Obesity

Metabolic rewiring with CB1 inhibition

Many individuals suffering from the chronic physiological and mental effects of obesity and overweight have been given new hope by the powerful impacts of breakthrough GLP-1 receptor-targeting weight loss drugs. The results of these drugs have also revealed the need for improved clinical outcomes that may require different mechanisms of action.

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 expects to advance its peripheral CB1 inhibitor, nimacimab, into Phase 2 in Q3 2024.

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.

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 promotes the expenditure of energy stored in fat, and therefore the breakdown of fat. Reduced fat mass can in turn reduce heighted 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 disorders² compared to, for example, one of today’s leading GLP-1 agonist weight-loss drugs, semaglutide³.

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. 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. Skye started its CBeyond^TM Phase 2 study of nimacimab in obesity 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 CBeyond^TM Phase 2 study

In this Phase 2 study 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.