Petrelintide (formerly ZP8396) is an investigational, long-acting amylin analog for chronic weight management, given as a once-weekly subcutaneous injection. Zealand Pharma discovered it, and Zealand and Roche are now developing it together. Unlike GLP-1 medicines such as semaglutide, it is designed to act on the amylin pathway.
On September 22, 2026, Zealand Pharma announced that it and Roche had initiated the global registrational Phase 3 ZUPREME program. Three trials are planned, together enrolling about 7,000 people with overweight or obesity, with or without type 2 diabetes and established cardiovascular disease (Zealand Pharma, Sept. 22, 2026).
In the Phase 2 ZUPREME-1 trial, the most effective petrelintide regimen produced up to 10.7% mean body-weight reduction at week 42, compared with 1.7% for placebo, under the trial’s efficacy estimand (Roche, March 5, 2026). Petrelintide has not been approved for weight management by any regulatory authority.
Medical information: Petrelintide is an investigational medicine. This page summarizes company announcements, trial registries and published reviews. It is not medical advice and should not be used to make treatment decisions. Approved obesity treatments are discussed with a qualified healthcare professional.
Information current as of September 29, 2026.
In this article
- Petrelintide at a glance
- What is petrelintide?
- How does petrelintide work?
- Why is amylin drawing research interest?
- What did ZUPREME-1 show?
- What are the side effects of petrelintide?
- How the Phase 3 ZUPREME program is designed
- Petrelintide vs GLP-1 weight-loss drugs
- Petrelintide plus enicepatide: the combination program
- The Roche and Zealand Pharma agreement
- Open questions after Phase 2
- What happens next for petrelintide?
- Frequently asked questions about petrelintide
- Summary
Petrelintide at a glance
| Item | Current information |
|---|---|
| Drug class | Long-acting amylin analog (not a GLP-1 receptor agonist) |
| Administration | Once-weekly subcutaneous injection |
| Developers | Zealand Pharma and Roche (agreement announced March 2025) |
| Status | Investigational; Phase 3 ZUPREME program initiated September 22, 2026 |
| Phase 2 weight loss (ZUPREME-1) | Up to 10.7% at week 42 vs 1.7% with placebo (efficacy estimand) |
| Phase 2 tolerability | Mostly mild gastrointestinal events; 1.5% of participants discontinued because of GI adverse events |
| Phase 3 size | About 7,000 participants across ZUPREME-3, -4 and -5 |
| Approved? | No |
What is petrelintide?
Petrelintide is an amylin analog. Amylin is a hormone made by pancreatic beta cells and released with insulin after eating. Petrelintide is designed to reproduce and extend amylin’s activity so that it can be dosed weekly. It is being studied mainly for chronic weight management in adults with overweight or obesity.
According to Zealand Pharma, the molecule was engineered for chemical and physical stability, with no fibrillation around neutral pH, which allows co-formulation and co-administration with other peptides. That property matters for combination products, including the petrelintide–enicepatide combination described below.
How does petrelintide work?
Amylin is secreted by pancreatic beta cells in response to nutrients. It acts alongside insulin, but its functions differ. Research links amylin to meal-ending satiation, regulation of food intake, suppression of post-meal glucagon and slowing of gastric emptying, with appetite effects mediated by brain regions that regulate satiety.
An amylin analog is meant to strengthen that satiety signal. Petrelintide is designed to activate amylin-related receptors far longer than natural amylin, which makes once-weekly dosing possible. Earlier work has also explored interactions between amylin and leptin, though the clinical importance of that interaction for current obesity medicines remains under investigation.
The mechanism differs from GLP-1 receptor agonism. GLP-1 and GIP-based medicines act on incretin receptors, whereas amylin analogs act on a separate pathway, which is one reason the class draws research interest.
Why is amylin drawing research interest?
Incretin-based medicines showed that changing appetite pharmacologically can produce substantial weight loss, but obesity is biologically varied and not every person responds the same way. That leaves room for other drug classes.
Amylin has long been studied as an obesity target. Pramlintide, the first approved amylin analog, demonstrated proof of concept but was limited by modest efficacy and frequent dosing, and it is approved as an adjunct to insulin rather than for obesity (Alhazmi & le Roux, 2026; Bailey et al., 2026).
Several 2026 reviews indexed in PubMed describe long-acting amylin-based agents, including cagrilintide, eloralintide, petrelintide, MET-233i and AZD6234, as a developing class studied alone and in combination with incretin drugs. One review notes that nausea similar to that seen with GLP-1 receptor agonists is common when amylin analogs are started and up-titrated but mostly resolves with continued use (Bailey et al., 2026). Another examines how receptor pharmacology may shape the balance between weight loss and nausea (Fischer & Borner, 2026). Whether long-acting amylin analogs achieve that balance in large trials remains to be shown.
What did ZUPREME-1 show?
ZUPREME-1 is the main clinical dataset for petrelintide so far. It was a randomized, double-blind, placebo-controlled, dose-finding Phase 2 trial in adults with obesity, or overweight with weight-related complications, who did not have type 2 diabetes. Five petrelintide regimens were compared with placebo alongside reduced-calorie dietary guidance and increased physical activity. Doses were escalated every fourth week, over 16 weeks, and the primary endpoint was percentage change in body weight at week 28.
Participants. Roche’s topline report counted 493 participants, with a mean baseline weight of about 107 kg, a mean BMI of about 37 kg/m² and a mean age of 48; 53% were female. Zealand’s later American Diabetes Association (ADA) presentation described 485 randomized adults (mean age 47, BMI 36.7), and the companies’ releases do not explain the difference in counts (Roche, March 5, 2026; Zealand Pharma, June 5, 2026).
Weight loss. At week 42, the highest mean reduction was 10.7% with petrelintide versus 1.7% with placebo (p<0.001) under the efficacy estimand. Roche reported that results under the treatment-regimen estimand were largely consistent. Roche also reported that female participants lost considerably more weight than male participants.
Other measures at week 42 (Zealand’s ADA release): waist circumference fell by 7.9 to 10.8 cm across petrelintide arms versus 4.3 cm with placebo; high-sensitivity C-reactive protein fell 17% to 41% versus 6%; and triglycerides fell 12% to 21% versus 9%. Between 88% and 98% of participants escalated to their target maintenance dose.
How to read the numbers. An efficacy estimand estimates the treatment effect under defined assumptions, including that participants stayed on the investigational treatment and did not start another weight-loss therapy. It does not predict what every patient would experience. Cross-trial comparisons with semaglutide, tirzepatide or other investigational drugs are unreliable because populations, durations, dosing schedules and statistical methods differ; only head-to-head trials can settle relative performance.
What are the side effects of petrelintide?
Roche’s topline report stated that the most frequent adverse events in ZUPREME-1 were gastrointestinal and that most were mild. In the maximally effective arm, there was no vomiting and no discontinuation because of gastrointestinal adverse events. Discontinuation for any adverse event was 4.8% in that arm and 4.9% with placebo. Across petrelintide arms, withdrawal for any reason was 8.4%, compared with 13.6% with placebo. Diarrhea and constipation occurred at single-digit rates comparable to placebo, and nausea was mostly mild and became uncommon after participants reached their maintenance dose.
Zealand’s ADA release added figures for all petrelintide-treated participants (Zealand Pharma, June 5, 2026):
| Adverse event | Petrelintide | Placebo |
|---|---|---|
| Nausea | 19.6% | 6.2% |
| Vomiting | 3.0% | 6.2% |
| Diarrhea or constipation | Below 7.5% | Below 7.5% |
| Discontinuation because of GI adverse events | 1.5% | Not reported in the release |
More than 75% of gastrointestinal adverse events were reported as mild. Roche’s summary was that petrelintide “achieved meaningful weight loss with a well-tolerated dosing approach.” A trial of fewer than 500 people cannot reveal every uncommon reaction or establish long-term safety, which is one purpose of the Phase 3 program.
How the Phase 3 ZUPREME program is designed
According to Zealand Pharma’s September 22, 2026 announcement, the Phase 3a program comprises three randomized, double-blind, placebo-controlled trials designed to support marketing applications for petrelintide monotherapy in chronic weight management. In all three, the primary efficacy endpoint is percentage change in body weight from baseline to week 64. Secondary endpoints include waist circumference, HbA1c (glycated hemoglobin), cardiometabolic risk factors, physical functioning and eating behaviors.
| Trial | Main population | Approx. enrollment | Key timing |
|---|---|---|---|
| ZUPREME-3 | Overweight or obesity without type 2 diabetes | 3,900 | 12-week dose escalation; maintenance to week 64; safety follow-up to week 77; optional open-label extension |
| ZUPREME-4 | Overweight or obesity with type 2 diabetes | 600 | Same structure as ZUPREME-3 |
| ZUPREME-5 | Overweight or obesity with established cardiovascular disease, with or without type 2 diabetes | 2,500 | Week-64 weight assessment, then an event-maintenance phase; up to 3 years in total |
ZUPREME-3
ZUPREME-3 is the largest trial, at about 3,900 participants without type 2 diabetes. Eligible participants have obesity (BMI of at least 30 kg/m²) or overweight (BMI 27 to below 30 kg/m²) with at least one weight-related comorbidity.
ZUPREME-4
ZUPREME-4 enrolls about 600 participants with overweight or obesity and type 2 diabetes. Anti-obesity medicines can perform differently in people with diabetes, and the trial will also measure HbA1c alongside weight change.
ZUPREME-5
ZUPREME-5 enrolls about 2,500 participants with overweight or obesity and established cardiovascular disease, with or without type 2 diabetes. After the week-64 weight assessment, participants continue into an event-maintenance period, and Zealand states the trial can last up to three years.
Petrelintide vs GLP-1 weight-loss drugs
Petrelintide and GLP-1 medicines act through different receptors. GLP-1 receptor agonists such as semaglutide mimic the incretin hormone GLP-1, affecting appetite, glucose regulation and gastrointestinal function. Petrelintide is an amylin analog and acts on the amylin pathway.
No head-to-head trial has compared petrelintide with approved GLP-1 or GLP-1/GIP medicines, so no conclusion about relative efficacy or tolerability is available. The sponsors are also developing petrelintide as a possible partner to incretin drugs rather than only as an alternative to them.
Petrelintide plus enicepatide: the combination program
The Roche–Zealand agreement covers combination products as well as petrelintide alone. The partners are developing petrelintide with enicepatide (formerly CT-388), Roche’s investigational once-weekly dual GLP-1/GIP receptor agonist. The rationale is that an amylin analog and an incretin drug act through different pathways that may complement each other.
Roche has registered a Phase 2 dose-finding study of petrelintide with enicepatide in adults with obesity or overweight, ZYNERGY (NCT07589686). Zealand states that the Phase 2 combination trial was planned to begin in the second half of 2026 (Zealand Pharma, Sept. 22, 2026). The companies describe the combination as aimed at people who need greater weight loss or improved glycemic control than amylin monotherapy provides. Whether the combination offers a favorable benefit–risk balance will depend on trial results.
The Roche and Zealand Pharma agreement
Roche and Zealand announced a global collaboration and license agreement for petrelintide on March 12, 2025. Zealand receives upfront payments of $1.65 billion ($1.4 billion at closing and $250 million over the first two anniversaries), plus eligibility for up to $1.2 billion in development milestones, mainly tied to starting Phase 3, and $2.4 billion in sales milestones, for a total of up to $5.3 billion. The companies co-commercialize petrelintide in the United States and Europe and share profits and losses 50/50 there; Roche holds exclusive commercialization rights elsewhere and is responsible for commercial manufacturing and supply (Roche, March 12, 2025).
Open questions after Phase 2
Phase 2 addressed whether petrelintide could produce meaningful weight loss with acceptable short-term tolerability. Several questions remain for Phase 3 and later work:
- Replication. Whether the effect seen in one Phase 2 arm (a mean of up to 10.7% at week 42) holds across thousands of participants.
- Durability. Whether weight reduction is maintained over longer periods, given that obesity is a chronic condition.
- Safety. Larger and longer exposure can reveal adverse events too uncommon to appear in a 493-person trial.
- Type 2 diabetes. Roche’s March 2026 release stated that topline results from the Phase 2 ZUPREME-2 trial, in people with overweight or obesity and type 2 diabetes, were expected in the second half of 2026. The sources reviewed for this update do not report those results.
- Cardiovascular outcomes. ZUPREME-5 and later studies are intended to add evidence in people with established cardiovascular disease.
- Place in treatment. Placebo-controlled trials establish efficacy and safety. Comparative studies and real-world data would be needed to show which patients might be suited to amylin therapy rather than existing incretin treatments.
What happens next for petrelintide?
The program has moved from mid-stage development into registrational Phase 3 testing, and recruitment for ZUPREME-3, -4 and -5 is the next stage. ZUPREME-2 and the ZYNERGY combination study are further near-term sources of data. No regulatory approval date has been set: enrollment, follow-up, data analysis and regulatory review must all take place before petrelintide could be marketed.
Frequently asked questions about petrelintide
What is petrelintide?
Petrelintide is an investigational long-acting amylin analog being developed by Zealand Pharma and Roche for chronic weight management. It is designed as a once-weekly subcutaneous injection and is in Phase 3 development.
Is petrelintide a GLP-1 drug?
No. Petrelintide is an amylin analog, not a GLP-1 receptor agonist. Amylin is a pancreatic hormone involved in satiety and metabolic regulation, so amylin-based drugs act through a different pathway from incretin therapies.
How much weight loss did petrelintide produce?
In the Phase 2 ZUPREME-1 study, the most effective treatment group reached up to 10.7% mean body-weight reduction at week 42 under the efficacy estimand, compared with 1.7% with placebo. Individual results varied, and Phase 3 trials are needed to confirm the effect in larger populations.
Is petrelintide in Phase 3?
Yes. Zealand Pharma announced on September 22, 2026 that the global registrational Phase 3 ZUPREME program had been initiated. It consists of ZUPREME-3, ZUPREME-4 and ZUPREME-5.
How many people will take part in petrelintide Phase 3 trials?
About 7,000 participants are expected across the three trials: roughly 3,900 in ZUPREME-3, 600 in ZUPREME-4 and 2,500 in ZUPREME-5.
What are the most common petrelintide side effects?
In ZUPREME-1, gastrointestinal events were the most frequent, and most were mild. Zealand reported nausea in 19.6% of petrelintide-treated participants versus 6.2% with placebo, vomiting in 3.0% versus 6.2%, and gastrointestinal discontinuation in 1.5%. Larger trials are needed to define the safety profile.
Who makes petrelintide?
Zealand Pharma discovered petrelintide, and it is now co-developed with Roche under a global collaboration and license agreement announced in March 2025.
Is petrelintide approved by the FDA?
No. Petrelintide is investigational and has not been approved by the U.S. Food and Drug Administration or any other regulatory authority for weight management.
How is petrelintide different from semaglutide?
Semaglutide activates GLP-1 receptors, whereas petrelintide is designed around the amylin pathway. Both can affect appetite and food intake. No head-to-head trial has compared them.
When will petrelintide be available?
No launch or approval date has been announced. Phase 3 trials must generate efficacy and safety data before regulatory applications can be submitted and reviewed.
Summary
Petrelintide is an investigational once-weekly amylin analog. Phase 2 ZUPREME-1 reported up to 10.7% mean weight reduction at week 42 with mostly mild gastrointestinal adverse events, and Zealand Pharma and Roche initiated a three-trial registrational Phase 3 program on September 22, 2026. It has not been approved anywhere, and Phase 3 results will determine its efficacy, safety and place among obesity treatments. Related coverage: enicepatide (CT-388), the GLP-1/GIP agonist being combined with petrelintide in the Phase 2 ZYNERGY study.
Sources
- Zealand Pharma (Sept. 22, 2026): Initiation of the registrational Phase 3 ZUPREME program of petrelintide. Phase 3 design, enrollment and endpoints.
- Roche (March 5, 2026): Positive Phase II results for petrelintide. ZUPREME-1 design, weight loss and adverse events.
- Zealand Pharma (June 5, 2026): New ZUPREME-1 data at the ADA 2026 Scientific Sessions. Adverse-event rates and cardiometabolic measures.
- Roche (March 12, 2025): Collaboration and licensing agreement with Zealand Pharma.
- ClinicalTrials.gov NCT07589686: ZYNERGY, petrelintide with enicepatide.
- Zealand Pharma: Petrelintide pipeline page.
- Alhazmi & le Roux (2026), Diabetes Obes Metab: Amylin analogs, the next major class of weight loss therapy (PubMed 42452898).
- Bailey et al. (2026), Peptides: Long-acting amylin-related peptides as therapies for obesity and type 2 diabetes (PubMed 41747885).
- Fischer & Borner (2026), Pharmacol Res: Beyond GLP-1, amylin-based pharmacotherapy and better-tolerated weight-loss drugs (PubMed 42586227).