Treatment with a once-weekly injectable petrelintide, a novel human amylin analogue, yields up to 10.7 percent weight loss through week 42 in adults with obesity or overweight, according to the phase II ZUPREME-1 trial presented at ADA 2026.
“In this phase II dose-finding trial, petrelintide demonstrated statistically significant and clinically meaningful weight reduction across all dose cohorts at both weeks 28 and 42 in a gender-balanced population,” said study author Dr Timothy Garvey from the University of Alabama at Birmingham, Alabama, US.
Petrelintide is being developed as a weekly injectable intended for long-term obesity pharmacotherapy, leveraging a mechanism of action distinct from current therapies, which may enhance tolerability and support sustained use.
The ZUPREME-1 was a double‑blind, parallel‑group, dose‑finding study involving 485 adults (mean age 47 years, 53 percent female) who were obese or overweight (mean BMI 36.7 kg/m2; mean body weight 107.1 kg) and had related comorbidities. Participants were randomly assigned to receive weekly subcutaneous injections of one of five petrelintide doses (dose 1, n=79; dose 2, n=81; dose 3, n=83; dose 4, n=79; and dose 5, n=82) or a matching placebo (n=81) in addition to a lifestyle intervention for 42 weeks. The petrelintide dose was increased every 4 weeks over a 16‑week period until the assigned maintenance dose was reached.
The mean percent change in body weight from baseline to week 42, the primary endpoint of the study, decreased by 8.7 percent, 9.2 percent, 10.7 percent, 10.5 percent, and 10.2 percent in the petrelintide groups (doses 1–5, respectively) compared with a 1.7-percent reduction in the placebo group. [ADA 2026, abstract 3083-LB]
Petrelintide recipients also showed a greater reduction in waist circumference than placebo recipients (ranging from –7.9 to -10.8 vs –4.3 cm).
Moreover, patients treated with petrelintide showed improvements in cardiovascular risk factors, as shown by greater reductions in high-sensitivity C-reactive protein levels (ranging from –17 percent to –41 percent) and triglycerides (ranging from –12 percent to –21 percent) at 42 weeks than those treated with placebo (–6 percent and –9 percent, respectively).
In terms of safety, the rates of any adverse events (AEs) and serious AEs were similar between the petrelintide and placebo groups (70.8 percent vs 69.1 percent and 3.5 vs 3.7 percent, respectively).
The most common gastrointestinal-related AEs reported in both petrelintide and placebo groups were nausea (19.6 percent vs 6.2 percent), constipation (6.9 percent vs 3.7 percent), vomiting (3 percent vs 6.2 percent), and diarrhoea (7.4 percent for both).
Garvey noted that most gastrointestinal AEs were mild and occurred during the dose-escalation.
However, 1.5 percent of participants in the petrelintide group discontinued treatment owing to gastrointestinal AEs, whereas none in the placebo group did.
Overall, “these findings support the potential of petrelintide as an effective and well-tolerated obesity medication with a distinct mechanism of action,” said Garvey. “These properties offer the opportunity for petrelintide (and amylin-based therapies) to improve longer-term medication persistence.”
“Petrelintide, a novel amylin analogue, can potentially play an important role in the future of obesity pharmacotherapy, and phase III studies are scheduled to initiate in second half of 2026,” he added.