ZUPREME-1: Petrelintide Reduces Obesity, Maintains Tolerability in Phase 2 Trial

Petrelintide, an investigative human amylin analog, has demonstrated sustained weight loss in patients with obesity, maintaining high tolerability throughout the ZUPREME-1 trial.¹

Presented at the American Diabetes Association (ADA) Scientific Sessions 2026 in New Orleans, Louisiana, by Timothy Garvey, MD, a professor of medicine and director of the Diabetes Research Center at the University of Alabama at Birmingham, these data reflect petrelintide’s potential as a well-tolerated alternative to traditional weight loss therapies while acting through a unique method of action.¹

“When you look at the gastrointestinal side effects that are a problem with GLP-1-based therapies, rates of nausea with petrelintide are less than half of those observed with GLP-1 medications,” Garvey told HCPLive in an exclusive interview. “Rates of constipation, diarrhea, and vomiting roughly approximated those observed in placebo. This is a well-tolerated medication.”

ZUPREME Study Structure

ZUPREME was a randomized, double-blind, phase 2, dose-finding trial comparing once-weekly petrelintide to placebo. Conducted across 32 international locations, the trial enrolled patients with a body mass index (BMI) ≥30 kg/m2 or ≥27 kg/m2 with hypertension and/or dyslipidemia. Patients were excluded if they exhibited HbA1c ≥48 mmol/mol, a history of type 1 or type 2 diabetes, or uncontrolled thyroid disease, or had been treated with any medication or alternative remedies for weight loss within 6 months of screening.²

Eligible patients were then randomly assigned in a 5:1 ratio to weekly subcutaneous injections of 5 separate doses of petrelintide or to placebo. These doses were escalated for ≤16 weeks in 4-week steps to reach the assigned maintenance dose, which was then continued through week 42. The study’s primary outcome was the percent change in body weight from baseline to week 28. Secondary endpoints included the percent of patients achieving ≥5% and ≥10% weight loss at weeks 28 and 42, as well as change from baseline in waist circumference, HbA1c, and fasting glucose.^1,2

ZUPREME Study Findings

Garvey and colleagues ultimately enrolled 485 patients, among whom the average BMI was 36.7 kg/m2 and average body weight was 107.1 kg. Over 42 weeks, petrelintide led to mean reductions of up to 10.7% compared to 1.7% among patients receiving placebo (efficacy estimand; P <.001). Of the patients treated with petrelintide, 88-98% achieved the target dose.¹

The majority of gastrointestinal adverse events were mild, with nausea reported for 19.6% of participants on petrelintide and 6.2% on placebo. Vomiting was less common with petrelintide (3% vs 6.2% on placebo), and diarrhea and constipation were both <7.5% in both arms. Safety findings were consistent with expectations, and 1.5% of participants discontinued treatment due to gastrointestinal adverse events.¹

Ultimately, Garvey and colleagues concluded that, based on these data, petrelintide has the potential to be a very well-tolerated alternative for obesity therapy, providing sustained weight loss over a long period of time with a distinct method of action.¹

“There are GLP-1 medications that have achieved, on average, greater levels of weight loss, but this current level of 10-15% is sufficient to treat a large number of patients who have obesity,” Garvey said. “We engage in complication-centric care, so our job is to improve the health of patients. It’s the complications of the disease that impair health and quality of life. We’re all about preventing and treating these complications rather than the amount of weight loss, per se.”

Editors’ Note: Garvey reports disclosures with Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Pfizer, Fractyl Health, Zealand Pharma, and others.

References

1. Garvey T, Connery L, Dinesen M, et al. Petrelintide, a Human Amylin Analog for the Treatment of Obesity: Efficacy and Safety from the Phase 2 Trial, ZUPREME 1. Abstract presented at the American Diabetes Association (ADA) Scientific Sessions 2026, New Orleans, LA. June 5-8, 2026.

2. Zealand Pharma. Once-weekly Petrelintide Versus Placebo for Obesity or Overweight With Comorbidities (ZUPREME). ClinicalTrials.gov Identifier: NCT06662539. Updated March 23, 2026. Accessed June 7, 2026. https://clinicaltrials.gov/study/NCT06662539