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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receptor 1 (CB1R) inverse agonists demonstrated efficacy for weight loss and metabolic improvements, they were withdrawn due to psychiatric adverse events.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 phase. Given that first generation CB1R inverse agonists, such as rimonabant, faced serious safety concerns regarding psychiatric AEs, further research with a focus on psychiatric safety is warranted.8 The placebo/20 mg group had the highest number of withdrawals and AEs in the extension phase, comparable to the prevalence observed in the 20 mg group during the randomised phase.6 This likely reflects that in the other treatment groups, participants who did not tolerate the drug discontinued during the main phase. This study has some notable limitations. The treatment effect cannot be fully distinguished from the study effect, as there was no comparator in the extension phase. Imbalances in the baseline body weight and BMI during the extension phase of the study could affect the interpretation of the results. Additionally, this study only includes completers of the 16-week randomised phase of the trial. Those are the participants that tolerated monlunabant and were compliant with the trials, which introduces a significant selection bias to the results and challenges the generalizability of the studies. The presented efficacy is based on observed data with no imputation, which may cause overestimation of weight loss. The reported weight loss may also be biased by discontinuation rates. Furthermore, the open-label design following the double-blinded randomised phase could introduce observer and performance biases. It is also important to note that discontinuation after early study drug discontinuation may lead to missing information on AE outcome and duration. Lastly, when multiple AEs resulted in treatment discontinuation, a primary AE was not documented. These limitations could contribute to an underestimation of tolerability issues of monlunabant. In conclusion, in a selected population who participated in an open-label 36-weeks extension phase of a phase 2a trial, we observed a clinically meaningful weight loss which was sustained through the trial period and that the safety profile is consistent with the previous reporting from the randomised phase. Further research is still warranted, including larger, long-term randomised controlled trials, to determine the role of monlunabant in the treatment of obesity. This would be particularly important to address both uncertainty about long-term safety and efficacy at lower doses to determine if a clinically relevant dose range of monlunabant exists. Glenn Crater and Karine Lalonde contributed to the study design. Jean-Sebastien Paquette was involved in the conduct of the trial and contributed to data collection. The contract research organisation, Worldwide Clinical Trials, and Thomas Holst-Hansen did the statistical analyses. All authors interpreted the data. George Kunos, Dror Dicker and Louis Aronne contributed from their clinical and investigational expertise in the obesity field and added significant contributions to the interpretation of the data. All authors had full access to the data in the study and had final responsibility for the decision to submit for publication. All authors contributed to the data interpretation and manuscript writing (assisted by a medical writer employed at Novo Nordisk), approved the final version of the manuscript, and vouch for data accuracy and fidelity to the protocol. Thomas Holst-Hansen, Oscar Birkhan, Glenn Crater, and Jean-Sebastien Paquette have accessed and verified the underlying data reported in the manuscript. This trial was sponsored by Inversago Pharma Inc. (a Novo Nordisk company). The authors thank the trial participants, the investigators, and trial site staff who conducted the trial. Statistical analyses were provided by Worldwide Clinical Trials. Medical writing and editorial support were provided by Sabrina Mai Nielsen, PhD, Novo Nordisk, supported by Greg Markby, PhD, Novo Nordisk. George Kunos, MD, was supported by the Intramural Research Program of the NIH. Filip K. Knop, Ofir Frenkel, Oscar Birkhan and Thomas Holst-Hansen are employees and shareholders of Novo Nordisk. Glenn Crater and Karine Lalonde were employees of Inversago Pharma Inc. (a Novo Nordisk company) and owned Inversago Pharma Inc. stock options. George Kunos is listed as inventor on a United States patent (issued) covering monlunabant. Jean-Sebastien Paquette is a Site Principal Investigator for the study and is a Research Director of family medicine at Laval University. Louis Aronne received research funding from Eli Lilly, Novo Nordisk, Altimunne, and Skye Bioscience; consulting fees as consultant/advisory board from Boehringer-Ingelheim, Currax Pharmaceuticals, Eli Lilly, Altimmune, Janssen Pharmaceuticals, Jazz Pharmaceuticals, Novo Nordisk, Pfizer, Veru Pharmaceuticals, Zealand Pharma, and Amgen; honoraria for lectures/presentations from Boehringer-Ingelheim, Skye Bioscience, Zealand Pharma, Jamieson Wellness, and Pfizer; support for attending meetings and/or travel from Jamieson Wellness; patent pending for Flytehealth; part of the board of directors for Flytehealth, Jamieson Wellness, ERX Pharmaceuticals; equity interests from Jamieson Wellness, Flytehealth, Kallyope, Mediflix, MBX Bioscience, Syntis, Veru Pharmaceuticals, Skye Bioscience. Dror Dicker has received speaker and advisory board fees from Boehringer-Ingelheim, Eli Lilly, Novo Nordisk, Astra Zeneca, and Roche; research grants from Eli Lilly, Novo Nordisk, and Boehringer Ingelheim; support for attending meetings and/or travel from Novo Nordisk and Boehringer Ingelheim; participation in advisory board for Novo Nordisk, Boehringer-Ingelheim, and Astra Zeneca; participation in the executive committee for EFIM and EASO. The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/dom.70580. Individual participant data will be shared in datasets in a de-identified, anonymised format. Access request proposals can be found on the Novo Nordisk Trials website. Data will be made available after research completion and approval of the product and product use in the EU and the USA. Data will be shared with bona fide researchers submitting a research proposal requesting access to data. Access request proposal form and the access criteria can be found at novonordisk-trials.com. DATA S1: Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.