Nimacimab monotherapy did not meet its primary endpoint for weight loss; preliminary pharmacokinetic analysis showed lower than expected drug exposure, potentially indicating the need for higher dosing as a monotherapy.
Clinically meaningful additional weight loss observed with combination of nimacimab, a peripheral CB1 inhibitor, and semaglutide compared to semaglutide alone.
Nimacimab alone and in combination demonstrated a clean safety profile, with no added gastrointestinal adverse events and no nimacimab-associated neuropsychiatric adverse events reported.
Company to host conference call today at 8:00 a.m. ET.
Oct. 06, 2025 -- Skye Bioscience, Inc. (Nasdaq: SKYE) (“Skye”) a clinical-stage biotechnology company focused on unlocking new therapeutic pathways for obesity and other metabolic health disorders, today announced the topline data from its 26-week Phase 2a CBeyond™ proof-of-concept study of nimacimab, its peripherally-restricted CB1 inhibitor antibody.
In CBeyondTM, the nimacimab monotherapy arm did not achieve the primary endpoint of weight loss compared to placebo (-1.52% vs. -0.26 for placebo, mITT1). Preliminary pharmacokinetic analysis showed an association between exposure and response, suggesting that the 200 mg, subcutaneous weekly dose was suboptimal as a monotherapy.
In the combination cohort, nimacimab 200 mg (subcutaneous, weekly) plus semaglutide demonstrated a clinically meaningful magnitude of weight loss compared to semaglutide alone (-13.2% vs -10.25%, p=0.0372, mITT), with no plateau being observed through Week 26. This finding supports potential further studies to evaluate combinations of nimacimab and incretin-based therapies.
At the tested dose and exposure levels, nimacimab 200 mg demonstrated a favorable safety profile with placebo-like tolerability. In combination with semaglutide, there was no increase in gastrointestinal (GI) adverse events. Importantly, there were no increases in neuropsychiatric adverse events reported resulting from treatment with nimacimab.
“The 200 mg monotherapy arm provided important pharmacokinetic insight, showing that lower-than-expected drug exposure may have limited the observed effect and informing the dose-ranging strategy we are developing,” said Puneet Arora, MD, FACE, Chief Medical Officer of Skye Bioscience. “At the same time, the combination of nimacimab with semaglutide produced a clinically meaningful additional weight loss that exceeded semaglutide alone, with a favorable tolerability profile even in patients who achieved the highest exposure levels. With our preclinical data, toxicology safety margins, and PK modeling, we believe we have a path to support higher dosing, and we are evaluating the next stage of development to optimize dosing in potential future clinical trials."
“This is the first clinical study to show that the combination of a CB1 inhibitor and a GLP-1 therapeutic can drive clinically meaningful additional weight loss beyond a GLP-1 drug alone,” said Louis Aronne, MD, past President, The Obesity Society; past Chairman, American Board of Obesity Medicine; and clinical advisor to Skye. “Equally important, although the sample size is small, nimacimab achieved this without neuropsychiatric or additive gastrointestinal adverse events. I believe these results warrant further evaluation of the therapeutic potential of this novel CB1 inhibitor.”
“Gastrointestinal side effects remain a leading cause of discontinuation with obesity therapies,” said Sean Wharton, MD, Director, Wharton Medical Clinic and clinical advisor to Skye. “It was notable that nimacimab did not increase GI adverse events while adding clinically meaningful weight loss in combination with semaglutide. In my view, a next study with higher nimacimab dosing is the logical step to fully define its role in clinical practice.”
Monotherapy dosed at 200 mg demonstrated lower than expected drug exposure. In the monotherapy arm, nimacimab 200 mg did not achieve the primary endpoint, with placebo-subtracted weight loss of -1.26% at week 26 (p=0.2699, mITT). Preliminary pharmacokinetic analysis showed lower than expected drug exposure of nimacimab, supporting evaluation of higher dosing.
Clinically meaningful add-on efficacy with semaglutide. -13.2% weight loss in the nimacimab plus semaglutide combination arm at Week 26 compared to -10.25% in the semaglutide-alone arm (-2.95%, p=0.0372, mITT). Notably, no plateau was observed at 26 weeks, which indicates potential for future weight loss.
High frequency of responders in the combination arm. In the per protocol analysis, 100% achieved >5% weight loss (vs. 85% with semaglutide) and 67% achieved >10% weight loss (vs. 50% with semaglutide).
Body composition. An improvement in lean mass to fat mass ratio was observed at Week 26 comparing the nimacimab plus semaglutide combination arm to the placebo arm (0.26 vs. 0.02, p <0.0001), and the combination arm compared to semaglutide alone (0.26 vs. 0.13, p = 0.0126).
*Analyzed based on the primary efficacy estimand using a mixed model for repeated measures (MMRM).
** Modified intent to treat analysis (mITT) includes all randomized, treated participants
*** Per Protocol analysis excludes major protocol deviations and non-adherent subjects
Favorable tolerability results. Nimacimab 200 mg demonstrated a clean safety profile as a monotherapy with placebo-like tolerability. When combined with semaglutide, no increase in gastrointestinal (GI) adverse events were observed. In the safety analysis population, rates of GI adverse events were 27% with nimacimab alone versus 29.5% with placebo, and 57.1% in combination with semaglutide versus 66.7% with semaglutide alone.
Skye believes multiple factors support evaluation of nimacimab at higher doses, including the combination of preclinical toxicology margins and modeling; preclinical data showing dose-dependent increases in weight loss with nimacimab monotherapy and GLP-1 combinations; and the notable safety profile in this Phase 2a study. Skye is continuing to evaluate the data to determine next steps, including a potential follow-on Phase 2 study beyond the ongoing Phase 2a extension study.
The next set of detailed results from the 26-week treatment period of the CBeyondTM trial will be presented at ObesityWeek in November.
The randomized, placebo- and active-controlled, double-blind CBeyondTM Phase 2a trial enrolled 136 adults with overweight or obesity, including individuals with a BMI ≥27 kg/m² with at least one comorbidity. Patients were randomized across four arms, 2:2:1:1 to arms with weekly nimacimab 200 mg subcutaneously, placebo, nimacimab 200 mg plus semaglutide (Wegovy®), or placebo plus semaglutide, and were dosed weekly for 26 weeks. Patients not participating in a 26-week extension were monitored for 13 weeks post-treatment.
Patients who completed 26 weeks of treatment in the primary phase of the study were eligible to enroll in a 26-week extension for a potential full treatment duration of 52 weeks with a 13-week follow-up period. In the combination arms, patients will continue with blinded treatment with nimacimab or placebo and will continue receiving semaglutide (Wegovy®). Patients in the monotherapy arm will receive nimacimab 300 mg during the extension. Enrollment for the extension is complete. Skye expects to report data from the extension study in Q1 2026.
The 26 week treatment period was designed to evaluate efficacy, safety, and pharmacokinetics and exploratory endpoints, with the extension ongoing to further assess these endpoints, and follow-up to assess durability and weight regain. The trial population was broadly representative of adults living with obesity, with a mean BMI of ~36.84 kg/m2 and majority female participants.
Skye Bioscience will host a conference call and webcast to discuss these results at today at 8:00 a.m. ET. The webcast will be accessible at this link. (Please allow time for registration.) A replay will be available on the company’s Investor Relations website for 30 days following the live event.
Nimacimab is a potential first-in-class, peripherally-restricted monoclonal antibody inhibitor of the CB1 receptor. Unlike previous CB1-targeting drugs, nimacimab is designed to avoid central nervous system penetration, potentially limiting neuropsychiatric side effects seen with small-molecule antagonists. As a non-incretin, non-peptide agent, nimacimab acts independently of the GLP-1 pathway and has also demonstrated additive or complementary effects in combination with incretin-based therapies in preclinical and clinical studies.
Skye is focused on unlocking new therapeutic pathways for metabolic health through the development of next-generation molecules that modulate G-protein coupled receptors. Skye's strategy leverages biologic targets with substantial human proof of mechanism for the development of first-in-class therapeutics with clinical and commercial differentiation. Skye is conducting a Phase 2a clinical trial (ClinicalTrials.gov: NCT06577090) in obesity for nimacimab, a negative allosteric modulating antibody that peripherally inhibits CB1. This study is also assessing the combination of nimacimab and a GLP-1R agonist (Wegovy®).
1 Modified intention to treat analysis (mITT): All participants who were randomized and received any amount of study medication (IP, active or placebo comparator), regardless of adherence to the treatment plan. Participants were included in the treatment group corresponding to the study treatment they actually received.
The content above comes from the network. if any infringement, please contact us to modify.
