Petrelintide

ZUPREME 1: phase 2 in obesity without diabetes (493 adults)

ZUPREME 1 randomized adults without type 2 diabetes who had a BMI of 30 or more, or 27 or more with hypertension or dyslipidaemia, 5:1 to self-injected once-weekly petrelintide at maintenance doses of 1.0 to 9.0 mg or to placebo for 42 weeks including dose escalation, at 32 sites in Poland, Romania and the USA (PMID: 42810355). The primary end point was the percentage change in body weight at 28 weeks; the trial is registered as NCT06662539 and was completed on 7 March 2026 (PMID: 42810355).

Of 493 randomized adults, 485 received at least one dose; mean baseline body weight was 107.1 kg and mean BMI 36.7 (PMID: 42810355). At 28 weeks (efficacy estimand), body weight changed by 7.9 percent on 1.0 mg, 7.9 percent on 2.5 mg, 9.8 percent on 5.0 mg, 9.3 percent on 7.0 mg and 9.4 percent on 9.0 mg, all below baseline, against 1.7 percent on placebo, which gave estimated treatment differences of 6.2 to 8.1 percentage points (PMID: 42810355). Body weight continued to fall to week 42, with reductions of up to 10.7 percent (PMID: 42810355). A comment by Sten Madsbad and Jens J Holst, titled "Petrelintide and the evolving role of amylin agonism in obesity", appeared in the same journal (PMID: 42810353).

Phase 1: single and multiple ascending doses (132 people dosed)

Both phase 1 trials were randomized, double-blind and placebo-controlled and ran at one centre in Neuss, Germany (PMID: 42017294). The single-dose trial gave subcutaneous doses of 0.04 to 2.4 mg and one intravenous dose of 0.35 mg to men with normal weight or overweight (PMID: 42017294; ClinicalTrials.gov NCT05096598). The multiple-dose trial gave six weekly doses of 0.6 or 1.2 mg in its first part and, in its second part, 16 weekly doses escalated every 2 weeks to target doses of 2.4, 4.8 or 9.0 mg in 36 adults with overweight or obesity, against 12 on placebo (PMID: 42017294; ClinicalTrials.gov NCT05613387).

After 16 weeks without any lifestyle intervention, mean body weight fell 4.8, 8.6 and 8.3 percent in the three petrelintide cohorts and 1.7 percent on placebo, estimated differences in a post hoc analysis of 3.2, 7.0 and 6.7 percentage points (p of 0.0002 or less) (PMID: 42017294). Waist circumference fell 5.0, 7.2 and 7.6 cm against 1.9 cm, and HbA1c, about 5.5 percent at baseline, did not change (PMID: 42017294). Because of the escalation schedule, the two highest cohorts spent only 8 and 6 weeks at their target doses (PMID: 42017294).

Registered trials without published results (ClinicalTrials.gov, 27 October 2026)

• ZUPREME 2 (NCT06926842), a phase 2 Zealand Pharma trial, tested three petrelintide doses against placebo in 221 adults with overweight or obesity and type 2 diabetes taking metformin with or without an SGLT2 inhibitor; its primary end point was percentage change in body weight at 28 weeks, and it was listed as completed on 13 August 2026 with no posted results.
• Zealand Pharma's phase 1 renal impairment study (NCT07076030) measured pharmacokinetics in 39 participants and was listed as completed in November 2025 with no posted results.
• A phase 1 drug product concentration study (NCT07338214) by Zealand Pharma measured single-dose pharmacokinetics of four product concentrations in 48 participants with a BMI of 27 or more and was listed as completed in March 2026.
• Zealand Pharma's phase 1 hepatic impairment study (NCT07682818), a pharmacokinetic study with an estimated 36 participants, is recruiting.
• ZYNERGY (NCT07589686) is a phase 2 Hoffmann-La Roche trial of petrelintide given with enicepatide (listed as RO7795068, CT-388 and RG6640), each drug alone, or placebo in an estimated 486 adults with obesity or overweight for 40 weeks; it had not started recruiting on 27 October 2026.
• ZUPREME-3 (NCT07843498) is a phase 3 Hoffmann-La Roche trial in an estimated 3,900 adults with overweight or obesity, at least one weight-related comorbidity and no type 2 diabetes; its primary end point is percentage change in body weight at week 64.
• ZUPREME-4 (NCT07843485), another phase 3 Hoffmann-La Roche trial, involves an estimated 600 adults with overweight or obesity and type 2 diabetes, with percentage change in body weight at week 64 as its primary end point.
• ZUPREME-5 (NCT07843472), the third phase 3 Hoffmann-La Roche trial, has an estimated enrollment of 2,500 adults with overweight or obesity and established cardiovascular disease; its primary end point is percentage change in body weight at week 64, with primary completion estimated for July 2030.

Laboratory and animal studies

The 2025 design paper reports the design, receptor activity, chemical stability and rat studies summarized under mechanism of action (PMID: 41217931). A 2025 study from Soochow University used petrelintide as the starting point for a methylated analogue, BGM1812, and described petrelintide's agonist activity as insufficient compared with natural agonists (PMID: 40608546).

Phase 2: ZUPREME 1 (485 people dosed, 42 weeks)

Nausea was the most common adverse event with petrelintide, in 79 of 404 participants (20 percent) against 5 on placebo (6 percent) (PMID: 42810355). Vomiting occurred in 3 percent on petrelintide and 6 percent on placebo, diarrhea in 7 percent in both groups, and constipation in 7 percent against 4 percent (PMID: 42810355). The authors described the nausea as predominantly mild and occurring during dose escalation, and no deaths were reported (PMID: 42810355). A 2026 narrative review whose sources included company press releases reported discontinuation for adverse events in 4.8 percent with petrelintide and 4.9 percent with placebo in ZUPREME 1 (PMID: 42452898).

Phase 1 (132 people dosed)

The two phase 1 trials reported no serious or severe treatment-emergent adverse events and no adverse events of special interest, a category that covered suspected liver injury and pancreatic and biliary disease (PMID: 42017294). In the single-dose trial, nausea and vomiting occurred only at the two highest subcutaneous doses (PMID: 42017294). In the 16-week part of the multiple-dose trial, nausea affected 16.7 to 33.3 percent of petrelintide groups against 16.7 percent on placebo, and one participant stopped after the third dose because of moderate nausea and vomiting, the only vomiting reported in that part (PMID: 42017294).

Decreased appetite was reported more often with petrelintide than with placebo in the phase 1 trials (PMID: 42017294). Injection site reactions were mild and transient, mean pulse rate was about 5 beats per minute below baseline toward the end of multiple-dose treatment, and no participant developed anti-drug antibodies (PMID: 42017294).

What is not known

The longest published petrelintide treatment period is 42 weeks (PMID: 42810355). The phase 2 trial in adults with type 2 diabetes (ZUPREME 2, NCT06926842) is listed as completed with no posted results, and no report of it was found in PubMed on 27 October 2026. No human data in pregnancy, in children or on cardiovascular outcomes were found.