Roche has decided to pay $190 million upfront for an unusual obesity mechanism after viewing preclinical data that “clearly suggests” the modality can reduce weight while preserving lean muscle, Fierce has learned.
The Swiss pharma’s Genentech unit stumped up the cash last week for rights outside South Korea to HM17321, a corticotropin-releasing factor 2 (CRF2) receptor-selective urocortin-2 (UCN2) analog developed by South Korea’s Hanmi Pharm.
Researchers have known for decades that activating the CRF2 receptor with UCN2 can protect against muscle atrophy in animal models. Roche is betting that attribute could prove useful in weight loss.
“The [preclinical] data clearly suggests that through a non-incretin mechanism, you can still have weight loss—but more importantly, have weight loss through the preservation of lean mass, without losing muscle mass,” Manu Chakravarthy, M.D., Ph.D., global head of cardiovascular, renal and metabolism product development at Roche, told Fierce.
Preclinical studies also suggest the drug could improve muscle function, another feature that has caught Roche’s attention.
“So what we’re really excited about is the potential for improvement in muscle function and overall enhancing metabolic function as well,” Chakravarthy said.
The first clinical data will come from a phase 1 study that Hanmi is already overseeing. Chakravarthy wasn’t able to provide a timeline for that readout because the study is being run by Hanmi, but said Roche is keen for Genentech to take over and start a phase 2 trial “as quickly as possible.”
Roche remains cautiously optimistic about the preclinical findings, Chakravarthy said, while recognizing that not everything seen in animal studies will carry over to humans.
“Having done this for a few decades, I can tell you that translation ... doesn't always happen,” Chakravarthy said. “That's why, as much as I’m excited about the preclinical data that we've seen, we have to await the clinical data.”
The licensing of HM17321 follows a ramp-up in Roche’s obesity strategy last year, which included a bold goal of becoming one of the “top three” companies in the weight loss space.
The pharma’s weight loss pipeline includes enicepatide, the dual GLP-1/GIP receptor agonist brought over in the buyout of Carmot Therapeutics that Roche has previously said it hopes to take to market by 2030. There’s also another Carmot asset in phase 2, the oral GLP-1 receptor agonist CT-996, as well as petrelintide, the long-acting amylin analog Roche is developing with Zealand Pharma.
Chakravarthy said incretins, which include enicepatide and CT-996, and amylins are each a “foundational pillar” of Roche’s obesity strategy. A “third pillar” is FGF21 analogs, which Roche added when it acquired 89bio last year and which could help address obesity-related comorbidities such as MASH.
Even with this varied portfolio, Roche saw other unmet needs that required a more “holistic” approach, Chakravarthy said.
“You can certainly have agents that reduce weight, but how do you maintain that over some period of time?” he said. “And importantly, how do you do that while maintaining lean mass preservation as well? Because lean mass does go down, particularly in those that are vulnerable, like the elderly, those that are predisposed to falls, or even just having a predisposition to fractures.”
HM17321’s mechanism also has the potential to improve insulin sensitivity, Chakravarthy said. Insulin resistance is a fundamental feature of many metabolic diseases, making that potential particularly interesting to Roche.
“If you have an insulin sensitizer that can reset that core pathophysiological defect, that becomes very exciting, because now you're really able to go after the core defect, plus also maybe address some of the comorbidities of obesity, which also is one of our core anchors of our strategy,” Chakravarthy said.
Eli Lilly previously explored UCN2 in heart failure before scrapping a phase 1 UCN2 peptide program in 2019. Roche’s deal, however, represents a move into a largely unexplored use of the mechanism for obesity.
Does Chakravarthy expect others to follow?
“I wouldn't be surprised,” he told Fierce. “You know, usually, this is how it all typically happens—they look for a ‘validation event,’ and then things might happen.”
Despite pushing its obesity strategy into this underexplored area, Chakravarthy said Roche is “absolutely not done” looking for other mechanisms. The company's search for new approaches is driven by where the science is heading, he said.
“We always follow the science to see where it is breaking, where it is making an impact, and how we can translate that science to the benefit of patients,” Chakravarthy added.
