Petrelintide

SAN ANTONIO — It took decades to get to the GLP-1 breakthrough in obesity treatment. Now, the biopharma industry is clamoring over the field’s next frontier: staving off the losses in muscle or lean mass that have been seen with existing drugs. Muscle preservation has become an increasing focus as leaders gathered in Texas this week for ObesityWeek, one of the main medical research conferences centered around the chronic disease. “If you look at the field of incretins — whether it’s single agonists, dual agonists, triple agonists — in my mind, I don’t think we need more weight loss,” Scholar Rock CSO Mo Qatanani told Endpoints News on the sidelines of the confab. “As far as weight loss, I think we’re good; there’s a lot of advancement there,” he added. “I think the next step to look at is this healthier weight loss that you can maintain, that’s durable.” Muscle preservation is key for a variety of health reasons, including implications on metabolism and the overall endocrine system, said Volkan Granit, a Biohaven medical director and neurologist. Retaining muscle mass is particularly relevant for elderly patients, he said, noting the risk of sarcopenia. Biohaven and Scholar Rock are developing myostatin-focused drugs for both spinal muscular atrophy and obesity. If muscle is retained, it could also help extend the durability of obesity drugs and lead to more fat loss, leaders in the field said. Patients on GLP-1s are losing more muscle in a year than they normally would in 10 years, Veru CEO Mitchell Steiner said. The Miami-based biotech is testing an oral selective androgen receptor modulator called enobosarm in a Phase 2b trial in combination with Wegovy. The company will have 16-week data in January 2025, and it plans to run two Phase 3 studies in obesity, for which a partner “would be wonderful,” Steiner said. The GLP-1s aren’t alone in affecting muscle loss. Many types of weight loss approaches, like gastric bypass surgery and caloric restriction, also impair lean mass, according to leaders in the field. “The rule of thumb is you want to keep it 70/30: 70% loss of fat, 30% loss of lean body mass,” said Nikhil Dhurandhar, chair of the nutritional sciences department at Texas Tech University and editor-in-chief of the International Journal of Obesity . Studies have shown about 25% to 55% of lean body mass loss for the GLP-1 class, Dhurandhar said, describing it as a “big deal.” At this point, though, he said he’s a proponent of adding walking exercises and “adequate protein diet” interventions on top of GLP-1 treatment rather than additional obesity medicines. Eli Lilly and Novo Nordisk, the GLP-1 behemoths, are among those also developing medicines thought to have less of an impact on muscle loss. “We’re all waiting for the big gorilla in the room to materialize, which is the ongoing, now Lilly-sponsored trial with bimagrumab plus semaglutide,” SixPeaks Bio CEO Philip Just Larsen said. AstraZeneca has the option to buy his preclinical biotech, which is developing activin-focused drugs for what it calls “healthy weight loss.” Bimagrumab aims to block both activin and myostatin signaling. The drug was originally at Novartis, then swooped up by Versanis Bio, which Lilly bought for up to $1.9 billion last year. Versanis was testing bimagrumab in combination with semaglutide, but Lilly has yet to report those results. Last month, the Indianapolis-based pharma started a new trial testing the injectable in combination with tirzepatide. Nadia Ahmad, an associate VP who leads Lilly’s Phase 3 obesity trials, said it has to be thought of in a broader body composition lens. “With potential investigational medications like bimagrumab, it’s about the fat mass as much as it is about muscle preservation,” Ahmad said on the sidelines of ObesityWeek, “and being able to really hone in on efficacy from a fat mass reduction standpoint, because that’s the crux of what we’re trying to treat here.” Drug developers are also looking at the pancreatic hormone amylin as a potential way of honing in on selective fat loss. Zealand Pharma thinks its petrelintide asset, weeks away from entering Phase 2, could be a “ foundational ,” first-line approach that could rid the need for GLP-1 for some patients. Novo also has an amylin program, combined with semaglutide, that will have key Phase 3 data by year’s end. AstraZeneca also highlighted the potential for amylin earlier this week, as did Structure Therapeutics.

SAN ANTONIO — Zealand Pharma, hoping to create the next “foundational” therapy for obesity, detailed more Phase 1 data on its amylin analog that was the backbone of a $1 billion raise this summer. Researchers said Zealand’s drug, dubbed petrelintide, led to up to 8.6% mean weight loss in an early-phase trial. Also, all gastrointestinal disorders observed in the study were mild, save for a moderate case of nausea and a moderate incidence of vomiting. The data were presented Tuesday at the annual ObesityWeek conference in Texas. Zealand initially toplined the data in June and quickly raised $1 billion for the “ crown jewel .” Analysts have predicted petrelintide could reach peak sales of $10 billion. At week 16 in the Phase 1, patients on 2.4 mg petrelintide lost a mean 4.8% body weight. The middle-dose group, 4.8 mg, lost the most at 8.6%, and the 9 mg group saw 8.3% reductions, the researchers said. The drop was 1.7% for the placebo cohort. Petrelintide could potentially have GLP-1-like weight loss of 15% to 20% in larger studies, Zealand chief medical officer David Kendall told Endpoints News on the sidelines of the conference. It also believes amylin agonists could help preserve lean muscle mass, an issue that has come up with the GLP-1 class. The company will dose the first patient in a Phase 2 trial in the coming days or weeks, Kendall said. The study will “elucidate” the differences between the 4.8 mg and 9 mg doses, he said. Zealand is positioning the drug as a potential standalone replacement for GLP-1s or as the first medicine that patients go to for obesity, but the company isn’t excluding the opportunity to combine with GLP-1s or other mechanisms, Kendall said. Novo Nordisk and Eli Lilly have dominated the field so far, but their GLP-1-based medicines carry GI tolerability baggage, among other challenges. Rather than suppress appetite and give patients a “food aversion” signal like the GLP-1s, amylin emphasizes the satiety signal, Kendall said. In his career, he’s worked in both the amylin field at Amylin Pharmaceuticals and on GLP-1s and other mechanisms at Lilly. “If you’ve had a meal here in Texas, you know what satiety feels like. That sense of, I’ve had enough, maybe a little bit too much,” Kendall said. “It actually enhances that signal so you don’t have that same food aversion, the lack of interest. So people tend to eat.” Petrelintide has a 240-hour half-life, or about 10 days, Kendall said. Novo, Lilly, AstraZeneca and multiple other drugmakers are also working on amylin. The field awaits a key Phase 3 readout this quarter from Novo’s CagriSema, a combination of the amylin asset cagrilintide and its blockbuster semaglutide. Novo’s amylin drug “will always be tied to semaglutide,” Kendall said. “We see petrelintide as the next potentially foundational class of therapies going forward. I know it seems maybe aspirational to say over and above what is a pretty successful GLP-1-based therapeutic class.” Structure Therapeutics, which plans to start testing its amylin candidate in humans next year, is looking up to Zealand’s progress. “Zealand is probably the pioneer in terms of pushing the monotherapy as part of their strategy,” Structure CEO Raymond Stevens said in an interview on the sidelines of the conference. “Some of the hypothesis is: amylin has the potential for better tolerability by itself, amylin alone, versus GLP-1.” As Zealand works on the Phase 2, it is looking for a large pharma to help carry petrelintide into Phase 3 and make it a standalone drug. With a fresh $1 billion, though, Zealand is “not backs-against-the-wall,” Kendall said. “The most important thing is not just to find someone with lots of people and deep pockets, but someone who believes in the positioning we’ve talked about.” Zealand already has a partner for its lead obesity drug, the Boehringer Ingelheim-allied survodutide, a glucagon/GLP-1 receptor dual agonist.