nimacimab (RYI-018) / Skye Biosci - LARVOL DELTA

Peripheral cannabinoid-1 receptor antagonists in clinical development: therapeutic potential for the management of obesity and related metabolic disorders for the management of obesity and related metabolic disorders. (PubMed, Expert Opin Investig Drugs) - "Peripherally restricted CB1R antagonists aim to deliver the metabolic benefits of CB1R blockade while avoiding the toxicity that ended development of centrally acting agents such as rimonabant. Recent phase 2 data with monlunabant demonstrated dose-dependent psychiatric adverse events and high discontinuation rates. Nimacimab, an antibody-based approach, has shown only marginal efficacy. The future of this drug class will therefore likely depend on rigorous long-term safety evaluation, biased CB1R pharmacology, and multitarget strategies including combinations with incretin-based therapies."

Journal • Genetic Disorders • Metabolic Disorders • Obesity • Psychiatry

Preliminary Data on Continuing Weight Loss at 52 Weeks and Durable Weight Loss Off Therapy with Nimacimab, a CB1R Antibody, in Combination with Semaglutide (ADA 2026) - "Nimacimab in combination with semaglutide, results in durable weight loss after discontinuation of therapy, compared to semaglutide alone. Following 52 weeks of therapy, weight loss with the combination remains greater than semaglutide alone, even in comparison with a high responder subset of semaglutide treated participants. These findings validate the effectiveness of the combination therapy for weight loss seen after 26 weeks, despite a sub optimal dose of nimacimab, and suggest a more durable weight loss after therapy is discontinued"

Combination therapy • Metabolic Disorders • Obesity

Skye Announces Cohort Review Committee Approved Opening of Cohort 2 Based on Favorable Safety Data from First Four Participants Treated in Cohort 1 (The Manila Times) - "No Serious Adverse Events or Adverse Events of Special Interest Were Reported Following 4 Weeks of Treatment...The Expansion Study comprises two cohorts of nimacimab monotherapy (400 mg IV and 600 mg IV) compared with placebo, administered weekly over 15 weeks (16 doses), with a 12-week follow-up period, to generate preliminary safety and PK data with higher doses. Within each dose cohort, 8 participants will be randomized in a 3:1 ratio to nimacimab (n=6) or placebo (n=2). The CRC approved enrollment in Cohort 2 (600 mg IV) based on a favorable safety review of the first participants who completed 4 weeks of treatment in Cohort 1 (400 mg IV)."

DSMB • Trial status • Obesity

CBeyond Expansion Study (Part C) (The Manila Times) - "Cohort 1 is designed to evaluate nimacimab 400 mg IV (equivalent to ~700 mg SC) once weekly versus matched placebo, randomized 3:1, over a 16-week treatment period followed by 12 weeks of follow-up; The Cohort Review Committee (CRC) is scheduled to meet on May 18, 2026 to review available Cohort 1 safety data and determine whether safe-to-proceed criteria have been met to initiate enrollment in Cohort 2; Cohort 2 is designed to evaluate nimacimab 600 mg IV (equivalent to ~1000 mg SC) once weekly versus matched placebo, randomized 3:1, over the same treatment and follow-up period; Skye continues to expect topline clinical data from the CBeyond Expansion Study in Q4 2026. The study is designed to generate higher-exposure human safety and pharmacokinetic data to inform dose selection for a planned Phase 2b study."

DSMB • P2a data • Trial status • Obesity

Upcoming Anticipated Milestones (The Manila Times) - "Q2 2026: Complete feasibility work for the high-concentration nimacimab formulation program....Q4 2026: Finalize planned Phase 2b study design, including dose-selection rationale, protocol architecture and operational readiness plan."

New P2b trial • Obesity

Skye Bioscience Presenting at GLP-1-Based Therapeutics Summit (The Manila Times)

Clinical • Obesity

Skye Bioscience Treats First Patient in Nimacimab Higher-Dose Expansion Study Evaluating Exposure-Response to Inform Phase 2b Dose Selection for GLP-1 Combination Development (GlobeNewswire) - "Enrollment in Cohort 2 (600 mg IV) is contingent on a favorable safety review of the first participants completing four weeks of treatment in Cohort 1 (400 mg IV) by an independent Cohort Review Committee. We expect to report topline data from the expansion study in the fourth quarter of 2026....'We are using this regulatory input alongside our ongoing data analysis to refine the Phase 2b protocol. Final trial design and timing remain subject to the outcome of the Part C data, completion of our regulatory review, and capital considerations.'"

New P2b trial • P2a data • Trial status • Obesity

Upcoming Anticipated Milestones (GlobeNewswire) - "Q2 2026: Present nimacimab preclinical data at scientific/medical conferences; Q2 2026: Analyst event in conjunction with the Scientific Sessions of the American Diabetes Association (ADA) in June to introduce additional clinical and preclinical data, market research insights, and other aspects of the Company’s development program."

Clinical data • Preclinical • Obesity

Phase 2b (CBeyond 2): Regulatory Alignment and Protocol Finalization (GlobeNewswire) - "Completed an FDA Type C meeting and received written minutes. As Skye continues its review of the written feedback, the Company is using the minutes to sharpen its ongoing Phase 2b evaluation across key design elements (including dose, duration, endpoints and inclusion/exclusion criteria) and to assess the data package needed for potential combination development with an incretin therapy; Skye is evaluating a Phase 2b protocol that could study multiple doses of nimacimab as a monotherapy and in combination with an incretin therapy, using an adaptive design framework. Skye is continuing Phase 2b protocol development for the study....Q4 2026: Finalize Phase 2b (CBeyond 2) study design."

Clinical protocol • New P2b trial • Obesity

Skye Reports Positive CBeyond Phase 2a Extension Interim Study Results for Nimacimab in Combination With Semaglutide (GlobeNewswire) - "Of the 10 participants in the nimacimab plus semaglutide arm who joined the extension study, the mean weight loss at 26 weeks was 14.4%. Seven (7) participants completed the additional 26 weeks of treatment and lost an additional 7.9% of weight, resulting in a mean weight loss of 22.3% after 52 weeks of treatment with no weight loss plateau observed...The participants treated with nimacimab + semaglutide that continued to the 13-week off-therapy follow-up regained only 17.8% of the total weight loss at 26 weeks, which represents a greater than 50% mitigation of weight rebound."

P2a data • Obesity

Full topline reporting of the CBeyond Phase 2a extension data, including nimacimab monotherapy data and 13-week off-therapy follow-up, is expected in Q3 2026. (GlobeNewswire)

P2a data • Obesity

Skye Bioscience Highlights Attributes of its Peripherally-restricted CB1 Inhibitor Antibody at Keystone Obesity Conference (The Manila Times) - "Key takeaways from the DIO studies: Nimacimab showed significant additive weight loss effects when combined with suboptimal or clinically active dose levels of tirzepatide (39% and 46% weight loss respectively); Nimacimab weight loss was durable after treatment discontinuation; Nimacimab treatment after tirzepatide discontinuation improved the weight rebound profile (regain blunted by ~80%); Nimacimab weight loss was not primarily driven by caloric restriction; Nimacimab enhanced weight loss induced by semaglutide."

Preclinical • Obesity

Skye Bioscience to Present Poster at Keystone Obesity Conference (GlobeNewswire) - "Skye’s presentation addresses the following questions regarding the ability of its peripherally-restricted CB1-inhibitor antibody: Can nimacimab enhance optimal and suboptimal doses of incretin agonists? How durable is nimacimab’s effect on weight loss after treatment discontinuation? Can nimacimab be used as a maintenance therapy after tirzepatide discontinuation? Is caloric-restriction the primary mechanism of nimacimab-driven weight loss?"

Preclinical • Obesity

CBeyond: Study to Evaluate the Effect on Obesity of QW Nimacimab and QW Nimacimab Co-administered With Semaglutide vs Placebo (clinicaltrials.gov) - P2 | N=136 | Active, not recruiting | Sponsor: Skye Bioscience, Inc. | Trial completion date: Jan 2026 ➔ Feb 2027 | Trial primary completion date: Aug 2025 ➔ Nov 2026

Trial completion date • Trial primary completion date • Genetic Disorders • Obesity

Halozyme and Skye Bioscience Announce Global Collaboration and License Agreement to Evaluate Nimacimab Co-Formulated with ENHANZE for Obesity (PRNewswire) - "Under the collaboration, Skye has licensed Halozyme's ENHANZE drug delivery technology for the development and potential commercialization of a subcutaneous formulation of nimacimab for the treatment of obesity. The collaboration is intended to support Skye's evaluation of higher nimacimab subcutaneous doses through delivery of larger injection volumes....Skye will make milestone payments tied to the achievement of certain development and commercialization events....Skye is planning to initiate a Phase 2b clinical trial in obesity for nimacimab with ENHANZE in the middle of 2026."

Licensing / partnership • New P2b trial • Obesity

Extension Study Fully Enrolled (GlobeNewswire) - "Data from the 26-week extension is expected in Q1 2026 and will provide information on the potential full treatment duration of 52 weeks followed by a 12-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 a higher dose of nimacimab (300 mg), which we expect will assist in refining our PK model."

P2 data • Trial status • Obesity

CBeyond™, A Phase 2 Trial for Weight Loss With a Peripherally Acting CB1 Receptor Antibody (OBESITY WEEK 2025) - "Nimacimab is a peripherally acting inhibitory anti-CB1 antibody that has been shown to cause meaningful weight loss compared to placebo in humanized DIO mice. It is not expected to cross the blood-brain barrier, which helps mitigate concerns about neuropsychiatric adverse events found with small molecule-based CB1 inhibitors. Phase 1 studies support excellent safety and tolerability."

P2 data • Diabetes • Genetic Disorders • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity • Psychiatry

Skye Bioscience Late-Breaking Oral Abstract at ObesityWeek 2025 to Highlight Improvement in Rebound Weight Gain (GlobeNewswire) - "The presentation will highlight recent topline data from CBeyond, a Phase 2 proof-of-concept study of nimacimab....New data from an analysis of participants 12 weeks post-treatment demonstrated that nimacimab 200 mg (subcutaneous, weekly) plus semaglutide blunted rebound weight gain compared to semaglutide alone (18.1% versus 49.8% weight regain over 12 weeks). Moreover, at 12 weeks post-treatment, the nimacimab plus semaglutide group maintained significant weight loss compared to the placebo group (p=0.006), while the semaglutide alone group lost significance over the placebo group (p=0.12)..."

Late-breaking abstract • P2a data • Obesity

Skye Bioscience Reports Topline CBeyond Phase 2a Data from Nimacimab Monotherapy and Combination Clinical Trial (GlobeNewswire) - "In CBeyond, 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....The next set of detailed results from the 26-week treatment period of the CBeyond trial will be presented at ObesityWeek in November."

P2a data • Obesity

Skye Presents Phase 1b Data for its Peripheral CB1-inhibiting Antibody, Nimacimab, at European Association for the Study of Diabetes (EASD) Annual Meeting (GlobeNewswire) - "The study demonstrated that nimacimab was safe, well-tolerated, and exhibited predictable pharmacokinetics and low immunogenicity across multiple ascending dose cohorts. Importantly, there were no serious adverse events, no discontinuations due to adverse events, and no evidence of neuropsychiatric safety signals. Gastrointestinal side effects were infrequent and mild, underscoring the potential differentiated tolerability profile of this peripheral CB1-inhibiting antibody."

P1 data • Metabolic Dysfunction-Associated Steatotic Liver Disease

A multiple dose study to evaluate the safety and tolerability of nimacimab, a peripherally restricted, inhibitory CB1 antibody in subjects with metabolic associated fatty liver disease (EASD 2025) - P1 | "Nimacimab administered once weekly for 4 weeks at doses of 0.6, 1.2, and 2.5 mg/kg was well tolerated and demonstrated an overall favorable safety profile. Nimacimab does not cross the blood brain barrier, thus minimizing potential CNS-related side effects seen with small molecule CB1 inhibitors. Encouraging trends observed in markers of metabolism and tissue fibrosis warrant further clinical investigation of nimacimab for treatment of metabolic diseases."

Clinical • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity • Type 2 Diabetes Mellitus

Skye’s CB1 Inhibitor, Nimacimab, Demonstrates Superior Weight Loss and Differentiated Mechanisms from Monlunabant, and Continues to Show Enhanced Combination with Tirzepatide with Durable Post-Treatment Weight Maintenance in DIO Model (GlobeNewswire) - "Nimacimab + tirzepatide demonstrates over 40% weight loss in multiple preclinical DIO studies. Nimacimab demonstrates durable post-treatment weight loss compared to tirzepatide. Nimacimab reduced rebound weight gain following treatment with tirzepatide or nimacimab + tirzepatide....Top-line data from Phase 2 CBeyond study expected to be reported in late Q3/early Q4 2025."

P2 data • Preclinical • Obesity

Skye Completes 26-week Treatment Phase in Phase 2a CBeyond Study (GlobeNewswire) - "Skye expects to report topline data from the trial in late Q3/early Q4 of 2025...Skye has also completed enrollment of the 26-week extension of the Phase 2a trial that it announced in July 2025. This extension is designed to obtain data from 52 weeks of treatment using nimacimab as monotherapy or in combination with semaglutide (Wegovy), offering longer-term insight into weight loss driven by a peripheral CB1 inhibitor antibody...Skye expects to report data from the extension study in Q1 2026."

P2a data • Trial status • Obesity

Skye Bioscience to Host Virtual KOL Event and Provide Perspectives on Upcoming CBeyond Phase 2a Topline Clinical Data Readout (GlobeNewswire) - "Virtual KOL event will begin at 8:00 AM ET on Thursday, September 4, 2025."

P2a data • Obesity

Clinical Highlights: CBeyond Phase 2a Obesity Trial (GlobeNewswire) - "Phase 2a Study Update: Patients enrolled in the original Phase 2a study continue to receive active treatment and are progressing through scheduled follow-ups, supported by ongoing collaboration between the clinical team and study sites; Extension Study Enrolling: In July, the 26-week extension study began enrolling patients in both the combination and monotherapy arms and will potentially provide up to 52-week safety and efficacy data. We expect approximately 50% of patients from the original study will be eligible for enrollment....The independent Data Safety Monitoring Committee has completed four unblinded reviews with no concerns raised. The study continues per protocol."

DSMB • Trial status • Obesity