Copenhagen-based Zealand Pharma A/S (Nasdaq: ZEAL) has initiated the registrational Phase III ZUPREME program for petrelintide, its long-acting amylin analog, enrolling patients across three trials designed to support marketing applications for the drug as a monotherapy in chronic weight management.
The program comprises ZUPREME-3, ZUPREME-4, and ZUPREME-5, targeting adults with overweight or obesity without type 2 diabetes (T2D), with T2D, and with established cardiovascular disease (CVD) respectively. Combined enrollment is approximately 7,000 participants. All three trials are randomized, double-blind, and placebo-controlled, with a primary endpoint of percentage change in body weight from baseline to week 64. ZUPREME-5 extends into an event-maintenance phase and can run up to three years.
Petrelintide activates the amylin receptor, which has been shown to reduce body weight by restoring sensitivity to the satiety hormone leptin and inducing earlier satiation — a mechanism distinct from GLP-1 receptor agonism, the pathway shared by every high-efficacy agent currently approved for chronic weight management.
The Phase III initiation follows positive Phase II results from the ZUPREME-1 dose-finding trial, which reported up to 10.7% mean body weight reduction at 42 weeks versus 1.7% with placebo (p<0.001). The tolerability profile was also notable: treatment discontinuation due to adverse events was 4.8% with petrelintide versus 4.9% with placebo at the maximally effective dose, with no vomiting and no GI-related discontinuations at that dose level. Those data were presented at ADA 2026 in June alongside improvements in waist circumference, high-sensitivity C-reactive protein, and triglycerides.
The tolerability profile is central to Zealand and Roche's commercial thesis. GLP-1 receptor agonists — including Novo Nordisk's Wegovy (semaglutide) and Eli Lilly's Zepbound (tirzepatide), which have set the efficacy benchmark with mean weight losses of roughly 15% and 20-22% respectively in Phase III — carry well-documented nausea and vomiting profiles that drive discontinuation in a meaningful proportion of patients. Petrelintide's Phase II monotherapy weight loss of 10.7% at 42 weeks falls below those benchmarks, a gap that analysts have flagged as a commercial risk in a competitive market. The drug's value proposition in Phase III will depend on whether the tolerability advantage holds at scale and whether the cardiovascular outcomes data from ZUPREME-5 can establish a label comparable to semaglutide's March 2024 FDA approval for major adverse cardiovascular events reduction.
The program is being conducted with Roche, which entered an exclusive co-development and co-commercialization agreement with Zealand in 2025 for petrelintide and potential combination products. Under that deal, Zealand received USD 1.65 billion in upfront and anniversary payments, with potential total consideration of up to USD 5.3 billion including development and sales milestones. A Phase II combination trial evaluating petrelintide alongside Roche's dual GLP-1/GIP receptor agonist enicepatide (CT-388) is planned for initiation in the second half of 2026. Topline data from ZUPREME-2, evaluating petrelintide in overweight or obese patients with T2D, are also anticipated in the second half of 2026.
Access the AllSci platform to explore the science behind the news.
Spot something wrong? Report an issue with this article