This past month, I have been immersed in obesity science, and one thing’s clear: not every pathway moves the scales.
After dissecting everything from next-gen GLP-1 co-agonists to mitochondrial uncouplers, I’m struck by how imaginative this field has become.
After several online and in-person discussions about the ‘copycat’ chasing of blockbusters that deliver only a 1% gain, it has been refreshing to examine a therapy area where a broad range of pathways in various tissues are being tested.
Part of this diversity has been driven by the success of Lilly in launching the co-agonist tirzepatide, which targets both GIP and GLP-1, improving on the weight loss achieved by targeting GLP-1 alone. This has shifted the bar for what constitutes success, meaning that innovation and bold bets on different approaches are now needed to demonstrate value.
Researchers are now agonizing (Link) or antagonizing (Link) other hormone receptors and testing small molecules, siRNA (Link), and antibodies (Link) in animal models and human clinical trials to enhance weight loss, combat muscle loss, and mitigate tolerability issues.
But scientific breadth means some bets won’t pay off, and last week’s NLRP3 results were a reminder of that.
Ventyx Biosciences tested a CNS-penetrant NLRP3 inhibitor both alone and in combination with semaglutide in patients with obesity and cardiovascular risk factors (Link).
Preclinical and clinical data have associated NLRP3 activation with over 20 indications characterized by aberrant inflammation, including metabolic diseases like obesity (Link).
The trial met its safety and inflammation endpoints (hs-CRP), but showed no weight benefit, either alone or in combination with semaglutide, over the 12 weeks.
Interestingly, Ventyx was refreshingly clear in its conclusion: NLRP3 inhibition doesn’t move the scale on weight loss. With this bold statement, it didn’t take long for the next NLRP3 contender to respond.
Competitor NodThera posted a press release several days later announcing that it had dosed the first patient in its Phase 2, with its CMO commenting that it’s running the“ longest trials to date for any NLRP3 inhibitor” (Link).
NodThera is testing NT-0796 and investigating the impact on IL-6, fibrinogen, and hsCRP levels, while also measuring weight loss as a secondary outcome. The trial was designed ahead of the Ventyx results, but it will be interesting to see if there is any benefit in weight with the additional eight weeks.
If not, then the question becomes: can a cardiometabolic-first therapy find a niche among high-risk obesity patients, or will it struggle in a market driven by visible weight outcomes?
