Skye Bioscience Performs Poorly in Glaucoma Study but Works Hard on Its Obesity Program - MedCity News - Latest Global News

Skye Bioscience Performs Poorly in Glaucoma Study but Works Hard on Its Obesity Program – MedCity News

Despite some evidence that cannabis reduces intraocular pressure in glaucoma, it is not widely used by the ophthalmology community. One reason is that its short duration of action means that the patient must smoke or ingest a lot of marijuana to maintain the effects throughout the day. Skye Bioscience’s ambitions to offer glaucoma patients these therapeutic benefits in the form of twice-daily eye drops 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 and is intended for a different indication – weight loss. In doing so, Skye hopes to show that it can compete with a high-flyer in the obesity field.

Skye’s drug research focuses on the endocannabinoid system, a biological system that plays a role in regulating a number of physiological processes in the body. The results announced Monday come from a test of SBI-100 OE. This drug candidate targets the endocannabinoid receptor CB1 and activates it with a version of THC designed for greater stability and penetration of eye tissue. However, 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 pressure in glaucoma patients compared to placebo.

Another process regulated by CB1 is appetite. Its blocking is associated with weight loss. This approach is recognized by the pharmaceutical industry. Sanofi received European approval in 2006 for rimonabant, a small molecule that specifically targets and blocks CB1 receptors. While patients taking the drug lost weight, it was later found that the pill also caused mood swings and suicidal thoughts. A review by the European Medicines Agency concluded that the benefits of the drug, sold under the name Accompli, no longer outweighed the risks. In 2008, Sanofi withdrew its CB1-blocking molecule from the market.

In the years since, scientists have been studying how to safely deliver CB1 as a drug, Skye’s head of development Tu Diep said in an interview last week during the BIO conference in San Diego. Subsequent preclinical research has shown that it is not necessary to target CB1 receptors in the brain to achieve the weight loss shown by rimonabant. That goal has been confirmed by Inversago Pharma, whose lead program, INV-202, is peripherally restricted — it blocks CB1 receptors in areas such as 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.

Although Inversago’s drug is designed not to enter the brain, as a small molecule it partially enters the central nervous system, just like Sanofi’s drug, according to Diep. In contrast, Skye’s CB1-blocking drug nimacimab is an antibody. As a large molecule, nimacimab has difficulty penetrating the blood-brain barrier. Skye’s preclinical studies in monkeys have shown this, Diep said.

“We don’t see any accumulation of the drug in the brain over time, which is contrary to what we see with some of these small molecules, even the peripherally restricted ones,” he said. “With chronic dosing (of small molecules), you see there is some accumulation over time. Yes, you’ll probably see weight loss, as Inversago has shown, but what is the potential safety risk with prolonged, chronic dosing?”

Nimacimab has another advantage. It is an allosteric drug, meaning it binds to a site on CB1 that is different from the main binding site for that receptor. In a disease state where CB1 and the natural ligands that bind to these receptors are upregulated, these ligands represent 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 safety and tolerability risks.

Skye added nimacimab to its pipeline in an all-stock deal last August through its acquisition of Bird Rock Bio. Bird Rock had conducted Phase 1 testing of the antibody in patients with nonalcoholic fatty liver disease (NAFLD). Diep said the results showed that the antibody was well tolerated and had a low rate of gastrointestinal complications.

Skye is preparing for a phase 2 trial, the main goal of which is to show that nimacimab works better than a placebo for weight loss. This proof-of-concept trial has two additional control arms: One will test semaglutide, the main ingredient in Novo Nordisk’s GLP-1 agonists Ozempic and Wegovy, and another arm will look at the combination of nimacimab and semaglutide. Diep says these additional arms will help Skye understand how its drug compares to Novo Nordisk’s to see how they differ. Rather than seeing which drug leads to more weight loss, Diep says the goal is to show differences in the type of weight loss. For example, one problem with GLP-1 agonists is that some of the weight lost is muscle mass. Skye believes that inhibiting CB1 will lead to weight loss that retains more muscle mass.

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

The results could help recommend nimacimab as part of treatment combinations with different mechanisms of action, Diep said. The data could also help expand the scope of nimacimab to other metabolic diseases, such as liver and kidney disease.

In its first-quarter 2024 financial report, Skye said it had $83.3 million in cash as of March 31. Following the failure of SBI-100’s Phase 2a in glaucoma, Skye announced Monday that it is halting clinical development of that program, as well as all ophthalmic research. The company will evaluate data from the failed trial and intends to publish its results. In the short term, however, all clinical development resources will now go toward metabolic research, which Skye says will extend the company’s runway to 2027. By then, the company should have clinical data for nimacimab in obesity. The Phase 2 trial is scheduled to begin in the third quarter of this year. Skye expects final data from that clinical trial to be available in late 2025.

Photo: primeimages, Getty Images

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