SUMMARY
Background:
Monlunabant, a novel cannabinoid receptor 1 (CB1R) inverse agonist, has shown encouraging weight loss efficacy and tolerability. We aimed to determine the efficacy and safety of monlunabant in individuals with obesity and metabolic syndrome.
Methods:
This 16-week randomised, double-blind, placebo-controlled, dose-ranging phase 2a trial (ClinicalTrials.gov, NCT05891834) conducted at outpatient research centres in Canada, enrolled adults with obesity and metabolic syndrome. Participants were randomized (1:1:1:1) to once-daily oral tablets monlunabant 10, 20, 50 mg, or placebo. Primary endpoint was mean body weight change from baseline at week 16. Secondary endpoints were mean changes from baseline for markers of metabolic syndrome.
Findings:
From Sep-8, 2023 to Jan-26, 2024, 409 individuals were screened. In total, 243 individuals were randomised to monlunabant 10 mg (n=61), 20 mg (n=61), 50 mg (n=60), and placebo (n=61), 242 received treatment, including 167 (69%) females, and 183/242 (76%) completed the trial (50/61 [82%], 42/60 [70%], 34/60 [57%], and 57/61 [93%] participants, respectively). At week 16, monlunabant showed statistically significant weight loss compared to placebo (estimated treatment difference [95%CI] of −6·4 [−8·0;−4·9], −6·9 [−8·5;−5·3] and −8·0 [−9·7;−6·4] kg for 10, 20 and 50 mg, vs placebo, respectively), but no or minor improvements in lipids and markers of glucose control. Adverse events (AEs) were mostly mild to moderate gastrointestinal and psychiatric disorders. Withdrawals due to AEs appeared dose-dependent (8 [13%], 16 [27%], 25 [42%], and 0, respectively), driven by nausea, anxiety, diarrhoea, irritability, and sleep disorder. No deaths were reported.
Interpretation:
Monlunabant demonstrated statistically significant and clinically meaningful weight loss compared to placebo (also in post-hoc sensitivity analysis) for all tested doses with limited additional weight loss observed at higher doses, whereas AEs appeared dose dependent. Further investigation is needed to assess the safety and efficacy of lower doses of monlunabant, to evaluate its potential as an anti-obesity medication.
Funding:
Inversago Pharma Inc. (a Novo Nordisk company)
INTRODUCTION
Obesity and metabolic syndrome represent significant global health challenges, with a high prevalence and substantial impact on individual well-being, quality of life, morbidity and mortality.1 According to the World Health Organization, obesity, defined by body mass index (BMI) of at least 30 kg/m2, has more than doubled since 1990 among adults, and in 2022, 890 million adults were living with obesity.2 Obesity is a global problem, costing the US healthcare system $173 billion a year.3 The presence of abdominal obesity, together with dyslipidaemia, hypertension, and insulin resistance, generally defines the metabolic syndrome, a complex condition that increases the risk of type 2 diabetes and cardiovascular disease.5,6 The increasing worldwide burden of obesity and metabolic syndrome emphasises the urgent need for effective treatment options. Several anti-obesity medications are currently on the market covering diverse modes of action,7 but there continues to be a need for new treatment modalities for those not tolerating existing treatment options or needing additive metabolic benefits.
Endocannabinoids are lipid mediators that induce effects similar to those of plant-derived cannabinoids such as increased appetite, euphoria, and promotion of sleep and relaxation by interacting with the same receptors, cannabinoid receptor 1 (CB1R) and cannabinoid receptor 2 (CB2R). CB1Rs are highly prevalent in the brain, but they are also present at much lower yet functionally pertinent levels in various peripheral tissues. In contrast, CB2R expression is limited to cells of the immune and hematopoietic systems. Activation of CB1R boosts appetite, which prompted the development and approval of the first-in-class CB1R inverse agonist, rimonabant, as an anti-obesity agent. In people with obesity/overweight and metabolic syndrome, rimonabant not only reduced body weight and adiposity but also mitigated all aspects of the metabolic syndrome, including insulin resistance, dyslipidaemia, liver fat and hypertension.8–11 However, rare, but serious neuropsychiatric side effects related to the mode of action, particularly involving suicidal ideation and behaviour, led to rimonabant’s withdrawal from the market12 and ceased further pharmaceutical development of this class of medications.13
Preclinical evidence suggested, however, that activation of peripheral CB1R contributes to obesity and its metabolic complications via increased lipogenesis,14 so their selective targeting may retain the metabolic benefit of CB1R blockade while minimising its neuropsychiatric risks.15 Monlunabant (also known as MRI-1891 or INV-202) is a second-generation CB1R inverse agonist designed to reduce brain penetrance while retaining high potency and selectivity for CB1R. Monlunabant also displays signalling bias as it preferentially inhibits CB1R-induced β-arrestin 2 recruitment over G protein activation.16 In a mouse model of high-fat diet-induced obesity (DIO), chronic treatment with a maximally effective dose of 3 mg/kg/day monlunabant elicited significant weight loss accompanied by improved insulin resistance but did not result in acute brain CB1R occupancy or trigger behaviours which could be predictive of serious psychiatric adverse effects in humans.16 In a recent phase 1b trial in adults with features of metabolic syndrome, treatment for 28 days with 25 mg/day monlunabant resulted in reductions in body weight, waist circumference and BMI as well as decreases in total and low-density lipoprotein (LDL) cholesterol levels, with no serious or severe adverse effects.17 Here, we conducted a proof-of-concept phase 2a trial to determine the efficacy and safety of the novel CB1R inverse agonist, monlunabant, once daily as 10, 20 and 50 mg orally compared to placebo for 16 weeks in individuals with obesity and metabolic syndrome.
METHODS
Study design and participants
This phase 2a, randomised, double-blind, placebo-controlled, proof-of-concept, multicentre trial, with an ongoing optional open-label extension (ClinicalTrials.gov: NCT05891834), was conducted at 25 sites (out-patient clinical research centres) in Canada. The protocol (appendix pp 20–104) and amendments were approved by the institutional review board or an independent ethics committee at each site, and the trial complied with the International Conference on Harmonization Good Clinical Practice guidelines18 and the Declaration of Helsinki.19 All participants provided written informed consent.
Eligible participants were 18 to 75 years of age with BMI ≥30 kg/m2, and metabolic syndrome defined as the presence of at least 3 of the 5 following criteria at screening: i) Increased waist circumference (males, ≥102 cm; females, ≥89 cm), ii) Fasting glucose ≥100 mg/dL or 5·6 mmol/L or a haemoglobin A1c (HbA1c) >5·7%, iii) Triglycerides ≥150 mg/dL or 1·69 mmol/L, iv) high density lipoprotein (HDL) cholesterol <40 mg/dL or 1·03 mmol/L for males or <50 mg/dL or 1·29 mmol/L for females, and v) Hypertension (systolic >130 mmHg and/or diastolic >85 mmHg).
Key exclusion criteria included diabetes requiring medication for management, use of a glucagon-like peptide-1 (GLP-1) agonists or other weight loss drug, or significant weight change (>5 kg) in the past 3 months, history of bariatric surgery, use of systemic corticosteroids, active diagnosis or history of a significant psychiatric disorder, including but not limited to i) major depression within the last 2 years, ii) any history of a suicide attempt or suicidal ideation, iii) a history of other severe psychiatric disorder (e.g., schizophrenia, bipolar disorder), iv) taking any of the following medications: antidepressants, atypical antipsychotics and mood stabilisers, as well as a score on the 9-question Patient Health Questionnaire (PHQ-9) of ≥15 at baseline, active substance abuse in the past 12 months, use of cannabis or cannabinoid-containing compounds within 90 days, history of epilepsy or intracranial surgery, and use of a strong inducer or inhibitor of cytochrome P450 3A4, 2D6, or 2C19 by screening; these medications are prohibited during the entire duration of the trial. Full inclusion and exclusion criteria are provided in appendix (pp 3–4).
Randomisation and masking
Participants were randomised (1:1:1:1) to receive monlunabant 10 mg, 20 mg, 50 mg, or placebo. An unblinded biostatistician generated and implemented the randomisation scheme, and the randomisation occurred through an interactive response system. Monlunabant tablets contained 5, 10, or 25 mg per tablet, and two tablets were needed to reach the daily doses in each group. Placebo tablets were identical in appearance to the monlunabant tablets. The participants, site staff, sponsor, and contract research organisation were blinded to treatment allocation.
Procedures
The first dose was administered at the trial sites. The participants were instructed to self-administer monlunabant doses once daily as oral tablets with food at approximately the same time each day for 16 weeks. Compliance was assessed by tablet counts, based on drug bottles returned to the site at the visits. Noncompliance was defined as taking less than 80% or more than 120% of the assigned trial drug dose during any outpatient evaluation period (visit to visit). Discontinuation for noncompliance was at the investigator’s discretion.
The doses of 10, 20, and 50 mg/day monlunabant were chosen based on data from the phase 1 clinical development program. The program indicated good tolerability and no safety concerns in healthy volunteers (investigating up to 50 mg/day for 14 days), as well as in adults with features of metabolic syndrome (25 mg/day for 28 days), where a significant decrease in body weight was also demonstrated.17
Changes in concomitant therapy were discouraged. A list of prohibited medications is provided in appendix (p 5). No lifestyle intervention or advice was provided.
During the treatment period, participants attended the trial site visits at weeks 4, 8, 12, and 16. A structured retention program was not prospectively implemented. Instead, retention advice on managing gastrointestinal AEs was provided upon request. Dose reduction was not allowed; if participants could not tolerate the dose, they were discontinued. Participants who prematurely discontinued the trial were asked to attend an early termination visit and no further follow-up was done. The safety data were reviewed by an independent and external data and safety monitoring board on an ongoing basis.
Outcomes
The primary endpoint was the mean change from baseline in body weight (kg) at week 16, and the secondary endpoints were mean change from baseline at each site visit in body weight (%), waist circumference, lipids (triglycerides, high density lipoprotein [HDL] cholesterol, LDL cholesterol, very low density lipoprotein [VLDL] cholesterol, total cholesterol, apolipoprotein B), and markers of glucose control (HbA1c, insulin, C-peptide). The participants were not required to be fasting for the collection of blood samples, but only results from fasting participants were reported for insulin, glucose, C-peptide, triglycerides, and VLDL cholesterol. Exploratory endpoints were biomarkers of injury/inflammation and fibrosis (C-reactive protein [CRP], leptin, tumour necrosis factor alpha [TNF-α], interleukin 6 [IL-6], interleukin 18 [IL-18]). In a subpopulation of around 50 participants from selected trial sites, changes in body composition from baseline to week 16 were assessed using dual-energy X-ray absorptiometry (DXA), in terms of fat mass, fat-free mass, fat mass percentage, and fat-free mass percentage. Further measurements included fasting plasma glucose, as well as homeostasis model assessment-estimated insulin resistance (HOMA-IR), which was calculated post hoc. Sex (male/female) was self-reported.
Safety endpoints included adverse events (AEs), serious AEs (SAEs), pre-defined AEs of special interest, suicidality measured with the Columbia Suicide Severity Rating Scale (C-SSRS), symptoms of depression measured with PHQ-9, and symptoms of anxiety measured with General Anxiety Disorder-7 (GAD-7), clinical laboratory assessments, physical examinations, and vital signs.
Statistical analysis
A sample size of 240 participants (60 in each group) was required to provide more than 90% power at an overall significance level of 0·05 in the comparison of at least one dose of monlunabant versus placebo to detect a change in weight of 10%, assuming a standard deviation (SD) of 15 kg, a baseline weight of 108 kg and a dropout rate of 15%. Limited prior knowledge of the potential treatment effect was available hence details from the primary analysis was not incorporated explicitly.
Efficacy endpoints were assessed in all randomised participants (per the intention-to-treat principle, termed the full-analysis set [FAS]) and safety endpoints were assessed in all randomised participants who received at least one dose of trial product (per the treatment actually received, termed the safety-analysis set). The primary estimand applied a hypothetical strategy for handling intercurrent events, including data from FAS and including all observations after randomisation until withdrawal or end of treatment (week 16), but excluding observations after intercurrent events of prohibited medication that affect weight. Intercurrent events of early treatment discontinuation were handled through the study design where participants who permanently discontinued the trial drug would be requested to return for an early termination visit and discontinue the trial. This estimand aims at answering the question what is the effect of taking the drug as intended. It does not distinguish if treatment discontinuation was due to adverse events or lack of efficacy. The estimator for the primary estimand was analysed using a mixed model for repeated measurement (MMRM) model assuming missing data is missing at random (MAR) with treatment, visit, sex, and treatment-by-visit interaction as fixed effects, as well as baseline weight as a covariate, and participant as a random effect factor (intercept), implemented as an unstructured covariance structure. This makes the fewest assumptions on the variance at each visit and correlation between visits. The primary endpoint was presented as least-squares mean (LS mean) with 95% confidence intervals. The secondary endpoints were analysed in a similar manner. Exploratory endpoints were summarised with descriptive statistics. For the primary endpoint, subgroup analyses by sex (male/female) and baseline BMI (30·0–34·9/35·0–39·9/≥40 kg/m2), a per-protocol analysis and a post-hoc jump-to-reference sensitivity analysis were performed as well. For handling multiplicity, a hierarchical testing method was employed. Statistical testing was performed as a 1-sided test at a 0·05 overall significance level in the following prespecified order for the primary endpoint: 1) monlunabant 20 mg versus placebo, 2) monlunabant 50 mg versus placebo, 3) monlunabant 10 mg versus placebo. Formal testing would only continue if the treatment difference from previous steps was statistically significant. All secondary endpoints and supportive analyses were considered as descriptive evidence of efficacy and were analysed without any procedures to account for multiple comparisons. Summaries of safety outcomes were presented descriptively. Analyses were done using SAS (version 9.4) and according to a statistical analysis plan (appendix pp 105–153).
Role of the funding source
The funder of the study had a role in study design, data collection, data analysis, data interpretation, and writing of the report. This article was drafted under the guidance of the authors, with medical writing and editorial support by a medical writer employed at Novo Nordisk.
RESULTS
From September 8, 2023 to January 26, 2024, 409 individuals were screened, of whom 243 were randomly assigned to monlunabant 10 mg/day (n=61), 20 mg/day (n=61), 50 mg/day (n=60), or placebo (n=61) (figure 1). One participant in the 20 mg group was withdrawn before receiving treatment due to a protocol deviation (blood drawing difficulties), leaving 242 for analysis. A total of 183/242 (76%) completed the trial. There were more withdrawals at higher doses of monlunabant (11/61 [18%], 18/60 [30%] and 26/60 [43%] in the 10 mg, 20 mg and 50 mg groups, respectively), which were primarily due to AEs. In the placebo group, none withdrew due to AEs; 4/61 (7%) participants withdrew, including 2 withdrawals due to protocol deviation and 2 withdrawals by subject.
Figure 1: Trial profile.
The main reasons for screening failure were not fulfilling inclusion criteria 4 (i.e., presence of at least 3 of 5 criteria for metabolic syndrome) or exclusion criteria 12 (i.e., active diagnosis or history of a significant psychiatric disorder). Inclusion and exclusion criteria are available in appendix pp 3–4.
Baseline characteristics were well balanced across groups (table 1). Overall, most participants were female (69%), mean age was 53·5 (SD 12·1) years, most were white (85%), mean BMI was 39·7 (SD 6·7) kg/m2, mean body weight was 110·1 (SD 22·8) kg, and mean waist circumference was 119·9 (SD 15·1) cm. Mean HbA1c was 5·9% (SD 0·5), with 71% participants being in the prediabetic or diabetic range. A total of 7 (3%) had anxiety disorders and 20 (8%) had sleep disorders.
Table 1:
Demographics and baseline characteristics
| Monlunabant 10 mg (n = 61) | Monlunabant 20 mg (n = 60) | Monlunabant 50 mg (n = 60) | Placebo (n = 61) | Overall (n = 242) | |
|---|---|---|---|---|---|
| Age, years | 50·4 (13·4) | 52·7 (12·1) | 55·1 (10·7) | 55·9 (11·7) | 53·5 (12·1) |
| Sex | |||||
| Female | 42 (69%) | 44 (73%) | 39 (65%) | 42 (69%) | 167 (69·0%) |
| Male | 19 (31%) | 16 (27%) | 21 (35%) | 19 (31%) | 75 (31·0%) |
| Region: | |||||
| North America (Canada) | 61 (100%) | 60 (100%) | 60 (100%) | 61 (100%) | 242 (100·0%) |
| Race | |||||
| White | 48 (79%) | 53 (88%) | 52 (87%) | 53 (87%) | 206 (85·1%) |
| Black or African American | 7 (11%) | 3 (5%) | 2 (3%) | 3 (5%) | 15 (6·2%) |
| Asian | 5 (8%) | 4 (7%) | 6 (10%) | 5 (8%) | 20 (8·3%) |
| Multiple | 1 (2%) | 0 | 0 | 0 | 1 (0·4%) |
| Weight, kg | 112·6 (23·1) | 107·9 (17·1) | 112·0 (26·9) | 108·0 (23·3) | 110·1 (22·8) |
| BMI, kg/m2 | 40·6 (6·8) | 39·6 (5·4) | 39·7 (7·4) | 39·0 (6·9) | 39·7 (6·7) |
| 30·0 – 34·9 | 15 (25%) | 12 (20%) | 19 (32%) | 17 (28%) | 63 (26·0) |
| 35·0 – 39·9 | 17 (28%) | 25 (42%) | 20 (33%) | 23 (38%) | 85 (35·1) |
| ≥40·0 | 29 (48%) | 23 (38%) | 21 (35%) | 21 (34%) | 94 (38·8) |
| Waist circumference, cm | 121·3 (14·5) | 118·4 (12·5) | 120·2 (17·6) | 119·6 (15·4) | 119·9 (15·1) |
| HbA1c, mmol/mol | 40.8 (4.7) | 40.8 (5.1) | 41.4 (7.0) | 42.0 (6.3) | 41.2 (5.8) |
| HbA1c, % | 5·9 (0·4) | 5·9 (0·5) | 5·9 (0·6) | 6·0 (0·6) | 5·9 (0·5) |
| <5·7 | 19 (31%) | 19 (32%) | 17 (28%) | 15 (25%) | 70 (29%) |
| ≥5·7 | 42 (69%) | 41 (68%) | 43 (72%) | 46 (75%) | 172 (71%) |
| Systolic blood pressure, mmHg | 136 (14) | 133 (13) | 133 (12) | 133 (13) | 134 (13) |
| Diastolic blood pressure, mmHg | 84 (8) | 84 (9) | 84 (8) | 84 (7) | 84 (8) |
| Fasting triglycerides, mmol/L † | 1·7 (0·8) | 1·8 (0·9) | 1·8 (0·8) | 1·7 (0·9) | 1·8 (0·9) |
| HDL cholesterol, mmol/L | 1·3 (0·4) | 1·3 (0·3) | 1·3 (0·3) | 1·4 (0·4) | 1·3 (0·4) |
| LDL cholesterol, mmol/L | 3·4 (0·9) | 3·4 (1·1) | 3·3 (1·0) | 3·4 (1·0) | 3·4 (1·0) |
| Fasting VLDL cholesterol, mmol/L ‡ | 0·8 (0·4) | 0·8 (0·4) | 0·8 (0·4) | 0·8 (0·4) | 0·8 (0·4) |
| Total cholesterol, mmol/L | 4·8 (0·9) | 4·8 (1·2) | 4·8 (1·0) | 4·9 (0·9) | 4·8 (1·0) |
| Apolipoprotein B, g/L § | 0·84 (0·19) | 0·87 (0·23) | 0·82 (0·22) | 0·87 (0·21) | 0·85 (0·21) |
| Fasting plasma glucose, mmol/L ¶ | 5·4 (0·6) | 5·7 (0·9) | 5·7 (1·0) | 5·8 (1·2) | 5·6 (0·9) |
| Fasting insulin, pmol/L # | 161·6 (153·3) | 155·8 (159·7) | 147·8 (76·6) | 150·6 (101·0) | 153·9 (126·6) |
| C-peptide, nmol/L ** | 1·1 (0·5) | 1·1 (0·5) | 1·1 (0·4) | 1·1 (0·4) | 1·1 (0·5) |
| PHQ-9 total score | 1·8 (1·9) | 1·6 (2·2) | 1·9 (1·9) | 1·6 (2·2) | 1·7 (2·0) |
| GAD-7 total score | 0·6 (1·6) | 0·8 (1·3) | 0·7 (1·3) | 0·9 (1·6) | 0·8 (1·5) |
| Comorbidities * | |||||
| Hypertension | 24 (39%) | 32 (53%) | 34 (57%) | 37 (61%) | 127 (52·5%) |
| Dyslipidaemia | 13 (21%) | 17 (28%) | 19 (32%) | 14 (23%) | 63 (26·0%) |
| Sleep disorder †† | 6 (10%) | 4 (7%) | 5 (8%) | 5 (8%) | 20 (8·3%) |
| Glucose tolerance impaired | 3 (5%) | 4 (7%) | 2 (3%) | 2 (3%) | 11 (4·5%) |
| Attention deficit hyperactivity disorder | 1 (2%) | 2 (3%) | 4 (7%) | 1 (2%) | 8 (3·3%) |
| Anxiety disorders | 1 (2%) | 4 (7%) | 1 (2%) | 1 (2%) | 7 (2·9%) |
Values are mean (SD) or n (%). Percentages may not add up to 100 due to rounding. Data are shown for all randomised participants, except the participant who was withdrawn before receiving treatment (i.e., 242 participants in total).
Dyslipidaemia covers the preferred terms: Dyslipidaemia, Hypertriglyceridaemia, Hyperlipidaemia, Hypercholesterolaemia. Sleep disorder covers the preferred terms: Sleep disorder, Insomnia, Poor quality sleep. Anxiety disorders covers the preferred terms: Anxiety, Anxiety disorder, Post-traumatic stress disorder.
Data were available for 58, 57, 59, and 60 participants for monlunabant 10 mg, 20 mg 50 mg and placebo, respectively, i.e., 234 participants in total.
Data were available for 59, 57, 59, and 60 participants for monlunabant 10 mg, 20 mg 50 mg and placebo, respectively, i.e., 235 participants in total.
Data were available for 56, 58, 56, and 55 participants for monlunabant 10 mg, 20 mg 50 mg and placebo, respectively, i.e., 225 participants in total.
Data were available for 57, 57, 59, and 60 participants for monlunabant 10 mg, 20 mg 50 mg and placebo, respectively, i.e., 233 participants in total.
Data were available for 51, 52, 54, and 49 participants for monlunabant 10 mg, 20 mg 50 mg and placebo, respectively, i.e., 206 participants in total.
Data were available for 51, 52, 54, and 49 participants for monlunabant 10 mg, 20 mg 50 mg and placebo, respectively, i.e., 206 participants in total.
Self-reported by the participants.
BMI=body mass index. GAD-7=General Anxiety Disorder-7. HbA1c=glycated haemoglobin. HDL=high-density lipoproteins. LDL=low-density lipoproteins. PHQ-9=Patient Health Questionnaire-9. VLDL=very-low-density lipoproteins.
The treatment compliance was high across all groups, with median proportion of assigned doses taken being 98·2%, 99·4%, 98·5%, and 99·1% in the 10 mg, 20 mg, 50 mg and placebo groups, respectively. A total of 57 (93%), 50 (83%), 49 (82%), and 59 (97%) of the participants, respectively, were compliant (i.e., taking between 80% and 120% of the assigned trial drug dose). None of the participants were excluded due to non-compliance and no participants took prohibited medication that affect weight (i.e., intercurrent event) while on treatment.
Observed mean body weight decreased over the course of the trial in all monlunabant groups (figure 2A), reaching estimated mean weight loss of 7·1, 7·7, 8·8, and 0·7 kg in the 10 mg, 20 mg, 50 mg and placebo groups, respectively (figure 2B, table 2). Data were available for body weight at week 16 for 48/61 (79%), 39/60 (65%), 34/60 (57%) and 54/61 (89%) of the randomised participants in the groups, respectively. Monlunabant demonstrated statistically and clinically significant weight loss at 16 weeks across all tested doses compared to placebo (ETD ranging from −6·4 to −8·0 kg) (table 2). The estimated weight loss increased marginally with higher doses and did not appear to stabilise at week 16. The subgroup analyses showed trends towards females and participants with higher baseline BMI having higher estimated weight loss (appendix p 6). The per-protocol analysis results matched the primary analysis, as no participants were excluded for major protocol deviations. A post-hoc jump-to-reference sensitivity analysis confirmed statistically significant treatment effects compared to placebo and indicated clinical importance, although the treatment effects were smaller and more similar between doses (appendix p 6).
Figure 2: Body weight change from baseline.
(A) Observed mean change (SEM) in body weight (kg) for each group over time. Numbers shown in the lower panel are number of participants contributing to the mean. (B) Estimated change in body weight from baseline to week 16 (95%CI). The estimated treatment differences with 95% confidence intervals are noted for each monlunabant group compared to placebo group.
95%CI=95% confidence intervals. SEM=standard error of the mean.
Table 2:
Efficacy endpoints, change from baseline at week 16
| N | Change from baseline | Compared to placebo ETD (95% CI) | p value | |
|---|---|---|---|---|
| Primary endpoint | ||||
| Body weight, kg | ||||
| Monlunabant 10 mg | 61 | −7·1 | −6·4 (−8·0 to −4·9) | <0·0001 |
| Monlunabant 20 mg | 60 | −7·7 | −6·9 (−8·5 to −5·3) | <0·0001 |
| Monlunabant 50 mg | 60 | −8·8 | −8·0 (−9·7 to −6·4) | <0·0001 |
| Placebo | 61 | −0·7 | (reference level) | |
| Secondary endpoints | ||||
| Body weight, % | ||||
| Monlunabant 10 mg | 61 | −6·5 | −5·9 (−7·2 to −4·5) | <0·0001 |
| Monlunabant 20 mg | 60 | −6·9 | −6·3 (−7·7 to −4·9) | <0·0001 |
| Monlunabant 50 mg | 60 | −8·0 | −7·4 (−8·9 to −6·0) | <0·0001 |
| Placebo | 61 | −0·6 | (reference level) | |
| Waist circumference, cm | ||||
| Monlunabant 10 mg | 61 | −6·0 | −4·3 (−6·4 to −2·2) | 0·0001 |
| Monlunabant 20 mg | 60 | −5·5 | −3·8 (−6·0 to −1·6) | 0·0008 |
| Monlunabant 50 mg | 60 | −7·1 | −5·4 (−7·7 to −3·1) | <0·0001 |
| Placebo | 61 | −1·7 | (reference level) | |
| Triglycerides, mmol/L* | ||||
| Monlunabant 10 mg | 58 | −0·2 | −0·3 (−0·5 to −0·1) | 0·0021 |
| Monlunabant 20 mg | 57 | 0·1 | −0·1 (−0·3 to 0·1) | 0·45 |
| Monlunabant 50 mg | 59 | −0·1 | −0·3 (−0·5 to 0·0) | 0·031 |
| Placebo | 60 | 0·1 | (reference level) | |
| HDL cholesterol, mmol/L | ||||
| Monlunabant 10 mg | 61 | 0·0 | 0·0 (−0·1 to 0·1) | 0·93 |
| Monlunabant 20 mg | 60 | 0·0 | 0·0 (−0·1 to 0·1) | 0·90 |
| Monlunabant 50 mg | 60 | 0·1 | 0·1 (0·0 to 0·2) | 0·032 |
| Placebo | 61 | 0·0 | (reference level) | |
| LDL cholesterol, mmol/L | ||||
| Monlunabant 10 mg | 61 | −0·2 | −0·1 (−0·3 to 0·2) | 0·67 |
| Monlunabant 20 mg | 60 | −0·4 | −0·3 (−0·5 to 0·0) | 0·022 |
| Monlunabant 50 mg | 60 | −0·2 | −0·1 (−0·3 to 0·1) | 0·48 |
| Placebo | 61 | −0·1 | (reference level) | |
| VLDL cholesterol, mmol/L* | ||||
| Monlunabant 10 mg | 59 | −0·1 | −0·2 (−0·3 to −0·1) | 0·0009 |
| Monlunabant 20 mg | 57 | 0·0 | 0·0 (−0·1 to 0·1) | 0·54 |
| Monlunabant 50 mg | 59 | −0·1 | −0·1 (−0·2 to 0·0) | 0·049 |
| Placebo | 60 | 0·1 | (reference level) | |
| Total cholesterol, mmol/L | ||||
| Monlunabant 10 mg | 61 | −0·2 | −0·1 (−0·4 to 0·1) | 0·21 |
| Monlunabant 20 mg | 60 | −0·3 | −0·2 (−0·4 to 0·0) | 0·049 |
| Monlunabant 50 mg | 60 | −0·1 | 0·0 (−0·3 to 0·2) | 0·76 |
| Placebo | 61 | −0·1 | (reference level) | |
| Apolipoprotein B, g/L | ||||
| Monlunabant 10 mg | 56 | −0·033 | −0·021 (−0·07 to 0·03) | 0·41 |
| Monlunabant 20 mg | 58 | −0·058 | −0·046 (−0·10 to 0·00) | 0·077 |
| Monlunabant 50 mg | 56 | −0·039 | −0·027 (−0·08 to 0·03) | 0·32 |
| Placebo | 55 | −0·012 | (reference level) | |
| HbA1c, % | ||||
| Monlunabant 10 mg | 61 | −0·15 | −0·16 (−0·26 to −0·05) | 0·0028 |
| Monlunabant 20 mg | 60 | −0·15 | −0·16 (−0·26 to −0·05) | 0·0036 |
| Monlunabant 50 mg | 60 | −0·16 | −0·17 (−0·28 to −0·06) | 0·0029 |
| Placebo | 61 | 0·01 | (reference level) | |
| Insulin, pmol/L* | ||||
| Monlunabant 10 mg | 51 | −27·5 | −15·8 (−43·1 to 11·5) | 0·25 |
| Monlunabant 20 mg | 52 | −22·0 | −10·3 (−38·0 to 17·3) | 0·46 |
| Monlunabant 50 mg | 54 | 1·7 | 13·3 (−15·7 to 42·3) | 0·37 |
| Placebo | 49 | −11·7 | (reference level) | |
| C-peptide, nmol/L* | ||||
| Monlunabant 10 mg | 51 | −0·07 | −0·07 (−0·20 to 0·06) | 0·27 |
| Monlunabant 20 mg | 52 | −0·03 | −0·04 (−0·17 to 0·09) | 0·55 |
| Monlunabant 50 mg | 54 | 0·09 | 0·08 ( −0·05 to 0·22) | 0·23 |
| Placebo | 49 | 0·01 | (reference level) |
Change from baseline and treatment differences are LS means estimated for the hypothetical estimand based on a mixed model for repeated measures including treatment, visit, sex and the interaction between treatment and visit, as fixed factors, baseline body weight as a covariate, and participant as a random effect factor.
Only results from fasting participants were reported for insulin, C-peptide, triglycerides, and VLDL cholesterol. 95%CI=95% confidence interval. ETD=estimated treatment differences. HbA1c=glycated haemoglobin. HDL=high-density lipoproteins. LDL=low-density lipoproteins. VLDL=very-low-density lipoproteins.
Overall, the estimated mean percentage decrease in body weight was 6·4% to 8·0% in the monlunabant groups compared to placebo, and, notably, estimated mean waist circumference was reduced by 3·8 to 5·4 cm compared to placebo (table 2 and appendix p 7). Statistically significant estimated improvements of −0·16 to −0·17 %-points were noted for HbA1c across the monlunabant groups compared to placebo, with no clear dose-response trend (table 2 and appendix p 8). The proportion of observed participants losing at least 5% of their body weight compared to their baseline increased with dose while the proportion of participants achieving at least 10% weight loss was similar across dose levels (appendix p 9; post hoc). In the monlunabant groups, HbA1c improvements were mainly observed among participants with HbA1c ≥5·7% at baseline (observed mean change HbA1c of −0·21 to −0·23 %-points) in contrast to participants with HbA1c <5·7% (observed mean change HbA1c of 0·02 to −0·08 %-points) (appendix p 10; post hoc). For triglycerides, statistically significant, small estimated improvements were seen for the 10 mg and 50 mg groups compared to placebo (table 2). For most other lipids, no estimated improvements were noted, and no clear estimated improvements were seen for insulin and C-peptide compared to placebo.
Post hoc results for HOMA-IR indicated reductions in all groups which appeared numerically larger at lower doses (observed means: 10 mg, −1·9 [SD 6·7]; 20 mg, −1·5 [SD 7·0]; 50 mg - 0·1 [SD 3·0]; placebo, −0·4 [SD 3·4]), while no clear pattern was observed for fasting plasma glucose or blood pressure (appendix p 11).
Reductions were observed for leptin (observed mean ratio to baseline of 0·73 to 0·83 at week 16, with observed geometric means of 42·7 to 51·9 pg/mL at baseline) and CRP (observed mean ratio to baseline of 0·62 to 0·90 at week 16, with observed geometric means of 4·26 to 4·73 mg/L at baseline) in the monlunabant groups (appendix p 12). No meaningful changes were seen for the other biomarkers.
In the subpopulation that had DXA scans performed (n=52 at baseline and n=36 at week 16), the observed mean fat mass percentages at baseline were around 45% across the groups (appendix p 13). After 16 weeks, fat mass percentages had decreased with observed mean change of −0·9 (SD 2·2; n=10), −1·1 (SD 1·7; n=4), −2·8 (SD 2·9; n=8), 0·0 (SD 1·1; n=14) %-points in the 10 mg, 20 mg, 50 mg, and placebo groups, respectively. On average, the weight loss consisted of 34% fat mass and 67% fat-free mass in the 10 mg group, 65% fat mass and 35% fat-free mass in the 20 mg group, and 63% fat mass and 37% fat-free mass in the 50 mg groups.
In total, 42 (69%), 47 (78%), and 55 (92%) participants reported any AEs in the 10 mg, 20 mg, and 50 mg monlunabant groups, respectively (table 3). The number of participants who reported AEs in the placebo group (42 [69%]) was similar to the 10 mg group. The number of participants with early withdrawal from the trial due to AEs increased with higher doses of monlunabant. Most of the AEs were mild to moderate in severity and non-serious. Two serious AEs were reported in the trial, and both were considered not related to the trial product (malaria and stroke) by the investigators. Of 27 severe AEs, 20 were considered related to the trial product (mainly nausea, diarrhoea, and vomiting, but also adjustment disorder with mixed mood, weakness, dizziness, hot flashes, tearful and cries easily, increased anxiety, insomnia, abdominal pain, panic attack, irritability). No deaths were reported.
Table 3:
Adverse events
| Monlunabant 10 mg (n = 61) | Monlunabant 20 mg (n = 60) | Monlunabant 50 mg (n = 60) | Placebo (n = 61) | |||||
|---|---|---|---|---|---|---|---|---|
| N (%) | Events | N (%) | Events | N (%) | Events | N (%) | Events | |
| All AEs | 42 (69%) | 218 | 47 (78%) | 242 | 55 (92%) | 262 | 42 (69%) | 131 |
| Serious AEs | 1 (2%) | 1 | 1 (2%) | 1 | 0 | 0 | 0 | 0 |
| Fatal AEs | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Maximum severity | ||||||||
| Mild | 19 (31%) | 74 | 18 (30%) | 82 | 23 (38%) | 69 | 29 (48%) | 93 |
| Moderate | 19 (31%) | 36 | 22 (37%) | 55 | 26 (43%) | 66 | 12 (20%) | 17 |
| Severe | 4 (7%) | 8 | 7 (12%) | 7 | 6 (10%) | 10 | 1 (2%) | 2 |
| AEs of special interest * | 16 (26%) | 25 | 16 (27%) | 21 | 23 (38%) | 47 | 1 (2%) | 1 |
| Anxiety | 8 (13%) | 8 | 6 (10%) | 6 | 16 (27%) | 18 | 0 | 0 |
| Irritability | 6 (10%) | 6 | 6 (10%) | 7 | 10 (17%) | 10 | 1 (2%) | 1 |
| Sleep disturbance † | 7 (11%) | 8 | 4 (7%) | 4 | 10 (17%) | 10 | 0 | 0 |
| Depression | 2 (3%) | 2 | 3 (5%) | 3 | 5 (8%) | 5 | 0 | 0 |
| Tremors ‡ | 1 (2%) | 1 | 1 (2%) | 1 | 4 (7%) | 4 | 0 | 0 |
| Suicidality | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Seizure or convulsions | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| AEs leading to early withdrawal from the trial | 8 (13%) | 28 | 16 (27%) | 31 | 25 (42%) | 50 | 0 | 0 |
| Psychiatric disorders | 6 (10%) | 9 | 6 (10%) | 8 | 13 (22%) | 22 | 0 | 0 |
| Gastrointestinal disorders | 4 (7%) | 5 | 8 (13%) | 8 | 12 (20%) | 18 | 0 | 0 |
| Nervous system disorders | 3 (5%) | 4 | 4 (7%) | 5 | 1 (2%) | 1 | 0 | 0 |
| Vascular disorders | 3 (5%) | 3 | 2 (3%) | 2 | 4 (7%) | 4 | 0 | 0 |
| General disorders and administration site conditions | 3 (5%) | 3 | 2 (3%) | 4 | 0 | 0 | 0 | 0 |
| Investigations | 1 (2%) | 1 | 1 (2%) | 1 | 1 (2%) | 2 | 0 | 0 |
| Metabolism and nutrition disorders | 1 (2%) | 1 | 1 (2%) | 1 | 1 (2%) | 1 | 0 | 0 |
| Renal and urinary disorders | 1 (2%) | 1 | 0 | 0 | 1 (2%) | 1 | 0 | 0 |
| Skin and subcutaneous tissue disorders | 1 (2%) | 1 | 1 (2%) | 1 | 0 | 0 | 0 | 0 |
| Musculoskeletal and connective tissue disorders | 0 | 0 | 0 | 0 | 1 (2%) | 1 | 0 | 0 |
| Reproductive system and breast disorders | 0 | 0 | 1 (2%) | 1 | 0 | 0 | 0 | 0 |
Protocol-defined adverse events of special interest, i.e., anxiety (including a GAD-7 score ≥10), irritability (including a GAD-7 score ≥10), sleep disturbance, depression (including a PHQ-9 score ≥10), tremors, suicidality (defined as any type 4 or 5 suicidal ideation or any suicidal behaviour as per C-SSRS), and seizure or convulsion.
Of the 22 events of sleep disturbances, 20 were considered related to the trial product. Of these 12 were mild, 7 were of moderate severity, and 1 were of severe. All but three events were resolved.
Of the 6 events of tremors, 5 were considered related to the trial product. Of these, 3 were mild and 2 were of moderate severity. All events were resolved.
AE=adverse event. C-SSRS=Columbia Suicide Severity Rating Scale. GAD-7=General Anxiety Disorder-7. PHQ-9=Patient Health Questionnaire-9.
The AEs leading to early withdrawal from the trial mainly occurred in the first half of the trial (appendix p 14). The onset of most gastrointestinal AEs was immediately after initiating treatment (appendix p 14), whereas psychiatric AEs were distributed over the first half of the trial (appendix p 14).
The most frequent AEs in the monlunabant groups by system organ class were gastrointestinal disorders, followed by psychiatric disorders (figure 3). The most frequent AEs by preferred term were nausea, followed by hot flush, anxiety, decreased appetite, diarrhoea, vomiting, and irritability (appendix p 15). The most common AEs leading to early withdrawal from the trial were within the gastrointestinal and psychiatric disorders system organ classes (table 3 and appendix pp 16–17), driven by events of nausea, anxiety, diarrhoea, irritability, and sleep disorder.
Figure 3: Adverse events by system organ class.
Adverse events by system organ class in descending order by the 50 mg group.
* Gastrointestinal disorders were mainly nausea, diarrhoea, vomiting, soft faeces, abdominal pain, eructation, gastroesophageal reflux disease, and constipation.
† Psychiatric disorders were mainly anxiety, irritability, insomnia, depression, and affect lability.
‡ Metabolism and nutrition disorders were mainly decreased appetite and increased appetite.
§ Vascular disorders were mainly hot flush.
¶ General disorders and administration site conditions were mainly fatigue, asthenia, influenza like illness, and chills.
Psychiatric AEs were reported in 17 (28%), 20 (33%), 25 (42%), 1 (2%) in the 10 mg, 20 mg, and 50 mg, and placebo groups, respectively, with events of mainly mild to moderate severity, none were serious, and most were recovered (appendix p 18). The reported outcome of AEs with start date in the main phase includes observation until study discontinuation or database lock, whichever comes first..
Although anxiety was among the most frequent AE, mean scores for symptoms of depression, measured with PHQ-9, and anxiety, measured with GAD-7, stayed within the normal range, as the majority had minimal depression (i.e., scores of 0 to 4) and minimal anxiety (i.e., scores of 0 to 4) both at baseline and at week 16 (appendix p 19). A total of 6 participants were referred to a mental health specialist (4 events in 3 participants in the 10 mg group and 6 events in 3 participants in the 50 mg group).
Suicidality, measured with C-SSRS, showed no evidence of suicidal ideation in the participants, as no type 4 or 5 suicidal ideation or suicidal behaviour were reported (table 3). Two participants (one in the 10 mg group and one in the 50 mg group) reported suicidal ideation type 1, corresponding to low-risk suicidal ideation, and no type 2 to 5 suicidal ideation or any suicidal behaviour was reported.
There were no clinically relevant findings for safety-related clinical laboratory assessments, physical examinations, and vital signs.
DISCUSSION
This proof-of-concept phase 2a trial investigated the efficacy and safety of monlunabant in adults with obesity and metabolic syndrome for 16 weeks. The trial demonstrated statistically significant and clinically meaningful weight loss across all tested doses with ETDs ranging from −6·4 to −8·0 kg after 16 weeks compared to placebo. The weight loss increased only slightly with higher doses but did not appear to reach a plateau at week 16 and was accompanied by dose-dependent psychiatric and gastrointestinal AEs resulting in considerable rates of withdrawals. No severe suicidal ideation was reported.
The placebo-corrected weight loss estimated in the present study after 16 weeks was −6·4 to −8·0 kg or −5·9 to −7·4 %. Whether the weight loss effects from monlunabant will continue beyond the 16 weeks remains uncertain. The optional open-label extension phase of this study (36 weeks of treatment with 20 mg monlunabant with patients who completed 16 weeks of double-blind treatment) is ongoing and will provide further information on whether the weight loss may continue. The present study also indicated small reductions in waist circumference (ETDs of −3·8 to −5·4 cm), possibly reflecting reduced visceral adiposity, and the DXA findings (n=36) suggested improvement in body composition with increased fat-free mass percentage. Some improvements in HbA1c levels were noted as well, although these were small and were unlikely to be clinically meaningful in a population with obesity but mostly without diabetes, and there was no clear dose-response trend. Whether these small improvements in HbA1c are a result of weight loss or represent a direct effect of monlunabant cannot be deduced from the present study. No clear improvements were seen in lipid profile, except for small numerical improvements in triglycerides with no clear dose-response tendency, although the moderate degree of dyslipidaemia at baseline may have limited the effects of monlunabant. Finally, some reductions were observed for leptin and CRP in the monlunabant groups. Similar endpoints were previously investigated for first-generation CB1R inverse agonists, such as taranabant20,21, otenabant22, and rimonabant23, in individuals with overweight/obesity.
Dose-dependent AEs and early withdrawals due to AEs were observed, which were mainly due to gastrointestinal and psychiatric disorders, driven by events of nausea, anxiety, diarrhoea, irritability, and sleep disorder. The majority of AEs were non-serious and not severe. The types of most frequent AEs observed and types of most frequent AEs leading to drug withdrawals were overall similar to what was observed for taranabant and otenabant.20–22 Nausea was the most frequent AE and hot flush was the second most frequent AE in the present study. Hot flushes were reported for taranabant as well, but with lower frequency.20 The optional open-label extension phase of this study will provide further information on safety, including the nature of the adverse events beyond 16 weeks.
Until now, there has been no mechanistic evidence from well-designed clinical studies supporting that monlunabant has activities in the brain. However, the progressive increase in psychiatric AEs in the dose range tested in this study, suggests brain penetrance of monlunabant. The precise mode of action behind monlunabant-mediated gastrointestinal AEs remains unclear. Pre-clinical evidence has shown that chronic, but not acute, treatment of mice with a monlunabant dose of 10 mg/kg resulted in significant brain CB1R occupancy as documented by CB1R positron emission tomography, whereas treatment with the submaximal weight-reducing dose of 1 mg/kg did not result in brain CB1R occupancy following either acute or chronic administration.16 Previously, the withdrawal of rimonabant from the market due to serious safety concerns of neuropsychiatric safety, especially in the clinical setting after approval, led to the cessation of research of this therapeutic class. Other effective therapeutic classes of anti-obesity medications exist, but there remains a need for new modes of action for people who cannot tolerate existing options or do not achieve sufficient weight loss on existing anti-obesity medications, and for treatments which offer more convenient administration, such as oral medications. The findings of the present study suggest that a therapeutic window may exist for monlunabant, as the lower doses of monlunabant in the present study provided similar weight loss as the highest dose but with fewer side effects. In the present study, the weight reduction appeared to be near maximal at the 10 mg dose. This suggests that the dose dependence of weight loss effects may be below 10 mg. Further research is needed to determine if a specific dose range in which monlunabant is effective and safe exists. Currently, a lower dose range-finding phase 2b trial is under planning.
Strengths of the present study include the randomised, double-blinded and placebo-controlled design as well as the high treatment compliance (no individuals were excluded due to non-compliance). The study also has limitations. There was no follow-up on participants after treatment discontinuation. Overall, there was an imbalance in withdrawals in the monlunabant groups compared to placebo in a dose-dependent manner, mostly due to AEs. We have limited information about the withdrawn participants, both in terms of the primary AE leading to each withdrawal, and the outcome of the AEs after withdrawal. Consequently, data on the primary endpoint is available for about half of the participants in the 50 mg group at week 16, which introduces uncertainty, and could potentially introduce significant bias when interpreting the efficacy and safety endpoints. Using a hypothetical strategy to handle treatment discontinuations, the treatment effect is estimated as if the event did not occur or was mitigated. However, with high discontinuation rates due to adverse events, this assumption is less reliable and is a limitation of the trial results. This limitation is mostly explained by the study design and its purpose. Given that this study was a proof-of-concept phase 2a trial with a short duration and expected rapid enrolment, it was decided to permanently discontinue participants from the study following treatment discontinuation. Per the protocol, the required follow-up period after treatment discontinuation was 2 weeks, which limited the ability to confirm AE duration and resolution for AEs that were still ongoing at the time of discontinuation. There was no structured retention program created for this study. Dose reduction was not allowed and if a participant could not tolerate the dose, they were discontinued from the study. Furthermore, endpoints of fasting blood glucose, the proportion of patients who achieved higher than 5% or 10% weight loss, and changes in systolic and diastolic blood pressure, which are commonly included in obesity studies, were not predefined in the protocol. Another limitation is that baseline values of dyslipidaemia and insulin resistance were borderline pathologic, which makes it difficult to detect a statistically significant normalisation by treatment. Finally, the study was conducted in a single country, had strict inclusion and exclusion criteria for comorbidities and medication, and a comprehensive list of prohibited medication, which limit the generalizability of its findings.
In conclusion, this proof-of-concept phase 2a trial demonstrated statistically and clinically significant weight loss compared to placebo for all doses tested (10 mg, 20 mg, and 50 mg) in individuals with obesity and metabolic syndrome. AEs were mainly dose-dependent gastrointestinal and psychiatric disorders of mild to moderate severity. The rate of withdrawals was high, mainly due to AEs, more frequent at higher doses, and indicated that the 50 mg monlunabant dose was not tolerable. The high rate of dose-dependent withdrawals due to AEs challenges the interpretation of the results. Since the effects on weight loss appears to only increase marginally with higher doses and the AEs were dose-dependent, there may be a therapeutic window; further investigation of monlunabant at lower doses and with a close monitoring of AEs is needed to determine if a safe, effective, and clinically relevant dose range of monlunabant exists.
DATA SHARING
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.
Supplementary Material
RESEARCH IN CONTEXT.
Evidence before this study
On February 14, 2025, we searched PubMed for studies published from database inception, using the search “monlunabant OR MRI-1891 OR INV-202”, which yielded 6 results. Pre-clinical evidence showed significant weight loss accompanied by improved insulin resistance in a mouse model of high-fat diet-induced obesity (DIO), receiving 3 mg/kg/day monlunabant. A phase 1b trial is the only clinical evidence of monlunabant to date. It randomized 37 adults with features of metabolic syndrome to receive monlunabant 25 mg/day or placebo as once-daily oral tablets for 28 days. The trial showed that monlunabant was well tolerated and resulted in weight loss and improvements in other markers of metabolic syndrome.
Added value of this study
This trial provides new insights into the efficacy and safety of monlunabant, a novel cannabinoid receptor 1 (CB1R) inverse agonist, in individuals with obesity and metabolic syndrome. The findings demonstrate that monlunabant leads to statistically significant and clinically meaningful weight loss across all tested doses compared to placebo after 16 weeks treatment. Additionally, the trial highlights the dose-dependent nature of adverse events, primarily gastrointestinal and psychiatric disorders, which were mostly mild to moderate in severity. The high rate of early withdrawals due to adverse events, which appears dose-dependent, challenges the interpretation of the results. The findings of this study suggest that there may be a therapeutic window for monlunabant at lower doses.
Implications of all the available evidence
The implications of this trial, combined with existing evidence, suggest that monlunabant has potential as a novel treatment option for people with obesity and metabolic syndrome, if a safe and effective therapeutic window can be established. However, the dose-dependent adverse events highlight the need for careful dose optimization and monitoring. Future research should focus on long-term efficacy and safety, particularly at lower doses, to establish whether a safe and effective therapeutic range exists. Additionally, further studies are needed to explore the mechanistic pathways of monlunabant’s effects and to confirm its benefits in different populations with obesity.
ACKNOWLEDGEMENTS
This trial was sponsored by Inversago Pharma Inc. (a Novo Nordisk company). The authors thank the trial participants, and 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. George Kunos, MD, was supported by the Intramural Research Program of the NIH.
DECLARATION OF INTERESTS
FKK, OF and TH-H are shareholders and employees of Novo Nordisk. JL is an employee of Novo Nordisk. KL is an employee of Inversago Pharma Inc. (a Novo Nordisk company). GC was an employee of Inversago Pharma Inc. (a Novo Nordisk company) and owns Inversago Pharma Inc. stock options. GK is listed as inventor on a United States patent (issued) covering monlunabant. J-SP is a Site Principal Investigator for the study and is a Research Director of family medicine Laval University. LA 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 Pharmaceuticals, and Amgen; honoraria for lectures/presentations from Boehringer-Ingelheim, Skye Bioscience, Zealand Pharmaceuticals, Jamieson Wellness, and Pfizer; support for attending meetings and/or travel from Jamieson Wellness; patent pending for Flytehealth; part of board of directors for Flytehealth, Jamieson Wellness, ERX Pharmaceuticals; equity interests from Jamieson Wellness, Flytehealth, Kallyope, Mediflix, MBX Bioscience, Syntis, Veru Pharmaceuticals, Skye Bioscience. DD has received speaker and advisory board fees from Boehringer-Ingelheim, Eli-Lilly, Novo Nordisk, Astra Zeneca; 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 executive committee for EFIM and EASO.
Footnotes
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