Petrelintide

Origin and structure

Amylin is a hormone of 37 amino acids that the insulin-producing beta cells of the pancreas release together with insulin after a meal. It is a difficult starting point for a medicine, because human amylin readily clumps into amyloid fibrils and degrades in solution. Pramlintide (Symlin), approved in the US in 2005 and no longer made since 2025, prevents the clumping with three prolines, but its effect lasts only a few hours, and like related amylin analogues it has to be formulated in an acidic solution.

Petrelintide comes from the Danish company Zealand Pharma, which also invented lixisenatide and, together with Boehringer Ingelheim, survodutide; in development it was called ZP8396. Chemists at Zealand and Boehringer Ingelheim described its design in 2025 (Fischer Munch et al., J Med Chem). They kept human amylin as the backbone and took a different route from pramlintide. Two N-methyl groups, on glycine 24 and isoleucine 26 in the fibril-prone middle of the chain, take the place of pramlintide's prolines against clumping. Most of the asparagines, which break down easily, were replaced or, at positions 21 and 22, removed. The disulfide bridge near the start of the chain became a more stable lactam bridge, and the tyrosine at the end became hydroxyproline, which made the peptide more potent in cell tests. A 20-carbon fatty acid, attached through a glutamic-acid linker at the start of the chain, was added to lengthen its half-life.

Together these changes keep it stable at a near-neutral pH, without forming fibrils, and in laboratory tests it could be mixed in one solution with semaglutide without breaking down faster or either peptide clumping. That was a deliberate goal: a neutral formulation makes combination products in a single injection possible. In rats its half-life was 33.8 hours, which the developers took to mean one injection a week in people; in the first human trials it turned out to be about 10 days.

How it works

Petrelintide imitates amylin. Amylin makes people feel full sooner, slows the emptying of the stomach and holds back the release of glucagon after a meal, effects that run mainly through the hindbrain, especially the area postrema. Its receptors are built from the calcitonin receptor: on its own, or paired with one of three helper proteins (RAMP1, 2 or 3) to form amylin receptors 1 to 3.

In cell tests petrelintide activated amylin receptor 3 about as potently as human amylin and the calcitonin receptor about ten times more potently; the report on the first human trials describes it as a potent agonist of amylin receptors 1 and 3 and of the calcitonin receptor. In lean rats a single injection lowered body weight by about 10% within four days. In rats made obese on a rich diet, injections every other day for 20 days reduced food intake and held back weight gain in a dose-dependent way: at the highest doses weight rose about 4%, against 16.9% with an inactive injection.

Amylin and GLP-1 act through different receptors and brain circuits, and combining the two gave more weight loss than either alone in the trials of cagrilintide with semaglutide. That is the reasoning behind testing petrelintide together with Roche's GLP-1 and GIP agonist enicepatide (CT-388). The developers also cite rat data in which petrelintide reduced fat mass while sparing lean mass. Whether that holds in people has not been shown.

Is petrelintide approved?

No. No medicine containing petrelintide has been approved in the EU, the US or anywhere else, and no marketing application has been filed. In the Netherlands it is not a registered medicine, so it may not be sold or promoted for use in people. Our shop does not sell petrelintide.

• Partnership: on 12 March 2025 Zealand Pharma and Roche signed a collaboration and licence agreement to develop and sell petrelintide together, on its own and in combinations such as one with enicepatide (CT-388). Roche agreed to pay USD 1.65 billion upfront, in a deal worth up to USD 5.3 billion in total. The two companies share profits equally in the US and Europe, and Zealand receives royalties on sales elsewhere.
• Phase 3: on 22 September 2026 Zealand announced the start of the ZUPREME phase 3 programme: three placebo-controlled trials with about 7,000 participants in total, sponsored by Roche, all measuring weight change after 64 weeks. ClinicalTrials.gov expects the main phase of ZUPREME-3 and ZUPREME-4 to finish in late 2028; the companies have not said when they plan to apply for approval.
• EU and the Netherlands: no application has been made to the EMA. The first human trials ran in Germany, ZUPREME-1 had sites in Poland and Romania, and later small phase 1 trials were set up in Germany, Poland and Slovakia. The phase 3 trials also carry EU trial numbers, but their European sites had not been made public by late October 2026, and no Dutch site has been announced.
• US: petrelintide is an investigational drug and is not approved for any use.
• Sport: WADA class S0 prohibits at all times any substance that no other section of the list covers and that has no current approval for human therapeutic use anywhere, explicitly including drugs still in clinical development. Petrelintide is not named on the list, but it falls under this class for as long as no product containing it is approved anywhere. In the Netherlands the Dopingautoriteit applies the same list, where the class is called 'niet erkende stoffen'.

What the research shows

All human data come from trials funded by Zealand Pharma or Roche. Two phase 1 trials and the first phase 2 trial are published in full; the second phase 2 trial has so far been reported only in a company announcement, and the phase 3 trials started in September 2026. The main results:

• Phase 1 (Brændholt Olsen et al., Diabetes Obes Metab 2026): two placebo-controlled trials at one centre in Neuss, Germany, with 133 people randomised. Single and repeated doses were tested in lean or overweight men, then 16 weekly injections in 48 adults with overweight or obesity (12 per petrelintide group). After 16 weeks body weight had fallen 4.8%, 8.6% and 8.3% in the three petrelintide groups, against 1.7% on placebo, and waist circumference by 5.0 to 7.6 cm against 1.9 cm. These trials were built to test safety, not weight loss.
• ZUPREME-1 (Garvey et al., Lancet Diabetes Endocrinol 2026): 493 adults without type 2 diabetes, with obesity or with overweight plus high blood pressure or abnormal blood lipids, at 32 sites in the US, Poland and Romania, randomised 5 to 1 to one of five doses of petrelintide or placebo for 42 weeks, alongside a reduced-calorie diet and more physical activity. At 28 weeks, the primary endpoint, weight fell 7.9% to 9.8% depending on dose against 1.7% on placebo, estimated as if everyone had kept taking the treatment: 6.2 to 8.1 percentage points more than placebo.
• ZUPREME-1 at 42 weeks: weight kept falling, by 8.7% to 10.7% depending on dose against 1.7% on placebo, according to Zealand's figures. The middle dose gave the most; the two higher doses did not add to it. Roche reported that counting everyone, regardless of whether they kept taking the treatment, gave largely the same picture. By Zealand's subgroup figures for the most effective dose, women lost about 6 percentage points more than men, and European participants about 3 points more than those in the US.
• ZUPREME-2 (topline results, 7 October 2026, not yet published in a journal): 220 adults in the US with overweight or obesity and type 2 diabetes, on metformin with or without an SGLT2 inhibitor, with a mean BMI of 36.3 and a mean HbA1c of 8.0%. After 28 weeks on one of three doses, weight fell 7.4% to 9.2% against 2.0% on placebo, and HbA1c fell by up to 0.65 percentage points while it rose 0.23 points on placebo.
• Under way: ZUPREME-3 (about 3,900 adults without diabetes, with obesity or with overweight plus a weight-related condition), ZUPREME-4 (about 600 with type 2 diabetes) and ZUPREME-5 (about 2,500 with established heart or vascular disease, lasting up to 3 years), each against placebo; ZYNERGY, a phase 2 trial of petrelintide with enicepatide in about 486 adults, which ClinicalTrials.gov listed as not yet recruiting in October 2026; and a phase 1 study in people with reduced liver function.

Side effects and warnings

As with other amylin and GLP-1 drugs, the main side effects are gastrointestinal. In ZUPREME-1, 20% of participants on petrelintide reported nausea against 6% on placebo, while vomiting (3% against 6%), diarrhoea (7% against 7%) and constipation (7% against 4%) were about as common as on placebo. According to Zealand, 80% of the nausea events were mild, and Roche reported almost none after participants reached their maintenance dose. Over the 42 weeks, 4.5% of those on petrelintide stopped because of side effects, against 4.9% on placebo, and no deaths were reported. In ZUPREME-2, 1.9% stopped because of gastrointestinal side effects, against 1.7% on placebo.

In the phase 1 trials there were no serious or severe side effects and no antibodies against the drug. Decreased appetite was reported more often than on placebo, which fits the way amylin works, and the pulse rate fell by about 5 beats per minute, a change also seen with other long-acting amylin analogues. Mild injection-site reactions occurred mainly in participants who needed up to three injections per dose.

What is not known: the longest controlled data cover 42 weeks, in about 400 people on petrelintide, so rarer or long-term risks cannot be judged yet, and there are no data on heart outcomes, pregnancy or children. The older amylin analogue pramlintide carries a US boxed warning for severe low blood sugar when used with mealtime insulin. The published petrelintide trials did not include people using insulin; ZUPREME-4 admits people on basal insulin.

Petrelintide versus cagrilintide

Both are once-weekly amylin analogues with a 20-carbon fatty-acid chain, and both activate amylin receptors and the calcitonin receptor. They differ in how they keep amylin from clumping: cagrilintide, from Novo Nordisk, keeps pramlintide's prolines, while petrelintide uses two N-methyl groups and stays stable at a near-neutral pH, so that it can be combined with other peptides in one injection. Its half-life in people is about 10 days, against about a week for cagrilintide.

No trial has compared them directly. Cagrilintide alone lowered weight by an estimated 11.8% over 68 weeks in REDEFINE 1, and petrelintide by up to 10.7% over 42 weeks in ZUPREME-1, but the trials differ in length, population and design. Cagrilintide is further along: it has phase 3 results and, as part of CagriSema, an FDA filing, while the phase 3 trials of petrelintide only began in 2026. Each is also being developed with an incretin drug: cagrilintide with semaglutide, petrelintide with Roche's enicepatide.

Frequently asked questions

Is petrelintide approved, and when could it come on the market?

It is not approved anywhere and no application has been filed. Zealand Pharma and Roche started three phase 3 trials in September 2026, with about 7,000 participants and the main result after 64 weeks; ClinicalTrials.gov expects the main phase of ZUPREME-3 and ZUPREME-4 to finish in late 2028. An application to the EMA or FDA would follow those results, and the companies have not given a filing date.

How much weight do people lose on petrelintide?

In ZUPREME-1, adults without diabetes lost 7.9% to 9.8% of their body weight after 28 weeks, depending on dose, and up to 10.7% after 42 weeks, against 1.7% on placebo, estimated as if everyone had kept taking the treatment. In ZUPREME-2, adults with type 2 diabetes lost 7.4% to 9.2% after 28 weeks against 2.0% on placebo. Weight was still falling when ZUPREME-1 ended; the phase 3 trials run to week 64.

What is the difference between petrelintide and cagrilintide?

Both are once-weekly amylin analogues with a fatty-acid chain. Cagrilintide, from Novo Nordisk, keeps pramlintide's prolines against clumping, while petrelintide, from Zealand Pharma and Roche, uses N-methyl groups and stays stable at a near-neutral pH, which allows it to be mixed with other peptides. Cagrilintide is further along, with phase 3 results and an FDA filing as part of CagriSema. No trial has compared the two directly.

Is petrelintide legal in the Netherlands, and is it allowed in sport?

It is not a registered medicine in the Netherlands or anywhere else, so it may not be sold, advertised or supplied for use in people. DutchPeptides does not sell it. For athletes under anti-doping rules it is prohibited at all times as a non-approved substance (WADA class S0), which the Dopingautoriteit applies in the Netherlands.

What are the side effects of petrelintide?

Mainly nausea, mostly mild and during the weeks the dose is raised: 20% against 6% on placebo in ZUPREME-1. Vomiting, diarrhoea and constipation were about as common as on placebo, and 4.5% stopped because of side effects against 4.9% on placebo. The phase 1 trials found no serious side effects. Data beyond 42 weeks, and on heart outcomes or rare side effects, do not exist yet.

Storage and handling

Store according to product-label instructions and batch handling notes. Lyophilized research peptides are commonly kept dry, protected from light, and handled with clean laboratory technique.

References

Checked against these sources on 28 October 2026.

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