Monlunabant in adults with obesity and metabolic syndrome: Open‐label extension of a phase 2a trial

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Obesity and metabolic syndrome are major global health concerns that significantly raise the risk of type 2 diabetes and cardiovascular disease, among other conditions.1-4 Despite available effective anti-obesity medications,5 new treatments are needed for patients who do not respond or have poor tolerance to existing options. While first-generation cannabinoid receptor 1 (CB1R) inverse agonists demonstrated efficacy for weight loss and metabolic improvements, they were withdrawn due to psychiatric adverse events. Monlunabant is a novel second-generation CB1R inverse agonist. In a phase 2a trial, oral once-daily 10, 20, and 50 mg monlunabant for 16 weeks in obesity and metabolic syndrome demonstrated statistically and clinically significant weight loss compared to placebo.6 Adverse events (AEs) and withdrawals due to AEs were dose-dependent. The 16-week randomised phase was followed by an optional open-label extension phase. Here, we report on the open-label extension phase to investigate the long-term efficacy and safety of monlunabant 20 mg in individuals with obesity and metabolic syndrome. This study is a pre-specified open-label extension of a phase 2a trial (NCT05891834). Methods for the randomised phase were published previously.6 In brief, the randomised phase enrolled adults with body mass index (BMI) ≥30 kg/m2 and metabolic syndrome. Key exclusion criteria included diabetes requiring medication, use of weight loss drugs, recent significant weight change, or significant psychiatric disorder. Participants were randomised (1:1:1:1) to receive once-daily oral tablets of monlunabant 10 mg, 20 mg, 50 mg, or placebo for 16 weeks. Participants unable to tolerate the dose were discontinued, as dose reduction was not allowed. Participants discontinuing prematurely were asked to attend an early termination visit without further follow-up. All study activities were conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. The trial protocol and all related documents were approved by the relevant Institutional Review Boards or Independent Ethics Committees at each participating site prior to study initiation. All participants provided written informed consent before undergoing any study-specific procedures. Participants who completed the randomised phase without significant noncompliance and confirmed continued consent were eligible for an optional extension phase of 20 mg monlunabant for an additional 36 weeks (i.e., 52 weeks treatment in total). The outcome assessments in the randomised phase continued into the extension phase, and the primary endpoint was the mean change from baseline (week 16) in body weight (kg). Efficacy endpoints were assessed in all extension phase participants (full-analysis set) and safety endpoints were assessed in all extension phase participants who received at least one dose of trial drug in the extension phase (safety-analysis set). Observations were included for the on-treatment observation period (by study design) regardless of intercurrent events of prohibited medication that affect weight. There were no events of prohibited medication affecting weight during the extension phase. Anti-obesity medication remained prohibited during the extension phase and no lifestyle counselling was introduced during the study. All endpoints were summarised with descriptive statistics for the extension phase (change from week 16 to 52), and post hoc for the full trial (change from week 0 to 52). No statistical tests or handling of missing data were performed. Analyses were done using SAS (version 9.4) and according to the statistical analysis plan. Of the 183 participants completing the initial randomised phase, 177 continued into the extension phase, with 143 completing it (Figure S1). Withdrawals were most frequent in the placebo/20 mg group. At the beginning of the extension phase (week 16), imbalances in participant characteristics were noted between the original treatment groups for baseline body weight and BMI (Table S1). At the beginning of the randomised phase (week 0), the groups were balanced (Table S2). During the extension phase (week 16 to 52), observed mean changes in body weight were −4.7 (SD 6.5), −6.2 (6.2), −3.3 (4.7), and −9.9 (7.4) kg in the 10/20, 20/20, 50/20 mg, and placebo/20 mg groups, respectively (Table S3). Over the course of the full trial (week 0 to 52), the weight loss slowed down and reached a plateau, though less clearly for the 20/20 mg group, resulting in a total mean weight loss ranging from 10.6 to 14.4 kg (9.5% to 12.6%) across the groups (Figure 1), and 24%–34% of participants in the groups achieved weight loss of ≥15% (Table S4). In an exploratory post hoc analysis, females appeared to lose more weight, except in the placebo/20 mg group (Table S5). Triglycerides, high-density lipoprotein (HDL), and haemoglobin A1C (HbA1c) showed slight improvements across all groups during the full trial (Table S3 and Figure S2). There was no clear evidence of effect on most biomarkers of injury/inflammation and fibrosis, except for improvements in C-reactive protein (CRP) as well as in leptin (Table S6). In total, 30 (63.8%), 24 (58.5%), 18 (56.3%), and 50 (87.7%) participants reported AEs during the extension phase in the 10/20, 20/20, 50/20 mg, and placebo/20 mg groups, respectively (Table 1). Most AEs were mild or moderate in severity. Two participants in the 10/20 mg group reported each a serious AE during the extension phase, including hip fracture and gastrointestinal bleeding, both assessed as not related to the study drug. During the full trial, 53 (86.9%), 51 (85.0%), 55 (91.7%), and 54 (88.5%) participants reported AEs in the 10/20, 20/20, 50/20 mg, and placebo/20 mg groups, respectively (Table S7). Overall, higher proportions of females reported AEs compared to males across all groups (Table S8). No deaths were reported. The most frequently reported AEs during the extension phase were gastrointestinal disorders (mainly nausea, diarrhea, vomiting, constipation, and abdominal pain), psychiatric disorders (mainly anxiety, irritability, insomnia, and depression), and infections and infestations (mainly nasopharyngitis, COVID-19, bronchitis, upper respiratory tract infection, and urinary tract infection) (Figure S3). For the full trial, gastrointestinal disorders were the most frequently reported AEs across all groups (Figure S4). Among the AEs of special interest, no suicidality, seizure, or convulsions were reported during the trial (Table S7). AEs leading to early withdrawal during the extension phase (Table 1), and for the full trial (Table S7), were mainly due to psychiatric disorders (for the full trial, all AEs of psychiatric disorders were non-serious), followed by gastrointestinal disorders. Both AEs leading to early withdrawal from the trial and psychiatric AEs mainly occurred within the first 8 weeks of monlunabant treatment, whereas most gastrointestinal AEs occurred immediately after initiating treatment (Figure S5). However, new-onset psychiatric AEs were observed up to week 45. This open-label extension demonstrated, on a descriptive basis, that individuals in this cohort treated with monlunabant achieved sustained, progressive, and clinically meaningful weight loss. The weight loss appeared to reach a plateau by 40 weeks (less clearly for the 20/20 mg group). Small improvements in lipids and glycaemic control were observed, such as improvements in HDL cholesterol and HbA1c, commonly seen after weight loss.7 In the extension phase (and full trial), there were no study drug-related serious AEs, including serious psychiatric AEs, and no evidence of suicidality. Some participants experienced worsening or new-onset, non-serious psychiatric AEs during the extension phase. As onset of new psychiatric AEs was observed throughout the trial period, tight safety monitoring is advised throughout the treatment period and should not be limited only to the initiation

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