Rimonabant

iStock/ synthetick After psychological side effects doomed the first generation of cannabinoid receptor 1–targeting drugs for weight loss, Novo Nordisk, Corbus Pharmaceuticals and Skye Bioscience are betting that a new mechanism of action will improve the safety profile. Nearly 20 years after the FDA’s rejection of what would have been the first approved drug in the class, a new generation of CB1 receptor inhibitors is undergoing early- and mid-stage clinical trials for the treatment of obesity. Novo Nordisk, Corbus Pharmaceuticals and Skye Bioscience are all hoping the improved safety profiles of their therapies will lead to a new method of treating the disease. “What’s interesting about this is it’s a comeback story for a class that was entirely abandoned,” said Corbus CEO Yuval Cohen. “In 2006, it was viewed as an exciting class of drugs—and then it had a catastrophic setback at FDA.” Rimonabant, the first-in-class cannabinoid receptor 1 (CB1) receptor antagonist from Sanofi, which was approved in Europe for weight loss, worked to suppress appetite by blocking endocannabinoid receptors in the brain. While rimonabant successfully helped patients lose weight, it greatly increased instances of depression, anxiety and suicidality in patients. In the CRESCENDO study , four rimonabant-treated patients committed suicide. The FDA deemed the drug unapprovable in 2006, and European regulators withdrew it from the market in 2008. “After the rejection, none of the other [pharma companies] tried to file [with the FDA],” Cohen told BioSpace . “There was such a stigma around it that it was considered an untouchable mechanism of action.” A New Approach Now, Novo, Corbus and Skye are hoping to bring a version to the market that is safer and just as effective as the early class by avoiding the CB1 receptors in the brain. Instead, these compounds will work on peripheral receptors throughout the body, which will also allow for higher dosing, Cohen said. “There’s a lot of evidence out there of this particular target being found in the peripheral tissues, especially in adipose tissues and important organs like the liver, muscles and even the GI tract,” said Skye CEO Punit Dhillon. Peripherally restricted CB1-targeting drugs, such as Skye’s nimacimab, Corbus’s CRB-913 and Novo’s monlunabant , do not cross the blood-brain barrier, therefore reducing the chance of neuropsychiatric effects such as depression. “The idea was to keep the bits that are working but avoid some of the risks involved with the first class, which was too much of it went into the brain,” Cohen said. In Phase Ib studies of nimacimab, patients reported no serious adverse events. “We’ve been really successful in terms of having zero incidents of any neuropsychiatric [effects] or depression or any concerns in our Phase I data,” Dhillon told BioSpace . However, last month, Phase IIa results from monlunabant revealed “mild to moderate neuropsychiatric side effects,” such as anxiety, irritability and sleep disturbances. No serious adverse events were reported in relation to the neuropsychiatric side effects, according to Novo. Patients treated with the drug saw an average of 15 lbs of weight loss after 16 weeks of treatment, compared to just 1.5 lbs for the placebo group. ‘Amazing Little Engines’ CB1 receptors are a type of G-protein coupled receptor—what Cohen describes as “amazing little engines” that activate appetite in all living things and push them to find food. Activation of the receptors promotes food intake, fat storage and energy storage in the body. One type of CB1-targeting drug is an inverse agonist, which “puts this process in reverse and hits the gas pedal,” Cohen explained. “So suddenly, rather than being obsessed with food-seeking, we are no longer hungry and obsessed with food.” With appetite suppressed, fat in the body is converted to energy and weight loss can occur. But instead of acting on CB1 receptors in the brain, the new class of inhibitors bind to peripheral receptors throughout the body thanks to a smaller molecule. This metabolic rewiring can reintroduce insulin sensitivity, glucose tolerance and other healthy lipid profiles that are compromised in patients with obesity, Dhillon said. Cannabinoid pathways are also integral to signaling the presence of a hormone called leptin, which tells the brain how much fat is stored in the body. “It is possible to get that response peripherally. If you can sensitize the body to the effects of leptin, it’s possible to be able to more easily release fat from fat cells,” Louis Aronne, Sanford I. Weill professor of metabolic research at Weill-Cornell Medical College and director of the Center for Weight Management and Metabolic Clinical Research, told BioSpace . One hypothesis is that fat gets locked in fat cells, and it is difficult in obesity to get it out, Aronne noted. “If you could take fat out of fat cells and have it floating around in the bloodstream instead of locked away in the fat cells, your brain would be able to sense the fatty acids as nutrition floating around and would use that as a trigger to suppress your appetite,” he explained. “That’s one way peripherally acting drugs could have central mechanisms.” CB1/GLP-1 Combinations Weight loss medications are one of biopharma’s hottest current trends. GLP-1 drugs, such as Novo’s Wegovy and Eli Lilly’s Zepbound, exploded onto the market to regulate blood sugar and restrict caloric intake by curbing appetite and making patients feel full longer. While CB1-targeting drugs can be used on their own, they also could be paired with GLP-1s. In fact, Skye is combining nimacimab and Wegovy in a Phase II study . Forty patients will be randomized to either a treatment group that will receive nimacimab injection or a placebo in conjunction with Wegovy. “We feel there is a strong argument that [CB1 inhibitors] can be combined with GLP-1s really well,” Dhillon said. “If GLP-1s are doing a good job [with caloric restriction], and CB1s are doing a good job in re-establishing metabolic pathways, then we’re getting it from both sides and hopefully achieving a better body composition over time.” Meanwhile, Corbus’ CRB-913 was used in conjunction with GLP-1 medications Wegovy, Zepbound and liraglutide in preclinical testing . Mice with diet-induced obesity showed decreased body weight when given CRB-913. These effects were enhanced when GLP-1 drugs were added, including statistically significant reductions in body fat, liver triglycerides, liver fat deposits, insulin resistance and leptinemia. “What we have shown preclinically is if you combine CB1-targeting drugs with incretin-targeting drugs, you can add on to the different effects and lead to more weight loss,” Cohen noted. “What this ends up being in clinical usage remains to be seen. But there are important populations where modifying with CB1 makes a lot of sense.” These populations include those who cannot or do not want to use GLP-1 drugs, those who need a higher degree of weight loss with combined mechanisms of action, and those who have reached their goal weight on GLP-1 drugs and want to switch to a drug to help maintain that weight loss, he said. Combining a CB1-targeting drug with a GLP-1 medicine could also mean the patient would take a smaller dose of the GLP-1—which could lead to fewer gastrointestinal side effects and a greater chance of adherence to the medication regimen, Aronne said. “One of the things that may happen with GLP-1s is we may use too much of it in an effort to get someone’s weight down,” he continued. “If you had a mechanism that gave additive weight loss, but it didn’t have nausea or vomiting or any of the GI side effects, that might be a brilliant way to help.” Time Will Tell Aronne sees the field of obesity treatment going in a similar direction to treatment for hypertension or other indications where medication is started early before the condition gets out of hand. “Eventually, instead of having to treat people with BMIs of 40 and above, we’re going treat people as soon as they get to obesity,” Aronne said. “[That way], you never get to a BMI of 30, 40 or 50, where the damage accrues.” Whether CB1 inhibitors are part of that treatment process remains to be seen. Early data are promising, but the answers will come from the trials of nimacimab, monlunabant and CRB-913. “I think the class is at a potentially important fork in the road,” Cohen said. “If the data are good, that could really just provide a complete change in the mindset around this mechanism.”

16-week top-line weight loss data validates mechanism of action targeting peripheral CB1 receptors Skye highlights safety advantages of large-molecule CB1 inhibition compared to small-molecule approach SAN DIEGO, Sept. 23, 2024 (GLOBE NEWSWIRE) -- Skye Bioscience, Inc. (Nasdaq: SKYE) (“Skye”), a clinical-stage biopharmaceutical company focused on developing new therapeutics for metabolic health, is providing a statement regarding a recent announcement by Novo Nordisk on Phase 2a top-line data with monlunabant, Novo’s small-molecule oral cannabinoid receptor (CB1) inverse agonist. “We are encouraged to see that monlunabant met its primary endpoint and demonstrated at least a 6% placebo-adjusted weight loss at 16 weeks, which we see as broadly supportive of the mechanism of action for inhibition of peripheral CB1 receptors and its role in weight loss,” said Punit Dhillon, Skye’s Chief Executive Officer and Chairman of the Board. “The observation of dose-dependent neuropsychiatric side effects in this study was unfortunate, however, this highlights a key distinction between our large-molecule CB1 inhibitor and known small-molecule CB1 inhibitors currently in development. Nimacimab, a monoclonal antibody being developed by Skye, has demonstrated minimal accumulation of drug in the brain in preclinical non-human primate studies, and in our limited data set from the Phase 1 MAD study in non-alcoholic fatty liver disease (NAFLD), importantly, no neuropsychiatric adverse events (N=62) were observed.” “In pharmacodynamic models, the key advantages of nimacimab’s peripheral restriction from the brain have been underscored,” said Chris Twitty, Skye’s Chief Scientific Officer. “Modeling of Phase 1 pharmacokinetic and preclinical biodistribution data demonstrate* that both nimacimab and monlunabant have sufficient peripheral exposure to exceed their respective IC90 thresholds to inhibit CB1 signaling. However, as expected for a small molecule, monlunabant has reported notable leakage into the brain, leading to central exposure exceeding the IC75 concentration at all doses tested in the Phase 2a study. We believe these data demonstrate a critical challenge faced by current CB1 small molecules in development, which lack adequate restriction from the brain and an increased potential for neuropsychiatric side effects.” Mr. Dhillon added, “It is clear that with increased restriction from the brain, nimacimab provides a potential clear safety advantage over a small molecule approach. In addition, nonclinical studies have shown the predominant role of peripherally-driven CB1 inhibition in achieving weight loss and metabolic gains versus centrally-driven CB1 inhibition. To support our hypothesis, Skye has developed a murine mouse model expressing the human variant of the CB1 receptor, which will allow us to evaluate the effects on weight loss with nimacimab in a diet-induced obesity murine model. We expect to share results from these studies in the near future.” Skye launched its Phase 2 trial of nimacimab in obesity in August 2024. This trial, which is the first to also assess a GLP-1/CB1 inhibitor combination, is expected to report interim weight loss data in Q2 2025 and top-line data in Q4 2025. Following is a summary of Skye data and perspectives on the prospects for CB1 inhibition and nimacimab. Potency and Pharmacokinetics Nimacimab: Using both Skye’s Phase 1 clinical PK data and non-human primate biodistribution studies, a robust model was developed to predict both peripheral and central exposure of nimacimab at the current Phase 2 clinical dose (200 mg administered subcutaneously once-weekly). This model demonstrates* that the concentration of drug in the periphery greatly exceeds the dose required to inhibit CB1 receptor signaling (IC90), with highly limited exposure in the brain at a level 100-fold less than the IC50 and 600-fold less than the IC90, potentially mitigating the risk of promoting neuropsychiatric side effects. Monlunabant: Published Phase 1 clinical data as well as preclinical biodistribution and potency data for monlunabant has been used to establish a model that predicts both peripheral and central exposure at all Phase 2 clinical doses. This model underscores that while sufficient peripheral inhibition has been achieved at all doses, notable brain exposure* in this chronic setting exceeds the IC75 concentration at all doses, with the highest dose exceeding IC90 levels. This model is consistent with the dose-dependent increase in neuropsychiatric AEs reported in monlunabant’s Phase 2 trial.Nimacimab Wider Therapeutic Index: These models highlight that in contrast to the small-molecule-based CB1 inhibitors, nimacimab has a potentially wider therapeutic index that may lead to greater flexibility to dose considerably higher while still maintaining central levels well below the IC50. Of note, nimacimab’s Phase 1 clinical data has also demonstrated favorable tolerability, providing further support for a potential broader therapeutic index. Efficacy Monlunabant achieved approximately 6% weight loss at 16 weeks, which aligns with historical benchmarks achieved by rimonabant and is similar to oral semaglutide at similar time points (approximately 6% placebo-adjusted). This data is in line with and validates the trend for CB1 inhibitors, and is highly supportive of the 8% placebo-adjusted weight loss target at 26 weeks in Skye’s current Phase 2 obesity study of nimacimab. Neuropsychiatric Safety Concerns Monlunabant previously showed accumulation in the brain, preclinical and Phase 1 neuropsychiatric side effects were observed, and Phase 2 dose-dependent neuropsychiatric side effects were observed, reflecting the CNS exposure also seen with other small-molecule CB1 inhibitors.Nimacimab has had no known CNS safety concerns, showing no neurological toxicity in preclinical studies and zero neuropsychiatric side effects in its Phase 1 trial (with a larger N than the monlunabant Phase 1). Nimacimab Differentiation Monlunabant Dose Limitation: Limited weight loss at higher doses suggests a potential plateau in efficacy and reinforces potential PK/PD limitations that may compress the therapeutic index. While brain exposure is a critical hurdle that may require a lower clinical dose, these small molecules also have the disadvantage of targeting the orthosteric site of CB1, which necessitates competition with often high concentrations of peripheral endocannabinoids.Non-Competitive Inhibition of CB1 Signaling: Antibody-based CB1 inhibition not only drives its heightened peripheral restriction but also allows nimacimab to bind to the CB1 receptor away from the endocannabinoid binding pocket at the allosteric site. This binding still allows nimacimab to inhibit CB1 signaling as both an inverse agonist and an antagonist while avoiding competition with natural ligands (2-AG and AEA), ensuring a better PK/PD relationship even with higher endocannabinoid levels.* Graphs reflecting statements in this release are included in Skye’s investor deck About Nimacimab Nimacimab is a first-in-class humanized negative allosteric monoclonal antibody that inhibits CB1 signaling in the periphery as an inverse agonist and antagonist. Inhibition of CB1 has shown anti-fibrotic, anti-inflammatory, and metabolic mechanisms of action with potential to address a broad range of diseases with unmet medical needs such as obesity, chronic kidney disease, and metabolic dysfunction-associated steatohepatitis (MASH). About Skye Bioscience Skye is focused on unlocking new therapeutic pathways for metabolic health through the development of next-generation molecules that modulate G-protein coupled receptors. Skye's strategy leverages biologic targets with substantial human proof of mechanism for the development of first-in-class therapeutics with clinical and commercial differentiation. Skye is conducting a Phase 2 clinical trial (ClinicalTrials.gov: NCT06577090) in obesity for nimacimab, a negative allosteric modulating antibody that peripherally inhibits CB1. This study is also assessing the combination of nimacimab and a GLP-1R agonist (Wegovy®). For more information, please visit: www.skyebioscience.com. Connect with us on X and LinkedIn. CONTACTS Investor Relationsir@skyebioscience.com(858) 410-0266 LifeSci Advisors, Mike Moyermmoyer@lifesciadvisors.com(617) 308-4306 Media InquiriesLifeSci Communications, Michael Fitzhughmfitzhugh@lifescicomms.com(628) 234-3889 FORWARD LOOKING STATEMENTS This press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. In some cases, forward-looking statements can be identified by terminology including “anticipated,” “plans,” “goal,” “focus,” “aims,” “intends,” “believes,” “can,” “could,” “challenge,” “predictable,” “will,” “would,” “may” or the negative of these terms or other comparable terminology. These forward looking statements include, but are not limited to: statements regarding our product development, statements regarding the superior safety and tolerability profile of nimacimab relative to other small molecule CB1 inhibitors, statements relating to any expectations regarding the safety, including lack of neurosphyciatric effects, efficacy, tolerability or dosing of nimacimab, including based on preclinical models and the clinical information from the nimacimab Phase 1 study in NAFLD, statements regarding the ability of nimacimab to treat obesity or related indications, statements regarding the timing of receipt of interim and final data from Skye’s Phase 2 obesity study of nimacimab and statements regarding the therapeutic potential of nimacimab. Such statements and other statements in this press release that are not descriptions of historical facts are forward-looking statements that are based on management’s current expectations and assumptions and are subject to risks and uncertainties. If such risks or uncertainties materialize or such assumptions prove incorrect, our business, operating results, financial condition, and stock price could be materially negatively affected. We operate in a rapidly changing environment, and new risks emerge from time to time. As a result, it is not possible for our management to predict all risks, nor can we assess the impact of all factors on our business or the extent to which any factor, or combination of factors, may cause actual results to differ materially from those contained in any forward-looking statements the Company may make. Risks and uncertainties that may cause actual results to differ materially include, among others, our capital resources, uncertainty regarding the results of future testing and development efforts and other risks that are described in the Company’s periodic filings with the Securities and Exchange Commission, including in the “Risk Factors” section of Skye’s most recent Annual Report on Form 10-K and Quarterly Report on Form 10-Q. Except as expressly required by law, Skye disclaims any intent or obligation to update these forward-looking statements.