BioPharma, Pharma

Skye Bioscience Falls Short in Glaucoma Trial, But It’s Full Steam Ahead for Obesity Program

Skye Bioscience’s nimacimab blocks CB1, the same receptor targeted by an obesity drug candidate now in the hands of Novo Nordisk. But Skye contends its Phase 2-ready antibody drug has several advantages over the small molecule that joined Novo’s pipeline in a deal valued at $1 billion.

Despite some evidence that cannabis reduces intraocular eye pressure from glaucoma, the ophthalmology community hasn’t embraced its use. One reason cited: The short duration of effect means a patient must smoke or ingest a lot of marijuana to maintain its effect throughout the day. Skye Bioscience’s ambitions to bring glaucoma patients these therapeutic benefits in a twice-daily eye drop have missed the mark. The clinical-stage company is now turning its focus to another drug that targets the same receptor in a different way for a different indication — weight loss. In doing so, Skye aims to show it can compete with a juggernaut in the obesity space.

Skye’s drug research focuses on the endocannabinoid system, a biological system that plays a role in regulating a range of physiological processes in the body. The results announced Monday are from a test of SBI-100 OE. This drug candidate targets and activates the endocannabinoid receptor CB1 with a version of THC engineered for greater stability and penetration of eye tissue. But in the placebo-controlled Phase 2a clinical trial, San Diego-based Skye said the study drug arm did not show a statistically significant change in intraocular eye pressure in glaucoma patients compared to placebo.

Another process that CB1 regulates is appetite, and blocking the receptor is associated with weight loss. This approach has big pharma validation. Sanofi won European approval in 2006 for rimonabant, a small molecule designed to target and block CB1 receptors. While patients taking the drug lost weight, the pill was also later found to cause mood changes and suicidal thoughts. A European Medicines Agency review concluded that the benefits of the drug, marketed as Acomplia, no longer outweighed its risks. In 2008, Sanofi withdrew its CB1-blocking molecule from the market.

In the years since, scientists have been studying how to safely drug CB1, Skye Chief Development Officer Tu Diep said, speaking in an interview last week during the BIO Conference in San Diego. Subsequent preclinical research has demonstrated that it’s not necessary to target CB1 receptors in the brain to achieve the weight loss shown by rimonabant. That goal has been validated by Inversago Pharma, whose lead program, INV-202, is peripherally restricted — it blocks CB1 receptors in places like the gastrointestinal tract, kidneys, liver, and pancreas, but avoids that receptor in the brain. Impressed by the once-daily pill’s early clinical data, Novo Nordisk acquired Inversago last year for up to $1 billion.

While Inversago’s drug is designed to avoid entering the brain, Diep said that as a small molecule, some of it still gets into the central nervous system just as Sanofi’s drug did. By contrast, Skye’s CB1-blocking drug, nimacimab, is an antibody. As a large molecule, it’s difficult for nimacimab to penetrate the blood-brain barrier. Skye’s preclinical studies with monkeys have shown that, Diep said.

“We don’t see an accumulation of the drug in the brain over time, which is opposite from what we see with some these small molecules, even the peripherally restricted ones,” he said. “With chronic dosing (of small molecules), what you see is there’s some accumulation over time. Yes, you’re probably going to see weight loss, like Inversago has shown, but for longer, chronic dosing, what’s the potential safety liability?”

Nimacimab has another advantage. It’s a allosteric drug, which means it binds to a site on CB1 that’s different than the main binding site for that receptor. In a state of disease, where CB1 and the natural ligands that bind to these receptors are upregulated, those ligands pose competition for a small molecule drug designed to bind to the receptor’s main binding site. Consequently, a small molecule drug will require higher doses to achieve its therapeutic effect. Higher doses could increase the safety and tolerability risks.

Skye added nimacimab to its pipeline via the acquisition of Bird Rock Bio in a stock deal last August. Bird Rock had conducted Phase 1 testing of the antibody in patients with non-alcoholic fatty liver disease, or NAFLD. Diep said the results showed the antibody was well tolerated and had a low rate of gastrointestinal complications.

Skye has been gearing up for a Phase 2 test whose main goal is showing that nimacimab is better than a placebo at driving weight loss. This proof-of-concept study has two additional control arms: one will test semaglutide, the main ingredient in Novo Nordisk GLP-1 agonist metabolic disorder drugs Ozempic and Wegovy, and another arm will evaluate the combination of nimacimab and semaglutide. Diep said these additional arms will help Skye understand how its drug matches up to Novo Nordisk’s in order to see how they are differentiated. Rather than seeing which drug leads to more weight loss, Diep said the idea is to show differences in how weight is lost. For example, one problem with GLP-1 agonists is that some of the lost weight is lean muscle mass. Skye believes CB1 inhibition will lead to weight loss that preserves more lean mass.

“So we think we’re going to improve body composition, and also based on the mechanism of action we’ve seen with preclinical models, we think there’s a lot of complementary metabolic improvements that CB1 inhibition provides,” Diep said.

The results could help build the case for nimacimab as part of treatment combinations that employ different mechanisms of action, Diep said. The data might also support expanding the scope of nimacimab to other metabolic indications, such as liver and kidney disorders.

In its first quarter 2024 financial report, Skye said it had $83.3 million in cash as of March 31. With the Phase 2a failure of SBI-100 in glaucoma, Skye said Monday that it is discontinuing clinical development of that program as well as all of its ocular research. The company will evaluate the data from the failed study and intends to publish its findings. But in the near term, all clinical development resources will now go toward metabolic research, which Skye said will extend the company’s runway into 2027. By then, the company should have clinical data for nimacimab in obesity. The Phase 2 study is on track to start in the third quarter of this year. Skye anticipates final data from this clinical trial will become available in late 2025.

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