Zealand Pharma and Roche publish full Phase 2 ZUPREME-1 petrelintide data in The Lancet Diabetes & Endocrinology

Zealand Pharma and Roche have published the complete Phase 2 dataset for petrelintide, an investigational once-weekly amylin analog, in The Lancet Diabetes & Endocrinology, with additional results presented at the European Association for the Study of Diabetes (EASD) annual meeting on September 30, 2026 ^[1]. The publication discloses, for the first time, the trial's primary endpoint at week 28 and the results for each individual dose ^[2].

The ZUPREME-1 trial randomly assigned 485 adults — 53% female, mean age 47 years, mean body mass index 36.7 kg/m², mean body weight 107.1 kg — in a 5:1 ratio to once-weekly subcutaneous petrelintide at 1.0 mg, 2.5 mg, 5.0 mg, 7.0 mg or 9.0 mg, or to placebo, for 42 weeks including dose escalation ^[1]. The study enrolled 493 participants across 32 sites in the United States, Poland and Romania, and was run on top of a reduced-calorie diet and increased physical activity ^[1].

What the numbers show

At week 28, the primary endpoint, average weight loss was 7.9% in both the 1 mg and 2.5 mg arms and 9.8% at the 5 mg dose ^[2]. Higher doses did not do better: mean weight loss was 9.3% at 7 mg and 9.4% at 9 mg ^[2]. Placebo produced 1.7% weight loss at week 28, so the placebo-adjusted reduction peaked at 8.1% with the 5 mg dose ^[2]. Those figures come from the efficacy estimand analysis ^[2].

By week 42, petrelintide produced mean weight reductions of up to 10.7% versus 1.7% for placebo using the efficacy estimand, and up to 10.2% versus 1.4% using the treatment policy estimand, which handles people who stop treatment differently ^[1][2].

The companies have emphasized tolerability. Gastrointestinal side effects were described as generally mild and occurring at rates similar to placebo, and at petrelintide's maximally effective dose there were no cases of vomiting and no treatment discontinuations due to gastrointestinal adverse events ^[1]. Looking across the study, nausea was still more common on petrelintide than placebo — 20% versus 6% — and constipation was 7% versus 4%, while rates of vomiting and diarrhea were the same or lower than placebo ^[2].

On cardiometabolic measures, the trial reported reductions in waist circumference of up to 10.8 cm (versus 4.3 cm with placebo), reductions in high-sensitivity C-reactive protein of up to 41% (versus 6%), triglyceride reductions of up to 21% (versus 9%), and a mean pulse rate decrease of up to 2.9 beats per minute versus a 0.3 bpm increase with placebo ^[1].

Why it matters for patients

Petrelintide is not a GLP-1 drug. Amylin is a hormone made in pancreatic beta cells and released with insulin after eating; activating amylin receptors has been shown to reduce body weight by restoring sensitivity to the satiety hormone leptin, which makes people feel full sooner ^[1]. That different mechanism is the reason amylin drugs are being watched closely: the weight-loss numbers are lower than what approved GLP-1 medicines deliver, but the digestive side effects that lead many people to quit treatment appear milder.

Some physicians have speculated that amylin drugs could eventually be used first, before combination therapy. BMO Capital Markets analysts wrote in a June 6 note that "a future treatment paradigm may prioritize amylin agents first with combo treatments reserved for patients who need higher efficacy or are refractory" ^[2].

Petrelintide also may not be the strongest drug in its class. Eli Lilly's amylin receptor agonist eloralintide showed up to 11.3% weight loss at week 12 in a Phase 1 trial and up to 20.1% at week 48 in a Phase 2 study, though cross-trial comparisons are not direct head-to-head evidence ^[2].

Importantly, petrelintide is investigational. It is not approved or available by prescription in the United States, and Phase 2 results do not establish long-term safety or effectiveness.

What happens next

A global Phase 3 ZUPREME registrational program with petrelintide as monotherapy for chronic weight management has been initiated ^[1]. Three Phase 3 trials were scheduled to begin, covering people with obesity or overweight, obesity or overweight plus type 2 diabetes, and obesity or overweight plus cardiovascular disease ^[2]. The obesity and diabetes trials have primary completion dates in late 2028 ^[2].

Separately, a Phase 2 trial testing petrelintide combined with enicepatide was planned to start in the second half of 2026 ^[1]. Roche paid Zealand $1.65 billion upfront in 2025 to co-develop the drug ^[2]. Any US filing or approval timeline has not been disclosed.