Copenhagen-based Zealand Pharma announced positive petrelintide Phase II results from the ZUPREME-1 dose-finding trial, reporting up to 10.7% mean body weight reduction at 42 weeks in people with overweight and obesity.
Petrelintide is a long-acting amylin analog designed for once-weekly subcutaneous administration. The drug is being developed through an exclusive collaboration between Zealand Pharma and Roche signed in 2025, which grants Roche co-development and co-commercialization rights. The Phase II data for petrelintide produced weight loss below the levels reported for leading GLP-1–based therapies, with semaglutide demonstrating roughly 13%-15% reductions and tirzepatide around 20% in longer-duration Phase III trials. While this suggests more modest efficacy as a monotherapy, petrelintide showed a placebo-like safety profile. Roche has indicated that the drug may ultimately be positioned as part of combination regimens, potentially alongside its GLP-1 pipeline candidate CT-388, which the company acquired through its purchase of Carmot Therapeutics.
Trial specifics
ZUPREME-1 (NCT06662539) is a randomized, double-blind, placebo-controlled, parallel-group, multinational Phase II trial conducted across 33 sites in the United States, Poland, and Romania. The study enrolled 493 adults with obesity or overweight with weight-related comorbidities randomized across five petrelintide dose arms and placebo. Dosing involved once-weekly subcutaneous petrelintide with dose escalation every four weeks over a 16-week period, followed by maintenance through week 42 and a nine-week safety follow-up to week 51.
The primary endpoint, percentage change in body weight from baseline to week 28, was met across all five petrelintide arms with statistical significance versus placebo. Weight reduction continued through week 42, reaching up to 10.7% (efficacy estimand) compared to 1.7% with placebo (p<0.001). In the maximally effective arm, 98% of participants escalated to the targeted maintenance dose.
The tolerability profile was the trial’s distinguishing feature. Treatment discontinuation due to adverse events was 4.8% in the maximally effective petrelintide arm versus 4.9% with placebo. There were no cases of vomiting and no GI-related discontinuations at the maximally effective dose. Nausea rates were lower than in the prior 16-week Phase Ib trial, which used faster dose escalation, and nearly disappeared after participants reached maintenance dosing. No unexpected safety signals emerged, including for alopecia, fatigue, or neuropsychiatric events. Overall trial withdrawal was 8.4% across petrelintide arms versus 13.6% with placebo.
Zealand plans to initiate Phase III development later in 2026, with the ZUPREME-1 data informing trial design. Final results including the follow-up period are expected at a scientific conference in 2026. Topline data from ZUPREME-2, evaluating petrelintide in people with overweight or obesity and type 2 diabetes, are anticipated in the second half of 2026. A Phase II combination trial with CT-388 is planned for the first half of 2026.
Research context
Petrelintide mimics endogenous amylin, a peptide co-secreted with insulin from pancreatic beta cells in response to nutrient intake. Amylin receptor activation reduces body weight by restoring sensitivity to the satiety hormone leptin and inducing earlier satiation. This mechanism is distinct from GLP-1 receptor agonism, the pathway exploited by semaglutide and tirzepatide. The tolerability data from ZUPREME-1 are notable because GI side effects, particularly nausea and vomiting, remain the primary cause of treatment discontinuation with GLP-1-based obesity therapies, limiting long-term adherence.
The amylin analog weight loss space has drawn considerable investment. Key competitors include:
- Eli Lilly’s eloralintide, a selective amylin receptor agonist being readied for Phase III as a monotherapy and in combinations with other metabolic targets such as GLP-1 or GIP receptor agonists.
- Novo Nordisk’s amycretin, a dual GLP-1 and amylin receptor agonist in oral formulation that has produced Phase Ib/IIa weight loss data and is advancing toward Phase III.