A phase 2 randomised controlled trial of mazdutide in Chinese overweight adults or adults with obesity

After rapidly growing prevalence over the past four decades, overweight and obesity now affect more than half of adult population in China 1 . Often clustered with hypertension, dyslipidemia, hyperglycaemia and hyperuricemia, overweight and obesity account for ever-growing non-communicable diseases-associated mortality and pose a great threat to public health 2 . Multiple lines of evidence suggest that a body weight reduction of 5–15% could significantly improve metabolic disorders and reduce the risk for type 2 diabetes, cardiovascular diseases, metabolic liver diseases and other weight-related comorbidities 3 – 5 . Chinese clinical practice guidelines recommend pharmacotherapy for adults with obesity or overweight adults accompanied by weight-related comorbidities inadequately controlled by 3–6 month’s diet or exercise intervention 5 . However, only orlistat has been approved in China, and its clinical application is limited by modest weight loss efficacy and notable safety issues 1 , 5 . In 2021, the US FDA approved once-weekly semaglutide 2.4 mg for long-term body weight management 6 . In STEP 1 trial, patients with obesity receiving semaglutide 2.4 mg lost a mean body weight of 6% by week 12 and 12% by week 28, compared with a 2–3% body weight loss in those receiving placebo 7 . Tirzepatide, a dual GLP-1 and glucose-dependent insulinotropic polypeptide receptor agonist, showed placebo-adjusted weight reduction of more than 20% after 72 weeks of treatment 8 . Other endeavour on GLP-1-based weight loss therapies came from molecules that co-activate glucagon receptors, where synergistic weight loss effect was expected given glucagon’s effects to increase energy expenditure 9 – 11 . Mazdutide (also known as IBI362 or LY3305677), a mammalian oxyntomodulin analogue with a fatty acid side chain attached, is being developed as a once-weekly GLP-1 and glucagon receptor dual agonist for the treatment of obesity and type 2 diabetes. In a phase 1b clinical trial in Chinese overweight adults or adults with obesity, mazdutide dosed up 10 mg was well tolerated, with overall safety profiles similar to those of other GLP-1 receptor agonists and co-agonists 12 , 13 . At week 12, participants receiving mazdutide 6 mg and 9 mg lost a mean body weight of 6.1% and 11.7%, respectively 12 , 13 . Here, in a randomised, double-blind, placebo-controlled phase 2 trial, we further assess the efficacy and safety of mazdutide in Chinese overweight adults or adults with obesity. Mazdutide demonstrates robust and clinically meaningful body weight loss after 24 weeks of treatment, together with improvements on multiple cardio-metabolic risk factors. Mazdutide is well tolerated up to 6 mg over 24 weeks, with safety profile consistent with those observed in previous studies.

In the primary analysis using analysis of covariance (ANCOVA) model, the percentage change from baseline to week 24 in body weight was dose-dependent with mazdutide. The estimated mean percentage change from baseline to week 24 in body weight were −6.7% (SE 0.7) with mazdutide 3 mg, −10.4% (0.7) with mazdutide 4.5 mg, −11.3% (0.7) with mazdutide 6 mg and 1.0% (0.7) with placebo. The estimated treatment difference versus placebo were −7.7% (95%CI: −9.5, −5.9) with mazdutide 3 mg, −11.4% (−13.2, −9.6) with mazdutide 4.5 mg and −12.3% (−14.1, −10.5) with mazdutide 6 mg ( p < 0.0001) (Fig. 2a and Table 2 ). Sensitivity analyses using ANCOVA model with multiple imputation and mixed-effect model for repeated measures (MMRM) with all in-trial body weight data also supported the robust and dose-dependent body weight reduction with mazdutide at week 24. MMRM-estimated percentage reductions in body weight with mazdutide at week 24 were slightly greater than those in the primary analysis (Fig. 2b and Table S1 ). All mazdutide groups had significantly greater reductions in body weight than the placebo group at week 24 ( p < 0.0001) (Fig. 2c and Table 2 ). Fig. 2 Body weight efficacy endpoints. a Percentage change from baseline in body weight at week 24. Symbols and error bars represent LSM and SE, from the primary analysis for the primary endpoint (ANCOVA + LOCF), mITT population. Numbers are LSM. Violin plots represent observed percentage changes from baseline in body weight for participants in the mITT population. b Percentage change from baseline in body weight over time. Symbols and error bars represent LSM and SE, from the sensitivity analysis for the primary endpoint (MMRM), mITT population. Numbers are LSM. c Change from baseline in body weight at week 24. Symbols and error bars represent LSM and SE, from MMRM analysis, mITT population. Numbers are LSM. Violin plots represent observed changes from baseline in body weight for participants in the mITT population. d Proportion of participants reaching weight loss targets (≥5% and ≥10%), mITT population. Mazdutide 3 mg n = 62; mazdutide 4.5 mg n = 63; mazdutide 6 mg n = 61; placebo n = 62. ANCOVA analysis of covariate. LOCF last observation carried forward. LSM least squares mean. MMRM mixed model repeated measures. SE standard error. Source data are provided with this paper. Table 2 Changes in body weight and waist circumference, and proportion of participants achieving weight loss targets at week 24 Mazdutide 3 mg ( n = 62) Mazdutide 4.5 mg ( n = 63) Mazdutide 6 mg ( n = 61) Placebo ( n = 62) Mean p Mean p Mean p Mean Primary endpoint - Percentage change from baseline in body weight (primary analysis – ANCOVA + LOCF) Percentage change, % −6.7 (0.7) −10.4 (0.7) −11.3 (0.7) 1.0 (0.7) ETD versus placebo −7.7 (−9.5, −5.9) <0.0001 −11.4 (−13.2, −9.6) <0.0001 −12.3 (−14.1, −10.5) <0.0001 Secondary endpoints Proportion of participants achieving ≥5% weight loss, n (%) 36 (58.1) 52 (82.5) 49 (80.3) 3 (4.8) ETD versus placebo, % 53.2 (39.9, 66.5) <0.0001 77.3 (66.4, 88.1) <0.0001 75.1 (63.7, 86.5) <0.0001 ≥10% weight loss, n (%) 12 (19.4) 31 (49.2) 31 (50.8) 0 ETD versus placebo, % 19.4 (9.5, 29.2) 0.0003 48.9 (36.5, 61.3) <0.0001 50.1 (37.5, 62.8) <0.0001 ≥15% weight loss, n (%) 6 (9.7) 10 (15.9) 16 (26.2) 0 ETD versus placebo, % 9.7 (2.3, 17.0) 0.0125 15.7 (6.7, 24.6) 0.0013 25.4 (14.4, 36.4) <0.0001 Change from baseline in body weight, kg −6.4 (0.6) −9.1 (0.6) −9.9 (0.6) 1.1 (0.6) ETD versus placebo −7.4 (−9.0, −5.9) <0.0001 −10.2 (−11.7, −8.6) <0.0001 −10.9 (−12.5, −9.4) <0.0001 Change from baseline in BMI, kg/m 2 −2.3 (0.2) −3.3 (0.2) −3.6 (0.2) 0.4 (0.2) ETD versus placebo −2.7 (−3.2, −2.1) <0.0001 −3.7 (−4.2, −3.1) <0.0001 −4.0 (−4.6, −3.4) <0.0001 Change from baseline in waist circumference, cm −5.6 (0.7) −8.5 (0.7) −8.8 (0.7) −1.1 (0.7) ETD versus placebo −4.5 (−6.5, −2.4) <0.0001 −7.3 (−9.3, −5.3) <0.0001 −7.6 (−9.6, −5.6) <0.0001 For continuous variables, data are LSM (SE) for change and percentage change from baseline and LSM (95% CI) for ETD, from MMRM (secondary endpoints) or ANCOVA (primary endpoint) analysis, mITT population. For categorical varibles, data are n (%) and ETD (95% CI) from Mantel-Haenszel analysis, mITT population. Proportion of participants reaching weight loss targets (≥5%, ≥10% and ≥15%) was obtained by dividing the number of participants reaching respective targets at week 24 by the number of participants with baseline value and at least one non-missing post-baseline value. Participants with missing value at week 24 were treated as non-responders. All statistical tests were two-sided at a significance level of 0.05, and no adjustments were made for multiplicity. P values were nominal except for those of the primary analysis for the primary endpoint. ANCOVA analysis of covariate, ETD estimated treatment difference, LOCF last observation carried forward, LSM least squares mean, MMRM

Treatment-emergent adverse events of any grade were reported in 95.2% of participants receiving mazdutide and 80.6% receiving placebo, mostly mild or moderate in severity. Severe events considered to be related to the study treatment by the investigators included upper abdominal pain reported in one participant with mazdutide 3 mg and diarrhoea reported in one participant with mazdutide 6 mg. Serious adverse events were reported in nine participants receiving mazdutide in no one receiving placebo, and none of the events were considered to be related to the study treatment by the investigators. Events leading to treatment discontinuation were reported in only one participant with mazdutide 4.5 mg and considered unrelated to the study treatment by the investigator (Table 4 ). Dose reductions occurred in three participants with mazdutide 4.5 mg and seven with the mazdutide 6 mg, mostly due to gastrointestinal adverse events. Among participants who completed 24-week treatment, two participants with mazdutide 4.5 mg and five with mazdutide 6 mg were not on target doses. Table 4 Treatment-emergent adverse events Mazdutide 3 mg ( n = 62) Mazdutide 4.5 mg ( n = 63) Mazdutide 6 mg ( n = 61) Placebo ( n = 62) Any TEAEs 58 (93.5) 60 (95.2) 59 (96.7) 50 (80.6) Mild 43 (69.4) 32 (50.8) 29 (47.5) 41 (66.1) Moderate 14 (22.6) 28 (44.4) 28 (45.9) 9 (14.5) Severe 1 (1.6) 0 2 (3.3) 0 Serious TEAEs 1 (1.6) 4 (6.3) 4 (6.6) 0 TEAEs leading to treatment discontinuation 0 1 (1.6) 0 0 Adverse events occurring in at least 10% of participants in any treatment group a Diarrhoea 12 (19.4) 19 (30.2) 19 (31.1) 9 (14.5) Nausea 13 (21.0) 15 (23.8) 25 (41.0) 3 (4.8) Upper respiratory tract Infection 12 (19.4) 11 (17.5) 19 (31.1) 11 (17.7) Hepatic steatosis 13 (21.0) 10 (15.9) 7 (11.5) 13 (21.0) Vomiting 8 (12.9) 13 (20.6) 17 (27.9) 2 (3.2) Hyperuricaemia 8 (12.9) 13 (20.6) 5 (8.2) 14 (22.6) Decreased appetite 6 (9.7) 10 (15.9) 18 (29.5) 5 (8.1) Urinary tract infection 6 (9.7) 13 (20.6) 7 (11.5) 4 (6.5) Hyperlipidaemia 9 (14.5) 2 (3.2) 4 (6.6) 9 (14.5) Abdominal distension 6 (9.7) 7 (11.1) 7 (11.5) 2 (3.2) Other TEAEs of clinical interest Total hypoglycaemia (plasma glucose ≤3.9 mmol/L) 1 (1.6) 2 (3.2) 2 (3.3) 1 (1.6) Severe hypoglycaemia 0 0 0 0 Injection site reaction 3 (4.8) 1 (1.6) 2 (3.3) 4 (6.5) Hypersensitivity 1 (1.6) 1 (1.6) 0 1 (1.6) Cardiac disorders a 2 (3.2) 9 (14.3) 4 (6.6) 9 (14.5) Sinus tachycardia 1 (1.6) 5 (7.9) 1 (1.6) 2 (3.2) Sinus arrhythmia 1 (1.6) 2 (3.2) 1 (1.6) 4 (6.5) Supraventricular extrasystoles 2 (3.2) 0 2 (3.3) 2 (3.2) Sinus bradycardia 0 2 (3.2) 0 2 (3.2) Ventricular extrasystoles 1 (1.6) 1 (1.6) 0 0 Arrhythmia supraventricular 0 1 (1.6) 0 0 Tachycardia 1 (1.6) 0 0 0 Data are n (%), safety population. TEAE treatment-emergent adverse event. a By the Medical Dictionary for Regulatory Activities (MedDRA, version 24.0) preferred term. Gastrointestinal symptoms (diarrhoea, nausea and vomiting) were among the most common adverse events and appeared mazdutide dose-related (Table 4 ). Most gastrointestinal events were mild or moderate in severity. Diarrhoea, nausea and vomiting were more frequent during dose escalation and declined gradually in the latter part of the treatment period (Fig. S7 ). Only one participant with mazdutide 4.5 mg had aspartate aminotransferase (AST) exceeding three times the upper limit of normal (ULN) during the study and concurrent ALT elevation within three times the ULN at week 4 (Table S4 ). The elevation was transient and returned to normal for the rest of the study. One participant with mazdutide 3 mg experienced two episodes of lipase increase above three times the ULN at week 12 and 20 and completed the study with lipase slightly above the ULN at week 36. Another participant with mazdutide 6 mg had transient lipase increase above three times the ULN at week 9. The event of marked increase in lipase reported in the participant with mazdutide 3 mg was considered to be related to the study treatment by the investigator. No participant had amylase increase above three times the ULN during the study and no investigator-suspected pancreatitis was reported. No participant had calcitonin of 20 ng/L or higher during the study and there was no report of thyroid tumours, neoplasms or C-cell hyperplasia events (Table S4 ). Cardiac disorders of clinical interest were reported in 15 participants (8.1%) with mazdutide and nine (14.5%) with placebo, with no clear association with mazdutide doses. All events were revealed by electrocardiogram, mild in severity, asymptomatic and transient. The most common cardiac disorder was sinus tachycardia, reported in seven participants (2.8%) with mazdutide and two (3.2%) with placebo (Table 4 ). Heart rate increase was observed in all treatment groups and returned to normal during the off-treatment follow-up period. The mean change from baseline to week 24 in heart rate were 5.82 beats per minute, 5.38 beats per minute and 8.75 beats per minute with mazdutide 3

Trial oversight The study was conducted in accordance with local laws, the International Conference on harmonisation Good Clinical Practice guidelines, and the ethical principles outlined in the Declaration of Helsinki. The study protocol and informed consent form were approved by ethics committees of all study sites: Peking University People’s Hospital; The First Affiliated Hospital and Clinical Medicine College of Henan University of Science and Technology; The Fourth Affiliated Hospital of Harbin Medical University; Huzhou Central Hospital; Shandong Province Qianfoshan Hospital; Pingxiang People’ s Hospital; The First Affiliated Hospital of Bengbu Medical College; Jinan Central Hospital; The Second Hospital of Hebei Medical University; Chu Hsien-I Memorial Hospital; Jiangsu Province Hospital; Sun Yat-Sen Memorial Hospital; Shanghai Tenth People’s Hospital of Tong Ji University; Qilu Hospital of Shandong University; Inner Mongolia Autonomous Region People’s Hospital; Luoyang Central Hospital; Tonghua Central Hospital; Jingzhou Central Hospital; The First Affiliated Hospital of Nanyang Medical College. All participants provided written informed consent before study entry, between June 11, 2021 and Oct. 1, 2021.

Participants were eligible for the study if they were adults (aged 18–75 years, both inclusive), overweight (BMI ≥ 24 kg/m 2 ) accompanied by hyperphagia and/or at least one weight-related comorbidity (pre-diabetes, hypertension, dyslipidaemia or fatty liver within 6 months before screening; weight-bearing joint pain; obesity-related dyspnoea or obstructive sleep apnoea syndrome), or with obesity (BMI ≥ 28 kg/m 2 ); had body weight change less than 5% during the 2-week lead-in period; were able to understand the procedures and methods of the study and willing to comply with the study protocol; and were willing to sign the informed consent form. Participants were excluded if they had known allergies to the study drug or any components of the formulation or drugs of the same class; had self-reported body weight fluctuated by more than 5% in the 12 weeks before screening with diet and exercise alone; had used GLP-1 receptor agonists and co-agonists, anti-obesity drugs, glucose-lowering drugs, Chinese herbal medicine or health products that affect body weight, or investigational medication in other clinical trials within 3 months before screening; had a HbA1c level of 6.5% or above at screening or history of type 1 or type 2 diabetes; had a screening fasting blood glucose level of 7.0 mmol/L or above or 11.1 mmol/L or above 2 hours after a 75 g oral glucose tolerance test; had severe hypoglycaemia or recurrent symptomatic hypoglycaemia two times or more within 6 months; had obesity caused by increased cortisol hormone (such as Cushing’s syndrome), pituitary gland or hypothalamus injury, or dose reduction or withdrawal of weight loss drugs; had a history of bariatric surgery or planned bariatric surgery or acupuncture for weight loss, liposuction and abdominal fat removal during the study; had a history of moderate to severe depression or severe mental illness; had previous suicidal ideation or suicidal behaviour; had PHQ-9 of 15 points or more at screening; Had answered “yes” to either Question 4 or Question 5 on the “Suicidal Ideation” portion of the C-SSRS at screening; had major and medium-sized surgery, severe trauma or severe infection within 1 month before screening and were determined by the investigator as not being suitable for this study; had blood donation and/or blood loss ≥400 mL or bone marrow donation within 3 months before screening, or haemoglobinopathy, haemolytic anaemia, sickle cell anaemia. Medical history and concomitant disease-related exclusion criteria included retinopathy; uncontrolled hypertension within 1 month before screening; malignancy; myocardial infarction, angina pectoris, acute and chronic heart failure, cardiomyopathy, or cardiac surgery; haemorrhagic or ischemic stroke or transient ischemic attack within 6 months before screening; thyroid C-cell carcinoma, multiple endocrine neoplasia 2A or 2B, or relevant family history; acute or chronic pancreatitis, gallbladder disease, and pancreatic injury; Heart rate <50 beats/min or >100 beats/min on 12-lead ECG at screening; clinically significant cardiac condition at screening including second or third degree atrioventricular block, long QT syndrome, or QTcF >500 ms, left or right bundle branch block, pre-excitation syndrome or other significant arrhythmia (except sinus arrhythmia); average weekly alcohol intake of more than 21 units for males or 14 units for females; and history of drug abuse. Physical examination and laboratory results-related exclusion criteria included serum calcitonin ≥20 ng/L; ALT or AST > 3 × the ULN; serum total bilirubin (TBil) level >1.5 × the ULN; estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m 2 at screening; fasting triglycerides >5.64 mmol/L; thyroid-stimulating hormone <0.4 mIU/L or >6.0 mIU/L; blood amylase or lipase >2.0 × the ULN; international normalised ratio (INR) of prothrombin time >the ULN; haemoglobin <110 g/L (males) or <100 g/L (females); and serological evidence of HBV, HCV, HIV and syphilis infection at screening.

Mazdutide and placebo were provided as once-weekly and subcutaneous injections in prefilled devices. For each mazdutide dose level, there was a matching placebo with the same injection volume and doing schedule. Mazdutide was administered with one of the three doses: 3 mg (1.5 mg weeks 1–4; 3 mg weeks 5–24), 4.5 mg (1.5 mg weeks 1–4; 3 mg weeks 5–8; 4.5 mg weeks 9–24) and 6 mg (2 mg weeks 1–4; 4 mg weeks 5–8; 6 mg weeks 9–24). The dose escalation schedules are shown in Fig. S1 . Participants were required to maintain the original diet, exercise and lifestyle during the trial. Study visits occurred at screening, before and after lead-in, day 1 (randomisation), every week through week 10, week 12, week 16, week 20, week 23, week 24 and every 4 weeks thereafter through week 36. Body weight, vital signs, electrocardiogram and adverse events were monitored at every visit. Waist circumference was measured at screening, end of lead-in, day 1 and every 4 weeks thereafter through week 36. Local laboratory parameters were monitored at screening, day 1, every 4 weeks thereafter through week 24 and week 36. Central laboratory parameters (lipids and HbA1c) were monitored at day 1, week 12 and week 24 (Wuxi AppTec Inc., Shanghai ). Pharmacodynamic (fasting plasma glucose and fasting insulin) and immunogenicity parameters were monitored at day 1 and weeks 2, 4, 8, 16, 24 and 32 (Wuxi AppTec Inc., Shanghai ). Impact of Weight on Quality of Life–Lite (IWQOL-Lite) questionnaire assessment was conducted at baseline, week 12 and week 24. PHQ-9 and C-SSRS assessment were conducted at baseline and weeks 12, 24 and 36. Participants who discontinued the study treatment before week 24 were requested to attend the remaining visits. Participants who discontinued the study before week 24 were requested to undergo end-of-study procedures as those who completed the study.

The sample size of 240 participants was estimated to provide at least 95% power to show the superiority of optimal mazdutide dose to placebo in terms of body weight change from baseline to week 24, at a two-sided significance level of 0.05. In the calculation of the sample size, it was assumed the mean percentage change in body weight from baseline to week 24 of 2.3% with placebo and −10% with optimal mazdutide dose, a common standard deviation of approximately 8%, and a dropout rate of 20%. The efficacy endpoints were evaluated in mITT population, defined as all participants who received at least one dose of the study treatment and had both baseline and post-baseline body weight measurements. The safety endpoints were evaluated in the safety population, defined as all participants who received at least one dose of the study treatment. The primary analysis for the primary endpoint was done using ANCOVA model with treatment and stratification factor as fixed effects and the baseline body weight value as a covariate. Missing data at week 24 were imputed using last observation carried forward method. Treatment difference versus placebo were provided, with 95% CI and p values. A sensitivity analysis of the primary endpoint using ANCOVA model as mentioned above except that missing data at week 24 were imputation using multiple imputation approach assuming missing at random. Another sensitivity analysis of the primary endpoint was done using MMRM, with treatment, visit, treatment-by-visit interaction and stratification factor as fixed effects, and baseline body weight as a covariate. An unstructured covariance matrix was used to model relationship of within-participant errors. Continuous secondary efficacy endpoints were analysed using MMRM as the sensitivity analysis for the primary endpoint, with corresponding baseline values as covariates. For categorical secondary endpoints of body weight loss of 5% or more and 10% or more at week 24, Clopper-Pearson method was used for within-group CI calculation and Mantel-Haenszel method was used for between-group CI calculation. Cochran-Mantel-Haenszel method was used for statistical testing. Participants without week 24 body weight assessment were treated as non-responders. Post-hoc analysis of participant with body weight loss of 15% or more at week 24 was done using same method above. Safety data were summarised descriptively. All statistical analyses were done using SAS version 9.4. This study is registered with ClinicalTrials.gov, number NCT04904913 .

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Nature Communications thanks Amanda Adler, Richard Pratley and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. A peer review file is available.