Zealand Pharma Reports Petrelintide Phase 2 Results Showing 10.7% Weight Loss With Placebo-Like Tolerability

Copenhagen-based Zealand Pharma announced positive petrelintide Phase 2 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. Zealand Pharma petrelintide is a long-acting amylin analog designed for once-weekly subcutaneous injection, and the data position it as a potential entrant into the increasingly contested weight management drug landscape alongside GLP-1 receptor agonists. Roche and Zealand Pharma entered an exclusive collaboration in 2025 to co-develop and co-commercialize petrelintide for this indication.

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 (mean baseline BMI 37 kg/m²; 53% female), randomized across five petrelintide dose arms and placebo. All participants received a reduced-calorie diet and increased physical activity. 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 petrelintide clinical 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 Pharma 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. David Kendall, Zealand Pharma's Chief Medical Officer, stated: "These data reinforce petrelintide's potential to establish a new class of therapy and redefine the weight management experience for people living with overweight and obesity." Petrelintide has not received regulatory approval for any indication.

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.

The petrelintide obesity treatment program's differentiation rests on its tolerability claim. Whether placebo-like GI tolerability holds in larger Phase III populations, and whether 10.7% weight loss at 42 weeks proves sufficient as monotherapy against competitors delivering higher reductions, will determine its commercial viability in the weight management drug 2026 landscape and beyond.

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