The setback of CB1 for Obesity may not slow down the pursuit of next-gen obesity drugs

Last week, Novo Nordisk released preliminary headline data of their Phase 2a trial evaluating CB1R inverse agonist INV-202 in obesity. At week 16, INV-202 induced about ~5.8% placebo-adjusted weight loss, in line with 7.1% reduction from oral semaglutide and 9.3% from orforglipron, according to a J.P. 摩根 analyst report. Measured from the weight loss point of view, the data was good but not outstanding among the oral weight-loss drugs.

However, increasing dose of INV-202 led to increasing rate of neuropsychiatric side-effects, including anxiety, irritability, and sleep disturbance. Further data on the side effects will not be disclosed from this study. ?

The market reacted very negatively, wiping off 5%, or $20bn+, of Novo Nordisk’s market cap, along with ~60% drop of Corbus Pharmaceuticals ’ stock and 45%+ drop of Skye Bioscience Inc. ’s. Analysts from J.P. 摩根 currently attribute no value of INV-202 to Novo's stock.

MoA of CB1R for inducing non-muscle losing weight-loss

Modulation of CB1 pathway for obesity is not new and the mechanism is well understood, according to Corbus Pharmaceuticals 's corporate presentation.

Sanofi ’s rimonabant showed ~9% weight loss at week 52 and no reduction of lean mass. ?However, it caused serious neuropsychiatric side effects like suicide ideation and depression, which led to the rejection by the FDA and EMA.

Companies like Inversago (which initially developed INV-202 and was later acquired by Novo ) and Corbus believed CB1R inhibitors that do not penetrate much into the brain would reduce the neuropsychiatric side effects while preserve their maximal activity in the peripheral tissues.

Indeed, initial Phas1b data of 37 patients from INV-202 presented at last year’s ADA conference showed promising sign of reduced neuropsychiatric side effects, which led to its acquisition by Novo Nordisk. ?????

Writing off the Whole CB1 Class Seems Premature

Umer Raffat from Evercore pointed out that INV-202 might be active at less than 10 mg dose and there was no serious neuropsychiatric adverse effects, which together could bode well regarding the side effects.

Corbus lost 60% of their market cap, suggesting the majority of their previous valuation was based on their CB1 inverse agonist CRB-913, which is still at preclinical stage and scheduled to enter the clinic in 2025. A preclinical asset at hundreds of millions of dollars valuation was an exception but not a norm in the current biotech market, so the stock drop might be just a regression to the mean.

However, CRB-913 does have much lower brain penetration effect than the other CB1 assets, which may translate to a better safety profile, according to Corbus Pharmaceuticals .

CB1 Exuberance Is the Tip of The Iceberg of the Next-gen Obesity Drug Development

The small drama around 诺和诺德 ’s CB1 inhibitor reflects the field’s unprecedented enthusiasm in next-gen obesity drugs, which together are expected to reach ~$150bn market, the largest market in the next decade. It is a “MUST HAVE” market for any players in cardiometabolism space, and this pressure drives furious competition.

Incretins like WEGOVY and ZAPBOUND will become mega blockbuster drugs, which are being followed by a rich pipeline of dual or triple incretin agonists, oral peptide, or oral small molecule drugs. This becomes an over-competitive space that leaves very little room for newcomers.

Instead, many new entrants focus on next-gen obesity drugs that focus on the following features:

-????????? Non-muscle losing obesity drugs: Up to 40% of weight loss is reportedly lean mass like muscles, which could be big problem for frail or older patients, as well some young adults.

?-????????? Tolerability: Discontinuation rate of WEGOVY and MOUNJARO is high, and the patients regain the weight after stopping the use of the drugs. Nausea, vomiting, diarrhea, and constipation are the common side effects. ?

?-????????? Accessibility: ?A large portion of patients still prefer oral drugs over injectables, and the cost of injection device is significant as well. In addition, injectables require fridged storage and transportation, which may become a barrier when the drugs need to expand to emerging markets. ??

?-????????? Manufacturing cost and efficiency: The best selling drugs like WEGOVY and ZAPBOUND are peptides, whose production seem to be the limiting factor for their commercialization, according to a recent BioCentury podcast. Some next-gen drugs like 安进 ’s MariTide use up to 420 mg of drug product per injection. Given the complicated manufacturing process of MariTide, its cost of goods would be very significant and its roll-out in the commercial setting for hundreds of millions of patients would be daunting. ?

Take muscle-preservation pipeline for example, in addition to Novo Nordisk and Corbus that focus on CB1, Activin pathway, myostatin pathway, SARM, Apelin, and others are seeing tremendous activity, according to a recent report by Stifel Financial Corp.

Is Obesity Space Replicating the Story of Immuno-Oncology?

Last week, the Lasker Award was given to Joel Habener, Lotte Bjerre Knudsen, and Svetlana Mojsov , the 3 Scientists who made critical contribution to GLP-1 and set off the current frenzy in obesity drug development. Many believe the Nobel Prize might be just a few years away.

In recent years, GLP-1 drugs have been fueling the explosion of interest from academic scientists, Hollywood celebrities, to Elon Musk; GLP1s are projected to dethrone Keytruda to become the new drug king by revenue soon.

The current GLP-1 story feels strikingly similar to checkpoints like PD-1 and CTLA-4. In 2011, the first CTLA-4 inhibitor ipilimumab was approved, followed by the two PD-1 inhibitor nivolumab and pembrolizumab approvals in 2014. In 2015, James Allion, who discovered CTLA-4 and championed ipilimumab's development, won Lasker Award , and he later shared the Nobel with Tasuku Honjo, the key scientist for research around PD-1. A few years ago, when IO enthusiasm was at the peak, IO-related preclinical and clinical studies dominated AACR, ASCO, and ESMO.

My 2018 review published on Nature Review Drug Discovery found 3,394 active IO agents in development at the time , including 113 CD19-targeted and 105 PD1-targeted assets. Today, IO trial results generate largely lukewarm or even mixed interests in oncology, as the recent ESMO showed. Based on my personal experiences, IO projects often times induce negative sentiment among VCs and biopharma BD executives.

Looking at the current obesity space, one cannot help but have a strong sense of Déjà vu: led by the uber success of incretins, next-gen obesity drugs are flooding the pipeline. So many targets and modalities in obesity space are being evaluated, similar to Immuno-Oncology space 7 years ago. ?

Apple doesn't fall on us, but we can be the first one to pick it up when it does

History doesn’t repeat but rhymes. IO is currently at its mature stage, and many argue the decade-long IO frenzy has produced some winners but many more losers. At the time, the clear frontrunning MoA is T-cell modulation like blockage of PD-1, CTLA-4, TIGIT, LAG3, TIM-3 etc, while CD3 T-cell engagers received the least attention and smallest pipeline.

Today, PD-1 is the still the king yet with limited growth potential, while T-cell engagers have not only received multiple approvals in oncology but also catapulted themselves into the autoimmunity space, stealing the thunders of CAR-T and monoclonal antibody and opening a new frontier in Immunology & Inflammation (I&I).

To quote 英伟达 ’s Jensen Huang , “Even if you don’t catch the apple before it hits the ground, so long as you’re the first one to pick it up. [Therefore] You want to position yourself close to the opportunities.”

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