Skye Bioscience Photograph

Looking beyond the horizons of today’s obesity therapeutics with the goal of achieving healthier, sustainable outcomes.

CB1 inhibition is a differentiated energy-modulating and fat-burning mechanism with evidence showing its capability to induce weight loss. Skye is advancing its next-generation peripheral CB1 inhibitor, nimacimab, with the goal of uniquely realizing the potential of this mechanism as an alternative anti-obesity therapeutic with potentially healthier, more sustainable clinical outcomes. Skye believes nimacimab also offers the prospect of improving other comorbid conditions based on the broad role of CB1 in metabolic, inflammatory, and fibrotic processes. Skye started a Phase 2 clinical trial for its peripheral CB1 inhibitor, nimacimab, in August 2024 and expects to report interim and topline data in Q2 and Q4 2025.

Obesity therapeutics: Unmet needs

Current GLP-1 agonist therapies approved for chronic weight management have proven to be effective by reducing gastric motility and increasing the sense of “fullness,” causing reduced food intake and rapid weight loss. However, many patients experience significant gastrointestinal-related disorders such as nausea, diarrhea and vomiting – and, in the worst cases, irreversible paralysis of the stomach, called gastroparesis. These therapies appear to result in significant loss of muscle, which could be an issue for physical function, bone density and longevity for patients taking these drugs long-term. Patients can also regain lost weight once they stop taking these drugs. This suggests that GLP-1 agonists do not modify the underlying metabolic disorders associated with obesity and may not be conducive to achieving sustainable long-term health improvements. These results highlight important opportunities to achieve healthier weight loss, potentially through alternative therapeutic mechanisms.

Obesity Pipeline Overview

Number of Assets by Phase

Skye Bioscience Photograph
Skye Bioscience Photograph

Certain “mature” disease areas have many different commercialized therapeutic drug choices to meet myriad patient requirements, yet the obesity space is at a relatively early stage of development and served by a narrow set of therapeutic options. There are only seven FDA-approved anti-obesity drugs, and commercialized and Phase 3-stage drugs are dominated by incretin-focused mechanisms (GLP-1 and GIP). There is significant opportunity for new drugs with mechanisms of action that may avoid the shortcomings of the incretin drugs.

Peripheral CB1 inhibition: a mechanism with positive evidence and promise

Skye’s nimacimab employs a mechanism of action, peripheral CB1 inhibition, with potential to address various issues related to GLP-1 receptor agonists. CB1 is expressed throughout the body, especially in tissues important to metabolism and metabolic disorders such as adipose (fat), muscle, stomach, liver, and kidneys.

Preclinical studies have demonstrated that blocking CB1 receptors in these tissues can result in significant weight loss through multiple mechanisms. CB1 inhibition in fat tissue directly promotes the expenditure of energy stored in fat, and therefore the breakdown of fat.

Reduced fat mass can in turn reduce heightened levels of leptin caused by obesity and potentially reduce the cascading detrimental effects of that condition. Inhibition of CB1 in the gut also appears to modulate appetite-regulating hormones that act on the brain and support reduced caloric intake. These mechanisms may result in weight loss while preserving muscle and may allow patients to better maintain weight loss for longer periods of time. Importantly, previous clinical data show that small-molecule drugs that target CB1 had fewer issues with gastrointestinal disorders1 compared to, for example, one of today’s leading GLP-1 agonist weight-loss drugs, semaglutide2.

Complementary, Not Competitive

CB1 impacts key metabolic pathways that complement existing products & strategies

Skye Bioscience Photograph
Skye Bioscience Photograph

Considering the side effect profile of the incretin drugs and the capabilities and limitations of other anti-obesity mechanisms of action, CB1 inhibition offers attractive attributes to potentially play an important role in serving the growing and diverse needs of patients with obesity and overweight.

Nimacimab: a differentiated peripheral CB1 inhibitor

Nimacimab is a first-in-class CB1 inhibitor with unique characteristics supporting its potential to safely reduce weight through the mechanisms of increasing energy expenditure, improving leptin sensitivity, and modulating appetite and satiety. It is a monoclonal antibody that is a negative allosteric modulator inverse agonist of the CB1 receptor. Being a large molecule, nimacimab does not readily cross the blood-brain barrier and is to our knowledge the most peripherally restricted of CB1 inhibitors. This resulted in a very favorable safety profile in a Phase 1 trial assessing nimacimab in patients with nonalcoholic fatty liver disease. This included a less than 5% incidence rate of gastrointestinal adverse events and zero neuropsychiatric adverse events, which have been an issue with small-molecule CB1 inhibitors that have greater activity in the central nervous system. Notably, recent work by Skye to develop and then assess nimacimab in a diet-induced obesity model in animals achieved compelling results reported in November 2024. These results highlighted the significant role of peripheral CB1 inhibition to induce dose-dependent weight loss without reliance on central CB1 inhibition, and strongly favor nimacimab’s distinct positioning within the class compared to central CB1 inhibition. Skye started its CBeyondTM obesity Phase 2 study of nimacimab in August 2024.

Nimacimab binds to the allosteric site of the CB1 receptor, avoiding competition with endogenous ligands seeking to bind at the orthosteric site of the receptor and potentially enhancing its therapeutic window. With a pharmacokinetic profile of approximately 18-22 days and subcutaneous administration, nimacimab can be dosed weekly or possibly monthly, potentially improving patient adherence and convenience.

Given the distinct attributes of nimacimab, within the obesity landscape we see significant opportunity for it to complement GLP-1 agonists and other anti-obesity drug mechanisms of action as well as to have a potential role as a monotherapy.

Assessing nimacimab’s utility in the  CBeyondTM  Phase 2 study

Skye Bioscience Photograph
Skye Bioscience Photograph

In this Phase 2 study (ClinicalTrials.gov: NCT06577090) of nimacimab, which started in August 2024, four treatment groups will enroll 120 patients. Eighty (80) patients will subcutaneously receive either nimacimab 200 mg or nimacimab-matching placebo once-weekly in a double-blinded design. Forty (40) patients will receive either nimacimab + Wegovy® or nimacimab-matching placebo + Wegovy® once-weekly in a partially-blinded design. Wegovy® will be administered subcutaneously once-weekly following appropriate titration up to a maximum weekly dose of 2.4mg of semaglutide. Patients will be treated for 26 weeks and followed for safety for an additional 13 weeks.

The primary endpoint will compare weight loss of nimacimab against placebo. Secondary endpoints include safety and tolerability; neuropsychiatric and cognitive evaluation; change in body composition by DEXA. Exploratory endpoints include change in key metabolic parameters, triglycerides, insulin sensitivity, and leptin sensitivity; evaluation of the combination of nimacimab and Wegovy®; comparison of weight loss between nimacimab and Wegovy®; comparison of body composition between nimacimab and Wegovy®; and improvement in sleep.

The results of this study will help guide Skye’s development activities within the heterogeneous obesity market.

  1. Van Gaal et al., Efficacy and Safety of Rimonabant for Improvement of Multiple Cardiometabolic Risk Factors in Overweight/Obese Patients. Diabetes Care, Vol. 31, SUPPLEMENT 2, FEB 2008
  2. Wilding et al., Once-Weekly Semaglutide in Adults with Overweight or Obesity. New Eng J Med, 384;11, 2021