Zealand’s Petrelintide Shows 9.2% Weight Loss and HbA1c Benefit in ZUPREME-2

Zealand Pharma has announced positive topline results from the Phase 2b ZUPREME-2 trial evaluating petrelintide, a long-acting human amylin analog, in people with overweight or obesity and type 2 diabetes. The randomized, double-blind, placebo-controlled study met its primary endpoint, with once-weekly subcutaneous petrelintide producing statistically significant and clinically meaningful reductions in body weight from baseline to week 28 across all three treatment arms compared with placebo.

The study enrolled 220 participants in the United States, with a mean baseline body mass index (BMI) of 36.3 kg/m² and mean baseline HbA1c of 8.0%. Participants received one of three petrelintide doses or placebo alongside a reduced-calorie diet and increased physical activity. All participants were receiving metformin, with or without an SGLT2 inhibitor.

Petrelintide Achieved Up to 9.2% Mean Weight Reduction

At week 28, mean body weight reductions with petrelintide ranged from 7.4% to 9.2% across the three treatment arms, based on the efficacy estimand. The highest mean reduction was 9.2%, compared with a 2.0% reduction with placebo.

The company reported that the findings remained largely consistent when assessed using the treatment-regimen estimand, supporting the robustness of the topline weight-loss findings.

The primary endpoint was the percentage change in body weight from baseline to week 28. Prespecified secondary endpoints included the proportion of participants achieving at least 5% or 10% body weight loss, absolute change in body weight, waist circumference, HbA1c, high-sensitivity C-reactive protein, fasting glucose and fasting lipids.

HbA1c Improved Across Petrelintide Groups

Petrelintide was also associated with improvements in glycemic control. Placebo-adjusted HbA1c reductions ranged from 0.61% to 0.88% across the three petrelintide treatment arms.

When assessed as change from baseline, the maximum HbA1c reduction with petrelintide was 0.65%, while the placebo group showed a 0.23% increase. The distinction is important because the placebo-adjusted figures account for the change observed in the placebo group.

These findings provide topline evidence of an improvement in both body weight and glycemic control in participants with overweight or obesity and type 2 diabetes receiving background metformin therapy, with or without an SGLT2 inhibitor.

Safety Profile Remained Consistent

No unexpected safety signals were observed with petrelintide. The company reported that its safety and tolerability profile was largely comparable to placebo, with gastrointestinal adverse events representing the most frequently reported adverse events.

The vast majority of gastrointestinal adverse events were mild and occurred during the dose-escalation period. Treatment discontinuation because of gastrointestinal adverse events occurred in 1.9% of participants receiving petrelintide compared with 1.7% of those receiving placebo.

Zealand Pharma stated that the safety and tolerability findings were consistent with those observed in the 42-week Phase 2 ZUPREME-1 trial, which evaluated petrelintide in people with overweight or obesity without type 2 diabetes.

Phase 3 ZUPREME Program Underway

ZUPREME-2 was a multicenter, US-based Phase 2b study registered under ClinicalTrials.gov identifier NCT06926842. The trial included a screening period, up to 16 weeks of dose escalation with dose increases every fourth week, a maintenance period through week 28 and follow-up through week 38.

Following the Phase 2 findings, Zealand Pharma and Roche have initiated a Phase 3a program comprising ZUPREME-3, ZUPREME-4 and ZUPREME-5. The trials are evaluating once-weekly petrelintide versus placebo in different populations with overweight or obesity.

ZUPREME-3 is evaluating people with overweight or obesity without type 2 diabetes, while ZUPREME-4 is evaluating people with overweight or obesity and type 2 diabetes. ZUPREME-5 is evaluating people with overweight or obesity and established cardiovascular disease.

The three Phase 3 trials are expected to enroll approximately 7,000 participants in total, and the first participants have already initiated treatment. Zealand Pharma expects to present the full ZUPREME-2 results at an upcoming scientific conference.

What the ZUPREME-2 Results Mean

The ZUPREME-2 topline results show that once-weekly petrelintide reduced body weight and improved HbA1c compared with placebo in people with overweight or obesity and type 2 diabetes. The highest reported mean body weight reduction was 9.2% at week 28, while placebo-adjusted HbA1c reductions reached 0.88%.

The low rate of gastrointestinal adverse-event-related discontinuation and the absence of unexpected safety signals provide additional support for continued clinical development.

However, these remain topline findings. The complete ZUPREME-2 dataset, including the full analysis of prespecified outcomes, has not yet been presented. Further data from the Phase 3 program will be important for characterizing the efficacy, tolerability and safety of petrelintide in larger and broader patient populations.

Reference

Zealand Pharma announces positive Phase 2 ZUPREME-2 topline results for amylin analog petrelintide in people with overweight or obesity and type 2 diabetes, Zealand Pharma via GlobeNewswire, October 07 2026

Efficacy and Safety of Petrelintide in Participants With Overweight or Obesity and Type 2 Diabetes (ZUPREME 2), ClinicalTrials.gov ID NCT06926842