weight is reduced by at least 19%, the patient’s hs-CRP is reduced by at least 60%, or the patient’s SBP is reduced by at least 12 mmHg. In an embodiment, the amount of maridebart cafraglutide is about 420 mg and the patient’s weight is reduced by at least 18%, the patient’s hs-CRP is reduced by at least 55%, or the patient’s SBP is reduced by at least 11 mmHg.BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 A IB depict MariTide Phase 2 study design. This is a multinational Phase 2, double-blind, randomized, placebo-controlled, dose-ranging trial of MariTide, which included 2 cohorts: persons with Obesity (Cohort OB [protocol Cohort A]) and Obesity with Type 2 Diabetes (Cohort OB-T2D [protocol Cohort B]). Participants in Cohort OB were randomized in a 3:3:3:2:2:2:3 ratio to receive 52 weeks of MariTide with one of the following doses: 140, 280, or 420 mg every 4 weeks (Q4W) with no dose escalation (No-DE); or 420 mg once every 8 weeks (Q8W) with No-DE; or 420 mg Q4W with a 4-week dose escalation (4W-DE); or 420 mg Q4W with a 12-week dose escalation (12W-DE); or placebo, respectively (Figure 1A). The three dose levels were selected based on doseresponse analyses from the Phase 1 study to enable dose selection for Phase 3. The 420 mg Q8W was selected to see if the tolerability and efficacy were affected by less frequent dosing. The two DE regimens were selected to assess whether DE and duration of DE improves GI tolerability. Participants undergoing the 4-week DE received 70mg on Days 1 and 14, and then 420mg Q4W from Day 28 onward. Participants undergoing the 12-week DE received 70mg on Day 1, 140mg on Day 28, 210mg on Day 56, and 420mg Q4W from Day 84 onward. Participants in Cohort OB-T2D were randomized in a 1: 1: 1: 1 ratio to receive 52 weeks of MariTide 140, 280, 420 mg Q4W (all with No-DE), or placebo, respectively (Figure IB).

[0013] Figure 2 depicts M-INVR patient-reported outcome tool. Each symptom is scored independently from 1-5 where 1 represents no symptoms and 5 represents 7 or more episodes within a day. Each symptom score was evaluated separately (range 1-5) and collectively by summing up the individual symptom scores (range: 3-15).

[0014] Figures 3A-3B depicts Phase 2 Participant disposition. Participant disposition from randomization. In Cohort OB (Figure 3A), a total of 294 (76.0%) participants in the overall MariTide group and 48 (61.5%) of participants in the placebo group completed part 1 of study drug. For Cohort OB-T2D (Figure 3B), a total of 65 participants (68.4%) in the overall MariTide group and 22 participants (68.8%) in the placebo group have completed part 1 of study drug. 4W-DE, 4-week dose escalation; 12W-DE, 12-week dose escalation; no-DE, no dose escalation.

[0015] Figures 4A-4B depicts Change in body weight. Estimated marginal mean change in body weight from baseline to week 52 in Cohort OB derived from a mixed-model for repeated measures (Figure 4A) or treatment policy approach (Figure 4B). Estimated marginal meanchange in body weight from baseline to week 52 in Cohort 0B-T2D derived from a mixed-model for repeated measures (Figure 4C) or treatment policy approach (Figure 4D). Error bars representing 95% CI. 95% confidence intervals are not adjusted for multiplicity and should not be used for hypothesis testing. 4W-DE, 4-week dose escalation; 12W-DE, 12-week dose escalation; no-DE, no dose escalation.

[0016] Figures 5A-5B depicts Percentage of participants meeting weight-reduction thresholds. The percentages of participants with body-weight reductions of at least 5%, 10%, 15%, and 20% from baseline to week 52 are shown for cohort OB Figure 5 A) and cohort OB-T2D Figures 5 B). Treatment policy results are based on all randomized participants for the treatment policy estimand with missing data imputed using a constant weight of regain after investigational product discontninuation. Efficacy estimand results are based on a logistic

[0017] Figures 6A-6B depicts Waterfall plots of percent change in weight at week 52. Waterfall plot for Cohort OB (Figure 6A) and Cohort OB-T2D (Figure 6B) for observed percent change in weight from baseline at week 52 by treatment group. 4W-DE, 4-week dose escalation; 12WDE, 12-week dose escalation; no-DE, no dose escalation.

[0018] Figures 7A-7B depicts Change in waist circumference. Change in waist circumference derived using a mixed model for repeated measures (MMRM) analysis for the efficacy estimand in Cohort OB and Cohort OB-T2D. Error bars represent the 95% confidence interval. 95% confidence intervals are not adjusted for multiplicity and should not be used for hypothesis testing. 4W-DE, 4-week dose escalation; 12W-DE, 12-week dose escalation; no-DE, no dose escalation.

[0019] Figures 8A-8B depicts Change in BMI. Change from baseline in body mass index (BMI, kg / m2) derived using a mixed model for repeated measures (MMRM) analysis for the efficacy estimand. Error bars represent 95% CI. 95% confidence intervals are not adjusted for multiplicity and should not be used for hypothesis testing no DE, no dose escalation.

[0020] Figures 9A-9B depicts Change in systolic blood pressure. Change from baseline in systolic blood pressure (mm Hg) derived using a mixed model for repeated measures (MMRM) analysis for the efficacy estimand. Error bars represent the 95% CI. 95% confidence intervals are not adjusted for multiplicity and should not be used for hypothesis testing, no DE, no dose escalation.

[0021] Figures 10A-10B depicts Change in body composition. In a subset of subjects, body composition was assessed as a secondary endpoint. There was greater reduction in fat mass relative to lean mass per total body weight loss across all groups. Data plotted as estimated marginal mean percent change from baseline to week 52 and 95%CI. 95% confidence intervals are not adjusted for multiplicity and should not be used for hypothesis testing. Results are derived from a mixed model for repeated measures (MMRM) analysis for the efficacy estimand. For cohort OB, a subset of participants were included in the analysis, including for 140 mg Q4W (n = 20), 280 mg Q4W (n = 21), 420 mg Q4W (n = 21), 420 mg Q8W (n = 12), 420 mg Q4W-4WDE (n = 16), 420 mg Q4W-12WDE (n = 16), and placebo (n = 16). For cohort OB-T2D, a subset of participants were included in the analysis, including for 140 mg Q4W (n = 5), 280 mg Q4W (n = 4), 420 mg Q4W (n =9), and placebo (n = 7). 4W-DE, 4-week dose escalation; 12W-DE, 12-week dose escalation; no-DE, no dose escalation.

[0022] Figures 11A-11B depicts Incidence of nausea and vomiting (Cohort OB). *A11 events for each participant were counted and shown based on the start date of the event (eg, if a participant experienced multiple events in different weeks, each occurrence was counted and shown.) 4W-DE, 4-week dose escalation; 12W-DE, 12-week dose escalation; IP, investigational product; no-DE, no dose escalation.

[0023] Figure 12 depicts representativeness of the phase 2 trial.

[0024] Figure 13 depicts participants achieving HbAlc thresholds (observed).

[0025] Figure 14 depicts additional key secondary endpoints.

[0026] Figure 15 depicts additional secondary endpoints using the efficacy estimand.

[0027] Figure 16 depicts serious adverse event summary.

[0028] Figure 17 depicts nausea and vomiting adverse events by severity.

[0029] Figure 18 depicts hypoglycemia grade 2 and 3 events*

[0030] Figure 19 depicts change in bone mineral density.

[0031] Figure 20 depicts additional safety results.DETAILED DESCRIPTION

[0032] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0033] Unless otherwise defined herein, scientific and technical terms used in connection with the present application shall have the meanings that are commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0034] Generally, nomenclatures used in connection with, and techniques of, cell and tissue culture, molecular biology, immunology, microbiology, genetics and protein and nucleic acid chemistry and hybridization described herein are those well known and commonly used in the art. The methods and techniques of the present application 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. See, e.g., Sambrook et al., Molecular Cloning: A Laboratory Manual, 3rd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N. Y. (2001), Ausubel et al., Current Protocols in Molecular Biology, Greene Publishing Associates (1992), and Harlow and Lane Antibodies: A Laboratory Manual Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N. Y. (1990), which are incorporated herein by reference. Enzymatic reactions and purification techniques are performed according to manufacturer's specifications, as commonly accomplished in the art or as described herein. The terminology 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 can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients.

[0035] It should be understood that this invention is not limited to the particular methodology, protocols, and reagents, etc., described herein and as such may vary. The terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the disclosed, which is defined solely by the claims.

[0036] Other than in the operating examples, or where otherwise indicated, all numbers expressing quantities of ingredients or reaction conditions used herein should be understood as modified in all instances by the term “about.” The term “about” when used in connection with percentages may mean ±1%.

[0037] Following convention, as used herein “a” and “an” mean “one or more” unless specifically indicated otherwise.

[0038] As used herein, the terms “amino acid” and “residue” are interchangeable and, when used in the context of a peptide or polypeptide, refer to both naturally occurring and synthetic amino acids, as well as amino acid analogs, amino acid mimetics and non-naturally occurring amino acids that are chemically similar to the naturally occurring amino acids.

[0039] The present disclosure provides a method of treating a metabolic disorders, such as obesity and type II diabetes, and obesity related conditions, such as ASCVD and heart failure, by blocking or interfering with the biological activity of GIP receptor, while activating GLP-1 receptor signaling. In one embodiment, a therapeutically effective amount of an isolated human GIPR binding protein conjugated to a GLP-1 receptor agonist is administered to a subject in need thereof. Methods of administration and delivery are also provided.

[0040] Maridebart cafraglutide (also known as “AMG-133”, “AMG133”, and “AMG 133”) is engineered by conjugating a fully human monoclonal anti-human GIPR antagonist antibody and a GLP-1 analog agonist peptide using natural amino acid linkers. The heavy chain of maridebart cafraglutide consists of SEQ ID NO: 1. The light chain of maridebart cafraglutide consists of SEQ ID NO: 2. maridebart cafraglutide comprises a linker (SEQ ID NO:4) bound to cysteine 275 of SEQ ID NO: 1 via the C-terminal lysine of SEQ ID NO: 4. maridebart cafraglutide further comprises the C-terminal of SEQ ID NO: 3 bound to the N-terminal of SEQ ID NO: 4. Accordingly, the epsilon amino group of the C-terminal lysine of the peptide H[Aib]EGTFTSDYSSYLEEQAAKEFIAWLVKGGG GGGGSGGGGSGGGGSK (SEQ ID NO: 11) is bound to cysteine 275 of SEQ ID NO: 1 in maridebart cafraglutide molecule.

[0041] Maridebart cafraglutide comprises a CDRH1 comprising the amino acid sequence of SEQ ID NO:5, a CDRH2 comprising the amino acid sequence of SEQ ID NO:6, a CDRH3 comprising the amino acid sequence of SEQ ID NO:7, a CDRL1 comprising the amino acid sequence of SEQ ID NO:8, a CDRL2 comprising the amino acid sequence of SEQ ID NO:9, and a CDRL3 comprising the amino acid sequence of SEQ ID NO:10.

[0042] SEQ ID NO: 5 NYGMH

[0043] SEQ ID NO: 6 AIWFD ASDKYYAD AVKG

[0044] SEQ ID NO: 7 DQ AIFGVVPD Y

[0045] SEQ ID NO:8 RASQSVSSNLA

[0046] SEQ ID NO: 9 GAATRAT

[0047] SEQ ID NO: 10 QQ YNNWPLT

[0048] Maridebart cafraglutide comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 1, and a light chain comprising the amino acid sequence of SEQ ID NO:2.

[0049] SEQ ID NO: 1 QVQLVESGGG VVQPGRSLRL SCAASGFTFS NYGMHWVRQA PGEGLEWVAA IWFDASDKYY ADAVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCARDQ AIFGVVPDYW GQGTLVTVSS ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPCVKFNW YVDGVEVHNA KTKPCEEQYG STYRCVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSREE MTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPGK

[0050] SEQ ID NO: 2 EIVMTQSPAT LSVSPGERAT LSCRASQSVS SNLAWYQQKP GQAPRLLIYG AATRATGIPA RVSGSGSGTE FTLTISSLQS EDFAVYYCQQ YNNWPLTFGG GTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC

[0051] Maridebart cafraglutide comprises a GLP-1 agonist comprising the amino acid sequence of SEQ ID NO:3.

[0052] SEQ ID NO: 3 H[Aib]EGTFTSDYSSYLEEQAAKEFIAWLVKGGG, wherein “Aib” is 2-aminoisobutyric acid.

[0053] In maridebart cafraglutide, the antagonistic anti-GIPR antibody is linked to the GLP-1R agonist via a peptide linker comprising SEQ ID NO: 4.

[0054] SEQ ID NO: 4 GGGGSGGGGSGGGGSK

[0055] Accordingly, in one aspect, the present invention is directed to a method for treating obesity or promoting weight loss in a human patient comprising administering to the patient a pharmaceutical composition comprising maridebart cafraglutide at an amount of about 70 mg, about 140 mg, about 210 mg, about 280 mg, about 350 mg, or about 420 mg; wherein after the pharmaceutical composition is administered about every four weeks for one year the patient’s weight is reduced by at least 16%. In another aspect, the present invention is directedto use of maridebart cafraglutide for preparation of a medicament for treating obesity or promoting weight loss in a human patient in need thereof, wherein the medicament is formulated for administration at a dose of about 70 mg, about 140 mg, about 210 mg, about 280 mg, about 350 mg, or about 420 mg; and wherein after the pharmaceutical composition is administered about every four weeks for one year the patient’s weight is reduced by at least 16%.

[0056] In an embodiment, the patient’s weight is reduced by at least 16%, 17%, 18%, 19%, 20%, 21% 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or 30%.

[0057] In an embodiment, the patient’s high-sensitivity C-reactive protein (“hs-CRP”) level is reduced by at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, or 70%.

[0058] In an embodiment, the patient’s systolic blood pressure (“SBP”) is reduced by at least 8 mmHg, 9, mmHg, 10 mmHg, 11 mmHg, 12 mmHg, 13 mmHg, 14 mmHg 15 mmHg, 16 mmHg, 17 mmHg, 18 mmHg, 19 mmHg, or 20 mmHg.

[0059] In an embodiment, the amount of maridebart cafraglutide is about 280 mg and the patient’s weight is reduced by at least 19%, the patient’s hs-CRP is reduced by at least 60%, or the patient’s SBP is reduced by at least 12 mmHg. In an embodiment, the amount of maridebart cafraglutide is about 420 mg and the patient’s weight is reduced by at least 18%, the patient’s hs-CRP is reduced by at least 55%, or the patient’s SBP is reduced by at least 11 mmHg.

[0060] In another aspect, the present invention is directed to a method for treating type II diabetes or reducing HbAlc levels in a human patient comprising administering to the patient a pharmaceutical composition comprising maridebart cafraglutide at an amount of about 70 mg, about 140 mg, about 210 mg, about 280 mg, about 350 mg, or about 420 mg; wherein after the pharmaceutical composition is administered about every four weeks for one year the patient’s weight is reduced by at least 12%, and HbAlc level is reduced by at least 1.8%.

[0061] In an embodiment, the patient’s weight is reduced by at least 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21% 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or 30%.

[0062] In an embodiment, the patient’s HbAlc is reduced by at least 1.8%, 1.9%, 2.0%, 2.1% 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9% or 3.0%.

[0063] In another aspect, the present invention is directed to use of maridebart cafraglutide for preparation of a medicament for treating type II diabetes or reducing HbAlc in a human patient in need thereof, wherein the medicament is formulated for administration at adose of about 70 mg, about 140 mg, about 210 mg, about 280 mg, about 350 mg, or about 420 mg; wherein after the pharmaceutical composition is administered about every four weeks for one year the patient’s weight is reduced by at least 12%, and HbAlc level is reduced by at least 1.8%.

[0064] In an embodiment, the patient’ s high-sensitivity C-reactive protein (“hs-CRP”) level is reduced by at least 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, or 60%.

[0065] In an embodiment, the patient’s systolic blood pressure (“SBP”) is reduced by at least 8 mmHg, 9, mmHg, 10 mmHg, 11 mmHg, 12 mmHg, 13 mmHg, 14 mmHg 15 mmHg, 16 mmHg, 17 mmHg, 18 mmHg, 19 mmHg, or 20 mmHg.

[0066] In an embodiment, the amount of maridebart cafraglutide is about 280 mg and the patient’s weight is reduced by at least 12% or the patient’s SBP is reduced by at least 12 mmHg. In an embodiment, the amount of maridebart cafraglutide is about 420 mg and the patient’s weight is reduced by at least 16%, the patient’s SBP is reduced by at least 11 mmHg, or the patient’s hs-CRP is reduced by at least 60%.

[0067] In another aspect, the present invention is directed to a method for treating atherosclerotic cardiovascular disease or reducing high-sensitivity C-reactive protein (“hs-CRP”) in a human patient comprising administering to the patient a pharmaceutical composition comprising maridebart cafraglutide at an amount of about 70 mg, about 140 mg, about 210 mg, about 280 mg, about 350 mg, or about 420 mg; wherein after the pharmaceutical composition is administered about every four weeks for one year the patient’s weight is reduced by at least 16%, and hs-CRP level is reduced by at least 50%. In another aspect, the present invention is directed to use of maridebart cafraglutide for preparation of a medicament for treating atherosclerotic cardiovascular disease or reducing high-sensitivity C-reactive protein (“hs-CRP”) in a human patient in need thereof, wherein the medicament is formulated for administration at a dose of about 70 mg, about 140 mg, about 210 mg, about 280 mg, about 350 mg, or about 420 mg; wherein after the pharmaceutical composition is administered about every four weeks for one year the patient’ s weight is reduced by at least 16%, and hs-CRP level is reduced by at least 50%.

[0068] In an embodiment, the patient’s weight is reduced by at least 16%, 17%, 18%, 19%, 20%, 21% 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or 30%.

[0069] In an embodiment, the patient’s high-sensitivity C-reactive protein (“hs-CRP”) level is reduced by at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, or 70%.

[0070] In an embodiment, the patient’s systolic blood pressure (“SBP”) is reduced by at least 8 mmHg, 9, mmHg, 10 mmHg, 11 mmHg, 12 mmHg, 13 mmHg, 14 mmHg 15 mmHg, 16 mmHg, 17 mmHg, 18 mmHg, 19 mmHg, or 20 mmHg.

[0071] In an embodiment, the amount of maridebart cafraglutide is about 280 mg and the patient’s weight is reduced by at least 19%, the patient’s hs-CRP is reduced by at least 60%, or the patient’s SBP is reduced by at least 12 mmHg. In an embodiment, the amount of maridebart cafraglutide is about 420 mg and the patient’s weight is reduced by at least 18%, the patient’s hs-CRP is reduced by at least 55%, or the patient’s SBP is reduced by at least 11 mmHg.

[0072] In another aspect, the present invention is directed to a method for treating heart failure or reducing systolic blood pressure in a human patient comprising administering to the patient a pharmaceutical composition comprising maridebart cafraglutide at an amount of about 70 mg, about 140 mg, about 210 mg, about 280 mg, about 350 mg, or about 420 mg; wherein after the pharmaceutical composition is administered about every four weeks for one year the patient’s weight is reduced by at least 16%, and systolic blood pressure (“SBP”) is reduced by at least 8 mmHg. In another aspect, the present invention is directed to use of maridebart cafraglutide for preparation of a medicament for treating heart failure or reducing systolic blood pressure in a human patient in need thereof, wherein the medicament is formulated for administration at a dose of about 70 mg, about 140 mg, about 210 mg, about 280 mg, about 350 mg, or about 420 mg; wherein after the pharmaceutical composition is administered about every four weeks for one year the patient’s weight is reduced by at least 16%, and systolic blood pressure (“SBP”) is reduced by at least 8 mmHg.

[0073] In an embodiment, the patient’s weight is reduced by at least 16%, 17%, 18%, 19%, 20%, 21% 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or 30%.

[0074] In an embodiment, the patient’ s high-sensitivity C-reactive protein (“hs-CRP”) level is reduced by at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, or 70%.

[0075] In an embodiment, the patient’s systolic blood pressure (“SBP”) is reduced by at least 8 mmHg, 9, mmHg, 10 mmHg, 11 mmHg, 12 mmHg, 13 mmHg, 14 mmHg 15 mmHg, 16 mmHg, 17 mmHg, 18 mmHg, 19 mmHg, or 20 mmHg.

[0076] In an embodiment, the amount of maridebart cafraglutide is about 280 mg and the patient’s weight is reduced by at least 19%, the patient’s hs-CRP is reduced by at least 60%, or the patient’s SBP is reduced by at least 12 mmHg. In an embodiment, the amount of maridebart cafraglutide is about 420 mg and the patient’s weight is reduced by at least 18%, the patient’s hs-CRP is reduced by at least 55%, or the patient’s SBP is reduced by at least 11 mmHg.

[0077] In another aspect, the present invention is directed to a method for treating heart failure or reducing diastolic blood pressure in a human patient comprising administering to the patient a pharmaceutical composition comprising maridebart cafraglutide at an amount of about 70 mg, about 140 mg, about 210 mg, about 280 mg, about 350 mg, or about 420 mg; wherein after the pharmaceutical composition is administered about every four weeks for one year the patient’s weight is reduced by at least 16%, and diastolic blood pressure (“DBP”) is reduced by at least 2 mmHg. In another aspect, the present invention is directed to use of maridebart cafraglutide for preparation of a medicament for treating heart failure or reducing diastolic blood pressure in a human patient in need thereof, wherein the medicament is formulated for administration at a dose of about 70 mg, about 140 mg, about 210 mg, about 280 mg, about 350 mg, or about 420 mg; wherein after the pharmaceutical composition is administered about every four weeks for one year the patient’s weight is reduced by at least 16%, and diastolic blood pressure (“DBP”) is reduced by at least 2 mmHg.

[0078] In an embodiment, the patient’s weight is reduced by at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21% 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or 30%.

[0079] In an embodiment, the patient’s diastolic blood pressure (“DBP”) is reduced by at least 2 mmHg, 3 mmHg, 4 mmHg, 5 mmHg, or 6 mmHg.

[0080] In an embodiment, the amount of maridebart cafraglutide is about 280 mg and the patient’s weight is reduced by at least 19% and / or the patient’s DBP is reduced by at least 4 mmHg. In an embodiment, the amount of maridebart cafraglutide is about 420 mg and the patient’s weight is reduced by at least 18% and / or the patient’s DBP is reduced by at least 3 mmHg.

[0081] In another aspect, the present invention is directed to a method for treating atherosclerotic cardiovascular disease or reducing total cholesterol in a human patient comprising administering to the patient a pharmaceutical composition comprising maridebart cafraglutide at an amount of about 70 mg, about 140 mg, about 210 mg, about 280 mg, about 350 mg, or about 420 mg; wherein afterthepharmaceutical composition is administered about every four weeks for one year the patient’s weight is reduced by at least 16%, and total cholesterol is reduced by at least 4%.

[0082] In an embodiment, the patient’s weight is reduced by at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21% 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or 30%.

[0083] In an embodiment, the patient’s total cholesterol is reduced by at least 4%, 5%, 6%, 7%, 8%, or 9%.

[0084] In another aspect, the present invention is directed to a method for treating atherosclerotic cardiovascular disease or reducing low density lipoprotein cholesterol (“LDL-C”) in a human patient comprising administering to the patient a pharmaceutical composition comprising maridebart cafraglutide at an amount of about 70 mg, about 140 mg, about 210 mg, about 280 mg, about 350 mg, or about 420 mg; wherein after the pharmaceutical composition is administered about every four weeks for one year the patient’s weight is reduced by at least 16%, and total cholesterol is reduced by at least 4%.

[0085] In an embodiment, the patient’s weight is reduced by at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21% 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or 30%.

[0086] In an embodiment, the patient’s LDL-C is reduced by at least 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%, or 30%.

[0087] In another aspect, the present invention is directed to a method for treating atherosclerotic cardiovascular disease or reducing very' low density lipoprotein cholesterol (“VLDL-C”) in a human patient comprising administering to the patient a pharmaceutical composition comprising maridebart cafraglutide at an amount of about 70 mg, about 140 mg, about 210 mg, about 280 mg, about 350 mg, or about 420 mg; wherein after the pharmaceutical composition is administered about every four weeks for one year the patient’s weight is reduced by at least 16%, and total cholesterol is reduced by at least 4%.

[0088] In an embodiment, the patient’s weight is reduced by at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21% 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or 30%.

[0089] In an embodiment, the patient’s VLDL-C is reduced by at least 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%, or 30%.

[0090] In another aspect, the present invention is directed to a method for treating atherosclerotic cardiovascular disease or reducing non-high density lipoprotein cholesterol (“Non-HDL-C ”) in a human patient comprising administering to the patient a pharmaceutical composition comprising maridebart cafraglutide at an amount of about 70 mg, about 140 mg, about 210 mg, about 280 mg, about 350 mg, or about 420 mg; wherein after the pharmaceutical composition is administered about every four weeks for one year the patient’s weight is reduced by at least 16%, and total cholesterol is reduced by at least 4%.

[0091] In an embodiment, the patient’s weight is reduced by at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21% 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or 30%.

[0092] In an embodiment, the patient’s Non-HDL-C is reduced by at least 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%, or 30%.

[0093] In another aspect, the present invention is directed to a method for treating atherosclerotic cardiovascular disease or reducing triglycerides in a human patient comprising administering to the patient a pharmaceutical composition comprising maridebart cafraglutide at an amount of about 70 mg, about 140 mg, about 210 mg, about 280 mg, about 350 mg, or about 420 mg; wherein afterthe pharmaceutical composition is administered about every four weeks for one year the patient’s weight is reduced by at least 16%, and total cholesterol is reduced by at least 4%.

[0094] In an embodiment, the patient’s weight is reduced by at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21% 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or 30%.

[0095] In an embodiment, the patient’s triglycerides are reduced by at least 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%, or 30%.

[0096] In another aspect, the present invention is directed to a method for treating atherosclerotic cardiovascular disease or reducing free fatty acids in a human patient comprising administering to the patient a pharmaceutical composition comprising maridebart cafraglutide at an amount of about 70 mg, about 140 mg, about 210 mg, about 280 mg, about 350 mg, or about 420 mg; wherein afterthe pharmaceutical composition is administered about every four weeks for one year the patient’s weight is reduced by at least 16%, and total cholesterol is reduced by at least 4%.

[0097] In an embodiment, the patient’s weight is reduced by at least 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21% 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or 30%.

[0098] In an embodiment, the patient’s free fatty acids are reduced by at least 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%, or 30%.

[0099] In another aspect, the present invention is directed to a method for treating atherosclerotic cardiovascular disease or increasing high density lipoprotein cholesterol (“HDL-C”) in a human patient comprising administering to the patient a pharmaceutical composition comprising maridebart cafraglutide at an amount of about 70 mg, about 140 mg, about 210 mg, about 280 mg, about 350 mg, or about 420 mg; wherein after the pharmaceutical composition is administered about every four weeks for one year the patient’s weight is reduced by at least 16%, and total cholesterol is reduced by at least 4%.[000100] In an embodiment, the patient’s weight is reduced by at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21% 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or 30%.[000101] In an embodiment, the patient’s HDL-C is increased by at least 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15%.[000102] The amount or dose of maridebart cafraglutide can be administered in a single administration or divided among multiple administrations over the course of the dosing frequency period. For example, in certain embodiments, the therapeutically effective dose of maridebart cafraglutide is administered in a single administration each frequency period. Thus, in some embodiments, any of the doses of maridebart cafraglutide described herein can be administered to the patient once every four weeks (Q4W dosing). Patients on a Q4W dosing regimen are typically administered maridebart cafraglutide every 24 to 36 days, preferably, every 28 to 35 days, more preferably, every 28 to 31 days, or even more preferably, every 28 days or every 30 days. In these and other embodiments, the Q4W dose is administered to the patient as a bolus injection, for example, using syringes and vials, a pre-filled syringe, or a self-injection device as described herein. For instance, a monthly dose of 280 mg can be administered to the patient as a single bolus injection of 280 mg optionally with an autoinjector, pen injector, or prefilled syringe containing the 280 mg dose. In certain embodiments, the Q4W dose is given in two or more consecutive injections. By way of example, a monthly dose of 280 mg can be administered to the patient in two consecutive injections of 140 mg optionally with two injection devices (e.g. autoinjectors, pen injectors, or pre-filled syringes) containing a 140 mg dose.[000103] In certain embodiments, the dosing frequency period for the doses of maridebart cafraglutide that are described herein is monthly. In other words, the dosages of maridebart cafraglutide are monthly dosages (monthly dosages are equal to one every four weeks), but can be administered in a single administration (i.e. once a month; QM dosing) or divided among multiple administrations over the course of the month (e.g. % the monthly dose administered every two weeks).[000104] In certain embodiments, the patient has a body mass index (“BMI”) greater than 30 kg / m2, 35 kg / m2 or 40 kg / m2. In certain embodiments, the patient has a BMI greater than 30 kg / m2 and less than 40 kg / m2. In certain embodiments, the patient has a BMI greater than 35 kg / m2 and less than 40 kg / m2. In certain embodiments, the patient has a BMI greater than 30 kg / m2 and less than 35 kg / m2. The measurements can also be converted to lbs / in2.[000105] Body Mass Index (BMI) is a person’s weight in kilograms (or pounds) divided by the square of height in meters (or feet). A high BMI can indicate high body fatness.[000106] In certain embodiments, treating obesity comprises promoting weight loss in a patient. Accordingly, the present invention is directed to a method of treating obesity wherein the patient loses about 5% of body weight in 52 weeks, about 10% of body weight in 52 weeks, about 15% of body weight in 52 weeks, about 20% of body weight in 52 weeks, about 25% of body weight in 52 weeks, or about 30% of body weight in 52 weeks. “Body weight” means a patient’s weight before the first administration of the pharmaceutical composition.[000107] In certain embodiments, treating obesity comprises maintaining body weight by administering a maintenance dose to patient. Accordingly, the present invention is directed to a method of treating obesity wherein the patient’s body does not fluctuate more than ±0.5% of goal body weight, ±1.0% of goal body weight, ±1.5% of goal body weight, ±2.0% of goal body weight, ±2.5% of goal body weight, ±3.0% of goal body weight, ±3.5% of goal body weight, ±4.0% of goal body weight, ±4.5% of goal body weight, or ±5.0% of goal body weight. “Goal body weight” means the weight a patient means to maintain. A maintenance dose can be the same amount and frequency as a dose that promotes weight loss. Alternatively, a maintenance dose can be 1) lower amount than a dose that promotes weight loss, 2) administered less frequently than a dose that promotes weight loss, or 3) both a lower amount than a dose that promotes weight loss and administered less frequently than a dose that promotes weight loss.[000108] Hemoglobin A 1 c (“ HbAl c”) is formed through glycation of an N-terminus of a β chain of HbA1c, and is a glycation product of HbA0, which accounts for most hemoglobin. A presence ratio of HbA1c to a total hemoglobin amount reflects an average blood sugar level in 1 month to 2 months before blood collection from an individual to be tested, and hence is widely utilized as an indicator of a glycemic control state in diabetes, for clinical diagnosis or therapy selection.[000109] The presence ratio of HbAlc is calculated as a ratio (%) of a hemoglobin Ale concentration (pmol / L) to a hemoglobin concentration (pmol / L) in the case of NGSP %, or as a ratio (mmol / mol) of hemoglobin Ale (mmol) to 1 mol of hemoglobin in the case of an IFCC value. The calculated presence ratio of HbAlc is hereinafter sometimes generically referred to as HbA1c %. As a method of measuring HbA1c for calculating the HbA1c %, there have been reported an HPLC method, an immunoagglutination method, an electrophoresis method, and anenzymatic method. Of those, the enzymatic method is a method put into practical use in recent years, is applicable to an automated analyzer frequently used in the field of clinical examination, and has an advantage of less contamination of the automated analyzer (in particular, a reaction cell) with a reagent as compared to the immunoagglutination method, which is also applicable to the automated analyzer.[000110] Blood cells separated from whole blood are used as a sample for measurement of the HbA1c % in some cases, and whole blood is used as the sample in other cases. However, with regard to the enzymatic method, although there is a report on a case in which whole blood is used as the sample, technological accumulation is still insufficient.[000111] In certain embodiments, the patient has been diagnosed with Type II diabetes. In certain embodiments, the patient has HbAlc > 7% and < 10% (53 to 86 mmol / mol).[000112] High-sensitivity C-reactive protein (hereinafter referred to as “hs-CRP”) is a plasma protein that is synthesized in the liver. hs-CRP is synthesized by hepatocytes in response to cytokines released into the liver by activated leukocytes. hs-CRP is a nonspecific marker of inflammation and its level increases as a result of tissue injury or infection, elevating rapidly within 4 to 6 hours of the onset of acute levels of these conditions. hs-CRP may rise to 25-35 mg / L after surgery, and peak at 30-35 mg / L during acute bacterial infection. In situations of severe trauma, the hs-CRP concentration in plasma rises to 500-1,000 mg / L.[000113] hs-CRP is also a risk indicator for coronary heart disease. Among the various prognostic markers of heart disease, such as serum amyloid A, soluble intercellular adhesion molecule type 1, interleukin-6, homocysteine, total cholesterol, LDL, apolipoprotein B-100, HDL, and ratio of total cholesterol to HDL, hs-CRP is the strongest predictor of cardiovascular events. When apparently healthy adults are tested for CRP, the fourth quartile (upper 25%) of those tested have been shown to have over four times the risk of those in the first quartile (with a confidence level of 95%), a ratio significantly greater than those of each of the markers listed above.[000114] The method used for measuring the blood hs-CRP is not particularly limited as long as it is a high sensitivity CRP measurement method capable of measuring the C reactive protein of at least 0.1 mg / L, preferably at least 0.05 mg / L, and more preferably 0.01 mg / L.Exemplary such high sensitivity CRP measurement methods include ELISA, latex nephelometry, laser nephelometry, and improved latex immunonephelometry. Exemplary ELISA methodsinclude Banalyst Ace hs-CRP (SANWA KAGAKU KENKYUSHO CO., LTD., Nagoya, Japan), ELISA Kit High Sensitivity C-Reactive Protein (Immuno-Biological Laboratories, Inc., Minnesota, USA), and hs-CRP Human ELISA (BioVendor, Heidelberg, Germany). Exemplary latex nephelometry methods include N-latex CRP II (Siemens Healthcare Diagnostics, Tokyo, Japan), and the improved latex immunonephelometry may be conducted by using a commercially available assay kit such as Vitros microchip hs-CRP (Ortho Clinical Diagnostics, Tokyo, Japan).[000115] In some embodiments of the methods of the invention, maridebart cafraglutide is administered to the patient over the course of a set treatment period. A “treatment period” begins upon administration of a first dose of maridebart cafraglutide and ends upon administration of a final dose of anti-GIPR antibody or binding fragment. The treatment period may comprise from about 1 month to about 36 months, such as about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 18 months, about 21 months, about 24 months, about 27 months, about 30 months, or about 33 months. In some embodiments, the treatment period is about 6 months. In other embodiments, the treatment period is about 7 months. In yet other embodiments, the treatment period is about 12 months. In certain embodiments, the treatment period can be longer than 36 months, such as 48 or 60 or 64 months or more.[000116] Maridebart cafraglutide is generally administered to the patient in a pharmaceutical composition, which can include pharmaceutically-acceptable carriers, excipients, or diluents. “Pharmaceutically-acceptable” refers to molecules, compounds, and compositions that are non-toxic to human recipients at the dosages and concentrations employed and / or do not produce allergic or adverse reactions when administered to humans. In certain embodiments, the pharmaceutical composition may contain formulation materials for modifying, maintaining or preserving, for example, the pH, osmolarity, viscosity, clarity, color, isotonicity, odor, sterility, stability, rate of dissolution or release, adsorption or penetration of the composition. Methods and suitable materials for formulating molecules for therapeutic use are known in the pharmaceutical arts, and are described, for example, in REMINGTON’S PHARMACEUTICAL SCIENCES, 18th Edition, (A. R. Gennaro, ed.), 1990, Mack Publishing Company.[000117] In some embodiments, the selection of carriers and excipients for incorporation into the pharmaceutical compositions influences the physical state, stability, rate of in vivo release and rate of in vivo clearance of maridebart cafraglutide. In certain embodiments, the primary vehicle or carrier in a pharmaceutical composition may be either aqueous or nonaqueous in nature. For example, a suitable vehicle or carrier may be water for injection, physiological saline solution or artificial cerebrospinal fluid, possibly supplemented with other materials common in compositions for parenteral administration.[000118] In certain embodiments of the methods described herein, maridebart cafraglutide is administered to the patient parenterally. Parenteral administration includes intraperitoneal, intramuscular, intravenous, intraarterial, intradermal, subcutaneous, intracerebral, intracerebroventricular, and intrathecal administration. In one particular embodiment, the pharmaceutical composition comprising a therapeutically effective amount of maridebart cafraglutide is administered to the patient subcutaneously. In these and other embodiments in which the pharmaceutical composition is administered by parenteral injection, the pharmaceutical composition can be administered to the patient with a syringe. In some embodiments, the syringe is pre-filled with the pharmaceutical composition. In other embodiments in which the pharmaceutical composition is administered to the patient by parenteral injection, such as subcutaneous injection, the pharmaceutical composition is administered with an injection device, including devices for self-administration. Such devices are commercially available and include, but are not limited to, autoinjectors, dosing pens, microinfusion pumps, and pre-filled syringes. Exemplary devices for administering a pharmaceutical composition comprising a therapeutically effective amount of maridebart cafraglutide according to the methods of the invention include autoinjectors (e.g., SureClick®, EverGentle®, Avanti®, DosePro®, Molly®, and Leva®), pen injection devices (e.g., Madie® pen injector, DCP™pen injector, BD Vystra™ disposable pen, BD™ reusable pen), and prefilled syringes (BD Sterifill™, BD Hypak™, prefilled syringes from Baxter). In some embodiments, the pharmaceutical composition comprising a therapeutically effective amount of maridebart cafraglutide is administered to the patient with a pre-filled syringe. In other embodiments, the pharmaceutical composition comprising a therapeutically effective amount of maridebart cafraglutide is administered to the patient with an autoinjector. In certain related embodiments, the injection volume is about 1 mL or less.[000119] In one embodiment, maridebart cafraglutide is administered to a patient at a dose of about 70 mg, about 140 mg, about 210 mg, about 280 mg, about 350 mg, or about 420 mg every four weeks to promote weight loss in the patient, wherein the dose is delivered by a single subcutaneous injection. In related embodiments, the single subcutaneous injection is delivered with a pre-filled syringe. In other related embodiments, the single subcutaneous injection is delivered with an autoinjector.[000120] Illustrative pharmaceutical forms suitable for parenteral injection include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. Preferably, the pharmaceutical form is sterile and is sufficiently fluid to allow for delivery via a syringe (i.e., the formulation is not excessively viscous so as to prevent passage through a syringe). Sterilization can be accomplished by filtration through sterile filtration membranes. When the composition is lyophilized, sterilization using this method may be conducted either prior to or following lyophilization and reconstitution. Compositions for parenteral administration can be stored in lyophilized form or in a solution. Parenteral compositions can be placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle. Parenteral compositions can also be stored in syringes, autoinjector devices, or pen injection devices or cartridges adapted for use with such injection devices.[000121] The present invention also includes kits for treating obesity or type II diabetes in a patient in need thereof. In one embodiment, the kit comprises a pharmaceutical composition of maridebart cafraglutide described herein and packaging material that provides instructions regarding the use of the pharmaceutical compositions. The pharmaceutical composition of the kit may be present in a container, such as a vial or syringe. The pharmaceutical composition may be provided as a solution, suspension, gel, emulsion, solid, crystal, or as a dehydrated or lyophilized powder. In embodiments in which the pharmaceutical composition is provided as a powder, the kit may also comprise diluents (e.g. water, saline, phosphate-buffer saline) necessary to reconstitute the pharmaceutical composition as well as instructions for preparing the composition for administration. In some embodiments, the kits comprise an injection device for selfadministration (e.g. pre-filled syringe or autoinjector) pre-filled with the pharmaceutical composition as described herein. Any of the pre-filled syringes and autoinjectors described above can be included in kits.[000122] The following examples, including the experiments conducted and the results achieved, are provided for illustrative purposes only and are not to be construed as limiting the scope of the appended claims.EXAMPLES[000123] METHODS[000124] Trial Design[000125] This multinational Phase 2, double-blind, randomized, placebo-controlled, doseranging MariTide trial (NCT05669599) included 2 cohorts: persons with Obesity (Cohort OB; protocol Cohort A) and Obesity with T2D (Cohort OB-T2D; protocol Cohort B) (Fig. SI). The trial was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice guidelines and was approved by an independent ethics committee or institutional review board at each trial site.. The sponsor (Amgen) designed and oversaw the trial conduct. The first author wrote the first draft. All authors participated in data interpretation and critical manuscript review, vouch for data accuracy and completeness, and fidelity to the trial protocol (available at nejm.org). This Phase 2 trial has two parts. Part 1 (52 weeks), discussed here, investigated dose range, dose escalation (DE), and no dose escalation (no-DE). Part 2 (an additional 52 weeks) is investigating various maintenance dosing strategies. Additionally, herein, we describe a phase 1 pharmacokinetics (PK) low dose initiation (LDI) study, termed PK-LDI throughout, designed to inform and optimize initial dose and dose escalation for the Phase 3 program (Supplementary Appendix PK-LDI study, Figure PK-LDI SI).[000126] Participants[000127] Participants were >18yrs of age. Cohort OB included participants with body-mass index (BMI) >30kg / m2, or >27 with >1 obesity-related complication, andHbAlc <6.5%. Cohort OB-T2D included participants with BMI>27kg / m2 and established diagnosis of T2D (HbAlc >7% and <10%) treated with lifestyle alone or stable treatment with a sodium-glucose cotransporter 2 inhibitor, sulfonylurea, or metformin (combination or monotherapy). Key exclusions included history of pancreatitis, recent change in body weight, prior / planned surgery for weight loss, or use of weight gain / loss promoting medications. (Supplementary Appendix: full eligibility criteria)[000128] Procedures[000129] Cohort OB participants were randomized 3:3:3:2:2:2:3 to receive 52 weeks of MariTide 140, 280, or 420mg every 4 weeks (Q4W) without dose escalation (no-DE); or 420mgevery 8 weeks (Q8W) with no-DE; or 420mg Q4W with a 4-week dose escalation (4W-DE); or 420 mg Q4W with a 12-week dose escalation (12W-DE); or placebo, respectively (Fig. SI). Cohort OB-T2D participants were randomized 1: 1: 1: 1 to receive 52 weeks of MariTide 140, 280, 420mg Q4W (all with no-DE), or placebo, respectively (Fig. SI). Randomization was stratified by sex. Cohort OB enrollment of women was capped at 70%. In the PK-LDI study (Fig. PK-LDI SI) participants were randomized 1:1:1 to receive lower MariTide starting doses of 21, 35, or 70mg on Days 1 and 14, followed by 350mg. In addition to standard (unsolicited) adverse event (AE) reporting, we employed a modified patient-reported outcome (PRO) tool used in chemotherapy trials (Index of Nausea, Vomiting, Retching; M-INVR) (Fig. S2)l 1 to assess incidence, duration and frequency of nausea, vomiting, retching (dry heaves) in Cohort OB (daily for 7 days after each dose up to week 12) and the PK-LDI study (daily day 1 to 43).[000130] Endpoints[000131] Endpoints were measured from baseline to week 52. The primary endpoint was percent change in body weight. Key secondary endpoints included achieving weight reduction of >5%, >10%, >15%, >20%; change in HbAlc; MariTide pharmacokinetics; and measures of glucose metabolism. (Additional secondary outcomes in Table S4). Body composition was explored in a subset of participants. Safety assessment included adverse events (AEs) and serious AEs.[000132] Statistical Analysis[000133] Power analyses to determine sample size for each cohort is detailed in the Supplemental Appendix. Efficacy and safety endpoints were analyzed with data from all randomized participants who received at least one dose of investigational product (IP). Two estimands were used to assess the primary and key secondary endpoints: (1) treatment policy (intent-to-treat) used for proof-of-concept in which differences in percent change from baseline to week 52 in body weight were estimated regardless of adherence to IP, where body weight data for participants randomized to active treatment who discontinued IP were imputed using data from placebo participants 17; (2) efficacy estimand (hypothetical approach) that assumed adherence to IP and no use of glycemic rescue medications (glycemic endpoints) and assumes the same trajectories for those who discontinued or remained on IP. Efficacy analyses wereperformed separately by cohort. Statistical analyses of continuous end points for the treatment policy estimand were conducted with the use of an analysis-of-covariance model, and the efficacy estimand used a mixed model for repeated measures. Confidence intervals are not adjusted for multiplicity and should not be used for hypothesis testing. (Additional details in Supplementary Appendix).[000134] RESULTS[000135] Participants[000136] Part 1 of the trial (conducted January 2023-September 2024) included 592 participants (Cohort OB, n=465; Cohort OB-T2D, n=127). Demographics and baseline characteristics were similar between treatment groups for each cohort (Table 1). Table SI includes representativeness of the trial population. Overall, 72.5% of participants completed Part 1 on study drug (Cohort OB: 66.7-81.8% across MariTide groups, 61.5% in placebo; Cohort OB-T2D: 59.4%-80.6% across MariTide groups, 68.8% in placebo) (Fig. S3). (PK-LDI study: Table PK-LDI SI demographics / baseline characteristics; Fig. PK-LDI S2 participant disposition).[000137] Body Weight[000138] In Cohort OB, the mean percent change in weight from baseline to week 52 by treatment policy estimand (ITT) ranged from -12.3% (95% confidence interval [CI], -15.0, -9.7) to -16.2% (-18.9,-13.5) with MariTide, versus -2.5% (-4.2, -0.7) with placebo, and by efficacy estimand from -16.3% (-17.5,-15.2) to -19.9% (-21.4,-18.4) with MariTide, versus -2.6% (-3.6,-1.5) with placebo (Table 2; Fig. 1A, S4A, B).[000139] In Cohort OB-T2D, weight change by treatment policy estimand (ITT) ranged from -8.4% (-11.0,-5.7) to -12.3% (-15.3 to -9.2) with MariTide, versus -1.7% (-2.9, -0.6) with placebo, and by efficacy estimand from -12.1% (-14.2,-10.1) to -17.0% (-18.8,-15.3) with MariTide, versus -1.4% (-2.5, -0.3) with placebo (Table 2; Fig. IB, S4C, D).[000140] A greater proportion of participants achieved weight reductions from baseline of at least 5%, 10%, 15%, and 20% with MariTide compared with placebo (Figure S5, Table S3). (See Fig. S6 weight change waterfall plots; Fig. PK-LDI S3 weight change PK-LDI study).[000141] Anthropometric and Cardiometabolic Parameters[000142] From baseline to week 52, MariTide treatment was associated with greater improvements in HbAlc versus placebo (Fig. 1C, D; Table 2, S2) in both Cohorts. Improvements were observed in other key (Table 2, Table S3) and additional secondary outcomes (Table S4; Fig. S7-S10) including waist circumference (Fig. S7), BMI (Fig. S8), SBP (Fig. S9), DBP, high-sensitivity C-reactive protein (hs-CRP), and select lipid parameters (Table S4). Body composition was assessed by DXA in a sub-study (OB, n=191; OB-T2D, n=46) as an exploratory outcome, resulting in greater reduction in fat mass than lean mass (Fig. S10).[000143] Tolerability and Safety[000144] In Cohort OB, 90.2%-98.7% of participants treated with MariTide reported at least one AE, irrespective of causality, versus 68.4% with PBO (Table 3). In Cohort OB-T2D, 90.6%-96.9% of participants treated with MariTide reported at least one AE, versus 81.3% with PBO (Table 3). Thirty-five participants reported at least one serious AE (Table 3, S5). There were two deaths in the MariTide arms assessed as not related to study product by site investigators (Table 3).[000145] Reporting of GI AE in the electronic data capture (EDC) system included unsolicited reporting (without prompt or specific questionnaire), but participants in Phase 2 Cohort OB and the PK-LDI study were additionally solicited to complete the Modified Index of Nausea, Vomiting and Retching (M-INVR) PRO. It was at the investigator’s discretion whether to include the data captured in the M-INVR in the EDC AE reporting. The most frequently reported AEs were GI, most were mild to moderate, including nausea, vomiting, constipation, retching (dry heaves), and diarrhea, with higher incidence in the no-DE arms, and lower incidence in the arms which included DE and a lower starting dose (Fig. Sil, Table S6, Table PK-LDI S2, Fig. PK-LDI S4). The discontinuation rate of MariTide due to GI AEs in the DE arms was 7.7-7.8% (Cohort OB) compared with the no-DE arms where discontinuations were 11.7-27.5% (Cohort OB) and 6.5-15.6% (Cohort OB-T2D); most frequently due to vomiting or nausea (Table 3). Discontinuation rate due to GI AEs was 0% in the PK-LDI study (Table PK-LDI S2); notably, this study was shorter and not powered to detect the potential differences between study arms.[000146] Other AEs were generally balanced between groups. Among predefined AEs of interest (Table 3), hypersensitivity events were mild or moderate (all non-serious) and included injection site reactions, rash, urticaria, occurring in 5.2% of MariTide participants vs.3.9% of placebo (Cohort OB), and in 3.2% vs. 0%, respectively (Cohort OB-T2D). Gallbladder events were more frequent in the MariTide-treated groups than placebo (Table 3). Level 2, laboratory-confirmed hypoglycemia (glucose <54mg / dL) was reported in two participants in Cohort OB and three in Cohort OB-T2D (who were taking oral glucose-lowering medications) (Table S7). Bone mineral density (BMD) by DXA was measured in a sub-study (OB, n=191; OB-T2D, n=46) as an exploratory outcome. There were no changes in BMD at the spine, and those at the hip were not dose-related and were consistent with studies of diet-induced weight loss (Table S8).17- 19 Mood events were low frequency, all mild to moderate and accompanied by study drug discontinuation in two participants, one in the MariTide group and one in the placebo group (Table 3). In the MariTide-treated arms, heart rate, calcitonin, amylase, and lipase all increased with mean values remaining within normal limits, while liver aminotransferases decreased (Table S9). No cases of pancreatitis, diabetic retinopathy, or C-cell hyperplasia were reported.[000147] Pharmacokinetics[000148] MariTide plasma exposures increased with increasing dose and dosing frequency (Table PK-LDI S3; Fig. PK-LDI S5).11060-W001-SEC REPLACEMENT SHEETTABLE 1. Demographic and baseline clinical characteristicsCohort OB Cohort OB-T2DMariTideMariTide MariTidedose escalationnon-dose escalation (No-DE) non-dose escalation (No-DE)(DE)Characteristic 420 mg Placebo Total Placebo Total 420 mg140 mg 280 mg 420 mg 420 mg Q4W (n = 78) (n = 465) 140 mg 280 mg 420 mg (n = 32) (n =Q4WQ4W Q4W Q4W Q8W (12W- Q4W (n = Q4W Q4W 127)(4W-DE)(n = 77) (n = 77) (n = 79) (n = 51) DE) (n = 32) (n = 32)(n = 51) 31)(n = 52)Age, yr 49.1±13. 47.6±11. 55.1±11 iiHiii 49.0± 1 1.4 48.2±12.5 54.9±12.8 56.8.1 1 1.7111100(1 0 00115111100OOOOiOOlOO 2 Female sex - no. 33 49 29248 (62.3) 48 (62.3) 50 (63.3) 31 (60.8) 33 (63.5) 13 (41.9) 14 (43.8) 13 (40.6) 13 (40.6) 53 (41.7) (%) (64.7) (62.8) (62.8)Race or ethnic group - no. (%)American Indian0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (1.3) 2 (0.4) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) or Alaska Native 1 (1 9)1 1 31 (24.4 Asian 15 ( 19.0) 6 ( 19.4)(21.6) ||2i2)ll 001^(111)00Black or African 9 (7.1)6 (7.8) 4 (5.2) 4 (5.1) 3 (5.9) 6 (11.8) 2 (3.8) 7 (9.0) 32 (6.9) 2 (6.5) 2 (6.3) 0 (0.0) 5 (15.6) American33 51White OOiB iiiiiii 30 (58.8) OiioBiii oiioiiiii 86 (67.7(64.7)11060-W001-SEC REPLACEMENT SHEETNative Hawaiianor Other Pacific 1 (1.3) 1 (1.3) 0 (0.0) 1 (2.0) 0 (0.0) 0 (0.0) 1 (1.3) 4 (0.9) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) IslanderMultiple (> (0.0) 2 (3.9) 0 (0.0) 0 (0.0) ||(|1| 5 (1.1) 0 (0.0) <) (().()) 0 (O. O) Other 2 (2.6) 0 (0.0) 1 (1.3) 1 (2.0) 1 (2.0) 1 (1.9) 3 (3.8) 9 (1.9) 0 (0.0) 0 (0.0) 1 (3.1) 0 (0.0) 1 (0.8) Hispanic orgilibgiLatino - no. 9 ( 11.4) 4 (7.8) 9 (17.3)l lllill 6 (19.4) lllll 17 (13.4 lllll(%)109.9 103.4 108.6 106.9 109.3 102.3 110.1 107.4 106.0 101.0 106.7 101.8 103.9 Body weight, kg±26.7 ±18.3 ±25.3 ±28.4 ±21.9 ±19.7 ±31.7 ±25.2 ±24.6 ±16.8 ±26.5 ±18.0 ±21.73X.8 38.0 igiiiii).36.2 Igglglg IlBIllgg 35.8± 6.6kg / nr iiiilig ggiiilg ±6.2 igiiigi oioiig Body-mass index category - no. (%)<30 |b6)(||)|b 8 (10.4) 1 (2.0) 6 ( 11.5) gglgl)l 42 (9.0) 5 (16.1) 7 (21.9) |i7)(gl9)bg 25 (19.714 28 151>30 to <35 25 (32.5) 25 (32.5) 20 (25.3) 18 (35.3) 21 (40.4) 9 (29.0) 8 (25.0) 7 (21.9) 8 (25.0) 32 (25.2)(27.5) (35.9) (32.5)1420 (26.0) 22 (27.8) ggg|Og||15 (29.4) 9 (29.0) 39 (30.7 >35 to <40 llliii llgglglggllllg ll^gillll16 31 152>40 26 (33.8) 20 (26.0) 30 (38.0) 17 (33.3) 12 (23.1) 8 (25.8) 7 (21.9) 9 (28.1) 7 (21.9) 31 (24.4)(39.7) (32.7) (31.4)Waist1 14.4± 1 16.8± iiiiiiii iiillili 117.2± iiliiil iiiiii H2.0±circumference - ig lllligilil18.4 14 14.4.8 12.8 19.6 ggBingi g)ggB^8ggss cm11060-W001-SEC REPLACEMENT SHEETPrediabetes, no. 18 24 15326 (33.8) 27 (35.1) 24 (30.4) 23 (45.1) 11 (21.2) NA NA NA NA NA (%) (35.3) (30.8) (32.9)HbA lc, % 5.5±0.4 7. X J. O.(>Systolic blood125.0± 126.3± 128.6± 126.6± 130.0± 126.2± 125.9± 126.8± 128.3± 131.3± 131.0± 133.9± 131.1± pressure - 14.3 16.1 14.8 14.1 13.1 11.9 13.7 14.2 13.2 15.6 19.5 16.0 16.2 mmHgDiastolic blood80.41 10.pressure - 80.9±8.9 82.4±9.9 81.2±8.6 81.9±9.3 81.8±8.6 X-+.5.1. X.5 82.5±9.3 mmHg* Plus-minus values are means ± SD.t Prediabetes was defined as a glycated hemoglobin level of 5.7% to less than 6.5%.4W-DE, 4-week dose escalation; 12W-DE, 12-week dose escalation; No-DE, non-dose escalation.11060-W001-SEC REPLACEMENT SHEETTABLE 2. Primary and select key secondary end points*Cohort OB Cohort OB-T2DMariTide MariTide MariTidenon-dose escalation (No-DE) dose escalation (DE) non-dose escalation (No-DE)420 mg 420 mg Placebo Placebo 140 mg 280 mg 420 mg 420 mg (n = 76) 140 mg 280 mg 420 mg (n = 32)Q4W (4W- Q4WEstimate (95% CI) Q4W Q4W (n = Q4W (n = Q8W Q4W Q4W Q4WDE) (12W-DE)(n = 77) 77) 79) (n = 51) (n = 31) (n = 32) (n = 32)(n = 51) (n = 52)Treatment Policy Estimand (primary estimand)PrimaryBody Weight% Mean change from -13.6 -14.6 -14.1 -16.2 -2.5 -10.3 -8.4 -12.3 -1.7-15.5 -12.3baseline (primary (-15.5, (-16.8, - (-16.2, - (-18.9, - (-4.2, - (-13.2, - (-11.0, - (-15.3, - (-2.9, - (-17.7,13.4) (-15.0, -9.7)endpoint) -11.7) 12.4) 12.1) 13.5) 0.7) 7.4) 5.7) 9.2) 0.6) Mean % weight change -9.9 -13.8 NA -8.6 NlOils® INlOlsS) NA difference (active drug - gliiligg (- 14. K. -9.5 ) (-12.8. -6.9) (-14.3. -9.1) (-16.8. - (-11.6, - placebo) 10.7) iiiigiiigiKey Secondary0.1 Change in HbAlc (%) -0.3 gggiilgig ggnBigig 0.0 iigiiii iill^ii (-0.4, from baseline IlilO (-0.3. -O.2) (-0.4. -0.2) (-0.4, -0.3) (-0.1. 0.1) (-1.9. -1.2) Itllll) liBiiil 0.5) Change in mean fasting 0.1-1.7 -4.0 -3.8 -2.0 -4.2 -5.1 0.0 -1.7 0.4 -2.2serum insulin from (-2.6,(-4.0, 0.7) (-5.6, -2.4) (-5.4, -2.2)baseline (uIU / mL) (-4.1, 0.!) (-6.0, -2.4) (-6.6, -3.7) (-3.4, 3.4) (-4.7, 1.3) (-2.9, 3.6) (-5.7, 1.4)2.9)11060-W001-SEC REPLACEMENT SHEET9.2 Change in mean fasting -9.1 ooooi^i§ooo ooiBiio plasma glucose from lloBiiii ooooo||ooo0 -7.7 -10.6 -0.6 (- (-10.8. -6.5) (- 1 1.5. -<>.5 ) (-1 liiKo0.2, -5.3) (-12.9. -8.2) (-3.7. 2.6) 16.8.35.1 liiioiii)baseline (mg / dL)) Efficacy EstimandPrimaryBody Weight-17.7 -16.7 -2.6 - 19.9 iiiilliiii -1.4 (OoiBiooio Oool^iloooio OOOOiiiOOO oooiiiiooo % Mean change frombaseline (primary (-19.3, - (-21.4. - (-3.6, - (-2.5. - 1(111®endpoint) 16.1) 18.4) 10.4) 0.3) 1.5) loiiiii oooi^iiooo OOo^iliiooo oooiioiiooo-13.8 -17.3 -16.3 -15.1 -14.2 -17.4 -10.9 -10.7 -15.7 Mean % weight changeNA NA difference (active drug - (-15.3 - (-18.9, - (-18.0, - (-17.1, - (-15.8, - (-19.2, - (-13.0, - (-13.1, - (-17.8, - placebo) 12.25) 15.7) 14.6) 13.2) 12.5) 15.6) 8.7) 8.4) 13.6)Key Secondary0.1 -0.4 -0.4 -0.4 -0.4 -0.4 -0.4 0.0 -1.9 -2.0 -2.2 Change in HbAlc (%)(-0.4, from baseline (-0.5, -0.3) (-0.5, -0.4) (-0.4, -0.3) (-0.5, -0.3) (-0.5, -0.3) (-0.5, -0.3) (-0.1, 0.1) (-2.1, -1.6) (-2.2, -1.8) (-2.4, -2.0) 0.6) Change in mean fasting 1.2 -2.7 -0.5 ooooiiiioioo) OOOOBOIOOOIO OOOBOIOOOO 000)0301)000 serum insulin from (-1.6, Ooiloiii|o (-6.4. -4.0) (-6.9. -.3.1) (-8.0, -3.9) (-7.1. -5.1) (-3.2. 2.2) (-5.4. 1.4) ||1||||)| 3.9) baseline (uIU / mL)-12.3 -12.7 Change in mean fasting -13.0 -11.7 -43.6 -46.4 -58.2 22.0 -11.4 -11.7 -0.5(-15.3, - (-15.3, - (-56.5, - (-67.4, - plasma glucose from (-56.1, - (-8.9, (-13.8, - (-15.1, - (-13.3, -9.5) (-14.0, -9.5) (-3.7, 2.7)10.7) 8.1) 31.0) 36.4) 49.0) 53.0) baseline (mg / dL) 10.9) 10.3)11060-W001-SEC REPLACEMENT SHEET* Efficacy endpoint derived from an ANCOVA analysis for the treatment policy estimand (top part of table) and mixed model for repeated measures (MMRM) analysis for the efficacy estimand (bottom part of table). 95% confidence intervals are not adjusted for multiplicity and should not be used for hypothesis testing.4W-DE, 4-wcck dose escalation; 12W-DE, 12-wcck dose escalation; No-DE, no dose escalation.11060-W001-SEC REPLACEMENT SHEETTABLE 3. Safety and adverse eventsOB Cohort OB-T2D Cohort MariTide MariTide MariTidenon-dose escalation (No-DE) dose escalation (DE) non-dose escalation (No-DE)Placebo Placebo Adverse events during 140 mg 280 mg 420 mg 420 mg 420 mg Q4W, 420 mg Q4W, (n = 76) 140 mg 280 mg 420 mg (n = 32 treatment regardless of Q4W (n = Q4W (n = Q4W (n = Q8W (n = 4W-DE (n = 12W-DE (n = Q4W Q4W Q4W (n = causality 77) 77) 79) 51) 51) 52) (n = 31) (n = 32) 32)26 Adverse event 73 (94.8) 75 (97.4) 78 (98.7) 49 (96.1) 46 (90.2) 49 (94.2) 52 (68.4) 29 (93.5) 29 (90.6) 31 (96.9)(81.3) Serious adverse events|||||||| 0 (0.0 3 (5.8) 5 (6.6)(SAEs) llilll IIIIH 0 (0.0) Deaths* 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (1 9) 0 (0.0) 0 (0.0) 1 (3.1) 0 (0.0) 0 (0.0) Adverse events leading todiscontinuation of MariTide 11111111 15 (294) 5 (9.8) 6 ( 1 1 5) 1 (1.3) 4 (12 9) 6 (18.8) 1 (3.1) or placeboGI adverse events leading10 (13.0) 9 (11.7) 13 (16.5) 14 (27.5) 4 (7.8) 4 (7.7) 0 (0.0) 2 (6.5) 5 (15.6) 4 (12.5) 0 (0.0) to discontinuationMost frequent adverseevents leading todiscontinuationVomiting 9 (11.7) 8 (10.4) 12 (15.2) 12 (23.5) 3 (5.9) 1 (1 9) 0 (0.0) 1 (3.2) 3 (9.4) 4 (12.5) 0 (0.0) Nausea glglg^llg 1 1 (J 3 V) 8 ( 15.7) 3 (5.9) 1 (1 9) 0 (( ) ( 1) 0 (0.0) Retching 2 (2.6) 1 (1.3) 1 (1.3) 3 (5.9) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)11060-W001-SEC REPLACEMENT SHEETOB Cohort OB-T2D Cohort MariTide MariTide MariTidenon-dose escalation (No-DE) dose escalation (DE) non-dose escalation (No-DE)Placebo Placebo Adverse events during 140 mg 280 mg 420 mg 420 mg 420 mg Q4W, 420 mg Q4W, (n = 76) 140 mg 280 mg 420 mg (n = 32 treatment regardless of Q4W (n = Q4W (n = Q4W (n = Q8W (n = 4W-DE (n = 12W-DE (n = Q4W Q4W Q4W (n = causality 77) 77) 79) 51) 51) 52) (n = 31) (n = 32) 32)Headache ilJIlllg lllillll 2 (3.9) 0 (0.0) 0 (0.0) 0 (0.0) ||||||||; 0 (0.0) Diarrhea 0 (0.0) 1 (1.3) 3 (3.8) 0 (0.0) 1 (2.0) 0 (0.0) 0 (0.0) 1 (3.2) 1 (3.1) 0 (0.0) 0 (0.0) Fatigue loiiiiii 1 (2.0) 0 (0.0) 0 (0.0) 0 (0.0) Constipation 2 (2.6) 1 (1.3) 1 (1-3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Gastroesophageal reflux loiiiiii 0 (0.0) 1 (2.0) 0 (0.0) 0 (0.0) 0 (0.0) O (0.0) diseaseInjection site reaction 1 (1-3) 0 (0.0) 1 (1.3) 0 (0.0) 1 (2.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Malaise 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Adverse events occurring in at least 10% of participants in the overall MariTide treatment groups in Cohort OB or OB-T2DNausea 59 (76.6) 60 (77.9) 69 (87.3) 42 (82.4) 36 (70.6) 38 (73.1) 19 (25.0) 18 (58.1) 13 (40.6) 19 (59.4) 3 (9.4) Vomiting 69 (87.3) 47 (92.2) 22 (4.3.1) 23 (44.2) 2 (2.6) 14 (45.2) 16 (5O. O) 2 (6.3) Constipation 23 (29.9) 19 (24.7) 19 (24.1) 18 (35.3) 12 (23.5) 11 (21.2) 4 (5.3) 4 (12.9) 3 (9.4) 6 (18.8) 0 (0.0) Retching 13 (16.9) 18 (22.8) 1 1 (21.6) 5 (9.8) 8 ( 15.4) 1 (1.3) O (0.0) Diarrhea 8 (10.4) 5 (6.5) 17 (21.5) 6 (11.8) 7 (13.7) 10 (19.2) 4 (5.3) 3 (9.7) 5 (15.6) 5 (15.6) 3 (9.4)11060-W001-SEC REPLACEMENT SHEETOB Cohort OB-T2D Cohort MariTide MariTide MariTidenon-dose escalation (No-DE) dose escalation (DE) non-dose escalation (No-DE)Placebo Placebo Adverse events during 140 mg 280 mg 420 mg 420 mg 420 mg Q4W, 420 mg Q4W, (n = 76) 140 mg 280 mg 420 mg (n = 32 treatment regardless of Q4W (n = Q4W (n = Q4W (n = Q8W (n = 4W-DE (n = 12W-DE (n = Q4W Q4W Q4W (n = causality 77) 77) 79) 51) 51) 52) (n = 31) (n = 32) 32)Headache 1 1 (14.3) 8 ( 10.4) 13 (16.5) 10 (19.6) 3 (5.9) 5 (9.6) 5 (6.6) / / ||14| / / 4 (12.5 Gastroesophageal reflux8 (10.4) 8 (10.4) 8 (10.1) 7 (13.7) 4 (7.8) 7 (13.5) 0 (0.0) 2 (6.5) 2 (6.3) 2 (6.3) 0 (0.0) diseaseAdverse events of special interest^Hypersensitivity 3 (3.9) 4 (5.2) 2 (2.5) 3 (5.9) 4 (7.8) 4 (7.7) 3 (3.9) 1 (3.2) 1 (3.1) 1 (3.1) 0 (0.0) Injection site reactions 8 ( 10.1 ) 0 (0.0) 8 (15.7) 6 (11.5) 2 (2.6) lillil / 2 (6.3) Severe and / or serious6 (7.8) 2 (2.6) 9 (11.4) 5 (9.8) 1 (2.0) 1 (1 0 (0.0) 0 (0.0) 3 (9.4) 0 (0.0) gastrointestinal events.9) 1 (3.1)Acute renal events O (().()) 0 (0.0) 1 (2.0) 0 (0.0) ((>.(>) 0 (0.0) / iOil / / / (i / (ii| / / 0 (0.0) Diabetic retinopathy 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Acute pancreatitis 0 (0.0) 0 (0.0) 0 (().()) 0 (().()) 0 (0.0) (> (0.0) 0 (0.0) / iOi) / / / / Biiii / / 0 (0.0) Acute gallbladder diseases 1 (1.3) 1 (1-3) 5 (6.3) 1 (2.0) 0 (0.0) 2 (3.8) 0 (0.0) 0 (0.0) 1 (3.1) 0 (0.0) 0 (0.0) C-ccll hyperplasia, thyroid0 (O. O) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) malignanciesHeart rate increase 0 (0.0) 4 (5.2) 0 (0.0) 1 (2.0) 1 (2.0) 0 (0.0) 1 (1.3) 0 (0.0) 2 (6.3) 0 (0.0) 2 (6.3)11060-W001-SEC REPLACEMENT SHEETOB Cohort OB-T2D Cohort MariTide MariTide MariTidenon-dose escalation (No-DE) dose escalation (DE) non-dose escalation (No-DE)Placebo Placebo Adverse events during 140 mg 280 mg 420 mg 420 mg 420 mg Q4W, 420 mg Q4W, (n = 76) 140 mg 280 mg 420 mg (n = 32 treatment regardless of Q4W (n = Q4W (n = Q4W (n = Q8W (n = 4W-DE (n = 12W-DE (n = Q4W Q4W Q4W (n = causality 77) 77) 79) 51) 51) 52) (n = 31) (n = 32) 32)All depressivedisordcr / suicidal behavioro <o.o) iiiiiiii 5 (9.8) 1 (2.0) 0 (0.0) 0 (0.0) 1 (3.1) and ideation (mild, moderate,or severe)-5Severe or serious 0 (O. O) 0 (0.0 ) 1 (2.0) 0 (0.0) O (0.(1) 0 (().()) 0 (0.0)* Two deaths were reported; both were assessed as unrelated to the investigational product. A participant in Cohort OB died of traumatic intracranial hemorrhage two months after starting MariTide. A participant in Cohort OB-T2D died of sudden cardiac death eight months after starting MariTide, with underlying cardiovascular risk factors (Table S5).t Adverse events that led to discontinuation in 3 or more MariTide-treated participants including both cohorts.$ Adverse events of special interest were evaluated with the use of prespecified standardized Medical Dictionary for Regulatory Activities (MedDRA) search queries or customized clusters of MedDRA preferred terms. Mood adverse events include depressive disorder / Suicidal behavior and ideation and were evaluated with the prespecified standardized Medical Dictionary for Regulatory Activities (MedDRA) search query of MedDRA preferred terms.§ Severity of mood changes were mild (n=9 participants) and moderate (n=3 participants); one of the moderate events was a serious adverse event (SAE; Table S5). An SAE of suicidal ideation associated with an interrupted suicide attempt resulted in discontinuation of study drug in this participant. Additionally, one participant from the placebo group was discontinued due to suicidal ideation.4W-DE, 4-week dose escalation; 12W-DE, 12-week dose escalation; No-DE, no dose escalation

Claims

CLAIMSWhat is claimed:

1. A method for promoting weight loss in a human patient comprising administering to the patient a pharmaceutical composition comprising maridebart cafraglutide at an amount of about 70 mg, about 140 mg, about 210 mg, about 280 mg, about 350 mg, or about 420 mg;wherein after the pharmaceutical composition is administered about every four weeks for one year the patient’s weight is reduced by at least 16%.

2. The method according to claim 1, wherein after the pharmaceutical composition is administered about every four weeks for one year the patient’s high-sensitivity C-reactive protein (“hs-CRP”) level is reduced by at least 50%.

3. The method according to claim 1 or 2, wherein after the pharmaceutical composition is administered about every four weeks for one year the patient’s systolic blood pressure (“SBP”) is reduced by at least 8 mmHg.

4. A method for promoting weight loss in a human patient comprising administering to the patient a pharmaceutical composition comprising maridebart cafraglutide at an amount of about 70 mg, about 140 mg, about 210 mg, about 280 mg, about 350 mg, or about 420 mg;wherein after the pharmaceutical composition is administered about every four weeks for one year the patient’sa) high-sensitivity C-reactive protein (“hs-CRP”) level is reduced by at least 50%, andb) systolic blood pressure (“SBP”) is reduced by at least 8 mmHg.

5. The method according to any one of claims 1-4, wherein the amount of maridebart cafraglutide is about 140 mg.

6. The method according to any one of claims 1-3, wherein the amount of maridebart cafraglutide is about 280 mg and the patient’s weight is reduced by at least 19%.

7. The method according to any one of claims 1-3, wherein the amount of maridebart cafraglutide is about 420 mg and the patient’s weight is reduced by at least 18%.

8. The method according to any one of claims 2-4, wherein the amount of maridebart cafraglutide is about 280 mg and the patient’s hs-CRP is reduced by at least 60%.

9. The method according to any one of claims 2-4, wherein the amount of maridebart cafraglutide is about 420 mg and the patient’s hs-CRP is reduced by at least 55%.

10. The method according to claims 3 or 4, wherein the amount of maridebart cafraglutide is about 280 mg and the patient’s SBP is reduced by at least 12 mmHg.

11. The method according to claims 3 or 4, wherein the amount of maridebart cafraglutide is about 420 mg and the patient’s SBP is reduced by at least 11 mmHg.

12. A method for reducing HbAlc levels in a human patient comprising administering to the patient a pharmaceutical composition comprising maridebart cafraglutide at an amount of about 70 mg, about 140 mg, about 210 mg, about 280 mg, about 350 mg, or about 420 mg;wherein after the pharmaceutical composition is administered about every four weeks for one year the patient’ sa) weight is reduced by at least 12%, andb) HbAlc level is reduced by at least 1.8%.

13. The method according to claim 12, wherein after the pharmaceutical composition is administered about every four weeks for one year the patient’s high-sensitivity C-reactive protein (“hs-CRP”) level is reduced by at least 40%.

14. The method according to claim 12 or 13, wherein after the pharmaceutical composition is administered about every four weeks for one year the patient’s systolic blood pressure (“SBP”) is reduced by at least 8 mmHg.

15. The method according to any one of claims 12-14, wherein the amount of maridebart cafraglutide is about 140 mg.

16. The method according to any one of claims 12-14, wherein the amount of maridebart cafraglutide is about 280 mg and the patient’s weight is reduced by at least 12%.

17. The method according to any one of claims 12-14, wherein the amount of maridebart cafraglutide is about 420 mg and the patient’s weight is reduced by at least 16%.

18. The method according to any one of claims 12-14, wherein the amount of maridebart cafraglutide is about 280 mg.

19. The method according to any one of claims 12-14, wherein the amount of maridebart cafraglutide is about 420 mg and the patient’s hs-CRP is reduced by at least 60%.

20. The method according to claims 13 or 14, wherein the amount of maridebart cafraglutide is about 280 mg and the patient’s SBP is reduced by at least 12 mmHg.

21. The method according to claims 13 or 14, wherein the amount of maridebart cafraglutide is about 420 mg and the patient’s SBP is reduced by at least 11 mmHg.

22. A method for reducing high-sensitivity C-reactive protein (“hs-CRP”) in a human patient comprising administering to the patient a pharmaceutical composition comprising maridebart cafraglutide at an amount ofabout 70 mg, about 140 mg, about 210 mg, about 280 mg, about 350 mg, or about 420 mg;wherein after the pharmaceutical composition is administered about every four weeks for one year the patient’sa) weight is reduced by at least 16%, andb) hs-CRP level is reduced by at least 50%.

23. The method according to claim 22, wherein after the pharmaceutical composition is administered about every four weeks for one year the patient’s systolic blood pressure (“SBP”) is reduced by at least 8 mmHg.

24. The method according to any one of claims 22 or 23, wherein the amount of maridebart cafraglutide is about 140 mg.

25. The method according to any one of claims 22 or 23, wherein the amount of maridebart cafraglutide is about 280 mg and the patient’s weight is reduced by at least 19%.

26. The method according to any one of claims 22 or 23, wherein the amount of maridebart cafraglutide is about 420 mg and the patient’s weight is reduced by at least 18%.

27. The method according to any one of claims 22 or 23, wherein the amount of maridebart cafraglutide is about 280 mg and the patient’s hs-CRP is reduced by at least 60%.

28. The method according to any one of claims 22 or 23, wherein the amount of maridebart cafraglutide is about 420 mg and the patient’s hs-CRP is reduced by at least 55%.

29. The method according to claims 22 or 23, wherein the amount of maridebart cafraglutide is about 280 mg and the patient’s SBP is reduced by at least 12 mmHg.

30. The method according to claims 22 or 23, wherein the amount of maridebart cafraglutide is about 420 mg and the patient’s SBP is reduced by at least 11 mmHg.

31. A method for reducing systolic blood pressure in a human patient comprising administering to the patient a pharmaceutical composition comprising maridebart cafraglutide at an amount ofabout 70 mg, about 140 mg, about 210 mg, about 280 mg, about 350 mg, or about 420 mg;wherein after the pharmaceutical composition is administered about every four weeks for one year the patient’sa) weight is reduced by at least 16%, andb) systolic blood pressure (“SBP”) is reduced by at least 8 mmHg.

32. The method according to claim 31, wherein after the pharmaceutical composition is administered about every four weeks for one year the patient’s high-sensitivity C-reactive protein (“hs-CRP”) level is reduced by at least 50%.

33. The method according to any one of claims 31 or 32, wherein the amount of maridebart cafraglutide is about 140 mg.

34. The method according to any one of claims 31 or 32, wherein the amount of maridebart cafraglutide is about 280 mg and the patient’s weight is reduced by at least 19%.

35. The method according to any one of claims 31 or 32, wherein the amount of maridebart cafraglutide is about 420 mg and the patient’s weight is reduced by at least 18%.

36. The method according to any one of claims 31 or 32, wherein the amount of maridebart cafraglutide is about 280 mg and the patient’s hs-CRP is reduced by at least 60%.

37. The method according to any one of claims 31 or 32, wherein the amount of maridebart cafraglutide is about 420 mg and the patient’s hs-CRP is reduced by at least 55%.

38. The method according to claims 31 or 32, wherein the amount of maridebart cafraglutide is about 280 mg and the patient’s SBP is reduced by at least 12 mmHg.

39. The method according to claims 31 or 32, wherein the amount of maridebart cafraglutide is about 420 mg and the patient’s SBP is reduced by at least 11 mmHg.

40. Use of maridebart cafraglutide for preparation of a medicament for promoting weight loss in a human patient in need thereof, wherein the medicament is formulated for administration at a dose of about 70 mg, about 140 mg, about 210 mg, about 280 mg, about 350 mg, or about 420 mg; andwherein after the pharmaceutical composition is administered about every four weeks for one year the patient’s weight is reduced by at least 16%.

41. Use according to claim 40, wherein after the pharmaceutical composition is administered about every four weeks for one year the patient’s high-sensitivity C-reactive protein (“hs-CRP”) level is reduced by at least 50%.

42. Use according to claim 40 or 41, wherein after the pharmaceutical composition is administered about every four weeks for one year the patient’s systolic blood pressure (“SBP”) is reduced by at least 8 mmHg.

43. Use of maridebart cafraglutide for preparation of a medicament for promoting weight loss in a human patient in need thereof, wherein the medicament is formulated for administration at a dose of about 70 mg, about 140 mg, about 210 mg, about 280 mg, about 350 mg, or about 420 mg;wherein after the pharmaceutical composition is administered about every four weeks for one year the patient’ sa) high-sensitivity C-reactive protein (“hs-CRP”) level is reduced by at least 50%, andb) systolic blood pressure (“SBP”) is reduced by at least 8 mmHg.

44. Use according to any one of claims 40-43, wherein the amount of maridebart cafraglutide is about 140 mg.

45. Use according to any one of claims 40-42, wherein the amount of maridebart cafraglutide is about 280 mg and the patient’s weight is reduced by at least 19%.

46. Use according to any one of claims 40-42, wherein the amount of maridebart cafraglutide is about 420 mg and the patient’s weight is reduced by at least 18%.

47. Use according to any one of claims 41-43, wherein the amount of maridebart cafraglutide is about 280 mg and the patient’s hs-CRP is reduced by at least 60%.

48. Use according to any one of claims 41-43, wherein the amount of maridebart cafraglutide is about 420 mg and the patient’s hs-CRP is reduced by at least 55%.

49. Use according to claims 42 or 43, wherein the amount of maridebart cafraglutide is about 280 mg and the patient’s SBP is reduced by at least 12 mmHg.

50. Use according to claims 42 or 43, wherein the amount of maridebart cafraglutide is about 420 mg and the patient’s SBP is reduced by at least 11 mmHg.

51. Use of maridebart cafraglutide for preparation of a medicament for reducing HbAlc in a human patient in need thereof, wherein the medicament is formulated for administration at a dose of about 70 mg, about 140 mg, about 210 mg, about 280 mg, about 350 mg, or about 420 mg;wherein after the pharmaceutical composition is administered about every four weeks for one year the patient’ sa) weight is reduced by at least 12%, andb) HbAlc level is reduced by at least 1.8%.

52. Use according to claim 51, wherein after the pharmaceutical composition is administered about every four weeks for one year the patient’s high-sensitivity C-reactive protein (“hs-CRP”) level is reduced by at least 40%.

53. Use according to claim 51 or 52, wherein after the pharmaceutical composition is administered about every four weeks for one year the patient’s systolic blood pressure (“SBP”) is reduced by at least 8 mmHg.

54. Use according to any one of claims 51-53, wherein the amount of maridebart cafraglutide is about 140 mg.

55. Use according to any one of claims 51-53, wherein the amount of maridebart cafraglutide is about 280 mg and the patient’s weight is reduced by at least 12%.

56. Use according to any one of claims 51-53, wherein the amount of maridebart cafraglutide is about 420 mg and the patient’s weight is reduced by at least 16%.

57. Use according to any one of claims 51-53, wherein the amount of maridebart cafraglutide is about 280 mg.

58. Use according to any one of claims 51-53, wherein the amount of maridebart cafraglutide is about 420 mg and the patient’s hs-CRP is reduced by at least 60%.

59. Use according to claims 52 or 53, wherein the amount of maridebart cafraglutide is about 280 mg and the patient’s SBP is reduced by at least 12 mmHg.

60. Use according to claims 52 or 53, wherein the amount of maridebart cafraglutide is about 420 mg and the patient’s SBP is reduced by at least 11 mmHg.

61. Use of maridebart cafraglutide for preparation of a medicament for reducing high-sensitivity C-reactive protein (“hs-CRP”) in a human patient in need thereof, wherein the medicament is formulated for administration at a dose ofabout 70 mg, about 140 mg, about 210 mg, about 280 mg, about 350 mg, or about 420 mg;wherein after the pharmaceutical composition is administered about every four weeks for one year the patient’sa) weight is reduced by at least 16%, andb) hs-CRP level is reduced by at least 50%.

62. Use according to claim 61, wherein after the pharmaceutical composition is administered about every four weeks for one year the patient’s systolic blood pressure (“SBP”) is reduced by at least 8 mmHg.

63. Use according to any one of claims 61 or 62, wherein the amount of maridebart cafraglutide is about 140 mg.

64. Use according to any one of claims 61 or 62, wherein the amount of maridebart cafraglutide is about 280 mg and the patient’s weight is reduced by at least 19%.

65. Use according to any one of claims 61 or 62, wherein the amount of maridebart cafraglutide is about 420 mg and the patient’s weight is reduced by at least 18%.

66. Use according to any one of claims 61 or 62, wherein the amount of maridebart cafraglutide is about 280 mg and the patient’s hs-CRP is reduced by at least 60%.

67. Use according to any one of claims 61 or 62, wherein the amount of maridebart cafraglutide is about 420 mg and the patient’s hs-CRP is reduced by at least 55%.

68. Use according to claims 61 or 62, wherein the amount of maridebart cafraglutide is about 280 mg and the patient’s SBP is reduced by at least 12 mmHg.

69. Use according to claims 61 or 62, wherein the amount of maridebart cafraglutide is about 420 mg and the patient’s SBP is reduced by at least 11 mmHg.

70. Use of maridebart cafraglutide for preparation of a medicament for reducing systolic blood pressure in a human patient in need thereof, wherein the medicament is formulated for administration at a dose ofabout 70 mg, about 140 mg, about 210 mg, about 280 mg, about 350 mg, or about 420 mg;wherein after the pharmaceutical composition is administered about every four weeks for one year the patient’sa) weight is reduced by at least 16%, andb) systolic blood pressure (“SBP”) is reduced by at least 8 mmHg.

71. Use according to claim 70, wherein after the pharmaceutical composition is administered about every four weeks for one year the patient’s high-sensitivity C-reactive protein (“hs-CRP”) level is reduced by at least 50%.

72. Use according to any one of claims 70 or 71, wherein the amount of maridebart cafraglutide is about 140 mg.

73. Use according to any one of claims 70 or 71, wherein the amount of maridebart cafraglutide is about 280 mg and the patient’s weight is reduced by at least 19%.

74. Use according to any one of claims 70 or 71, wherein the amount of maridebart cafraglutide is about 420 mg and the patient’s weight is reduced by at least 18%.

75. Use according to any one of claims 70 or 71, wherein the amount of maridebart cafraglutide is about 280 mg and the patient’s hs-CRP is reduced by at least 60%.

76. Use according to any one of claims 70 or 71, wherein the amount of maridebart cafraglutide is about 420 mg and the patient’s hs-CRP is reduced by at least 55%.

77. Use according to claims 70 or 71, wherein the amount of maridebart cafraglutide is about 280 mg and the patient’s SBP is reduced by at least 12 mmHg.

8. Use according to claims 70 or 71, wherein the amount of maridebart cafraglutide is about 20 mg and the patient’s SBP is reduced by at least 11 mmHg.

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