Obesity drug research is expanding to targets beyond GLP-1 with a goal of improving the side effect profile that leads many patients to stop treatment. A once-weekly injectable medication from partners Zealand Pharma and Roche has mid-stage clinical trial results showing tolerability comparable to a placebo, but the magnitude of weight loss has industry analysts questioning the drug’s competitive profile.
The drug, petrelintide, is a peptide engineered to bind to and activate the amylin receptor in order to promote satiety. The Phase 2 dose-finding study enrolled 493 participants with overweight or obesity. The main goal was measuring the percent change in weight loss from baseline at week 28.
In the preliminary results reported on March 5, Zealand did not specify the weight loss measure at week 28, saying only that all five treatment arms achieved statistically significant and clinically meaningful reductions in weight. The company said this weight reduction was sustained through week 42, where results showed a 10.7% average reduction in weight from baseline, not taking into account patient discontinuations. The average weight loss in the placebo arm was 1.7%. The trial enrolled more women than men, and Zealand said women lost “considerably more” weight compared to the men.
Zealand said full results from this Phase 2 study will be presented at a scientific conference this year. Preliminary data from a separate mid-stage test enrolling patients with overweight or obesity and type 2 diabetes is expected to yield data in the second half of this year.
Petrelintide came from the labs of Copenhagen-based Zealand, which reported Phase 1 results showing 8.3% average weight loss for the highest of three doses tested measured at 16 weeks. Nearly a year ago, Roche bought into petrelintide, paying $1.65 billion to share in the development of the asset.
In a note sent to investors, Wiliam Blair analyst Andy Hsieh said that while petrelintide’s tolerability is encouraging, the actual weight loss measures are disappointing. The investment bank had expected weight loss of about 16% without factoring in events like treatment discontinuations. That bar was set by the Phase 2 test of Eli Lilly’s amylin receptor-targeting drug, eloralintide.
Hsieh acknowledged that cross-trial comparisons have limitations and greater female representation in an obesity study generally leads to a greater magnitude of weight loss. But he added that William Blair believes the difference in weight loss between the two drugs is too large to attribute to patient enrollment alone. Hsieh said Zealand’s drug shows a ceiling effect starting at dose level 3, suggesting higher dose levels are unlikely to lead to greater weight loss.
“It is our view that this dynamic creates a challenging situation for petrelintide for which its tolerability profile supports higher dosing, but increasing the dose would be unlikely to lead to additional weight loss,” Hsieh said.
The upside for petrelintide is its tolerability profile. Hsieh noted that the frequency of gastrointestinal side effects was comparable to a placebo. At the most efficacious dose, the middle dose, about 70% of patients experienced no gastrointestinal side effect during the entire study and the discontinuation rate was comparable to placebo. That result leads William Blair to believe petrelintide’s most likely use will be as a maintenance treatment, where placebo-like tolerability is important for a drug taken chronically.
When Roche began the partnership ion petrelintide last year, the pharmaceutical company said it believed the drug offered potential for use as part of combination treatments. In particular, Roche is interested in pairing petrelintide with CT-388, a peptide engineered to activate the GLP-1 and GIP receptors. CT-388 came from Roche’s $2.7 billion acquisition of Carmot Therapeutics.
In its announcement of the drug’s Phase 2 results, Roche said the data support further development a monotherapy for weight loss while the tolerability confirms its value for potential treatment combinations. Roche said a Phase 2 study exploring combination of petrelintide and CT-388 will begin later this year.
Photo: Peter Dazeley, Getty Images
