Can CB1 Inhibitors Make a Comeback in Obesity?

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.”

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.

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.”

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.”

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.”