Amycretin: Novo's Next-Gen Dual Amylin/GLP-1 Drug

Amycretin is Novo Nordisk’s next-generation obesity candidate — a single molecule that activates both the GLP-1 receptor and the amylin receptor. The phase 1 oral readout (Gasiorek 2025 Lancet^[1]) reported −13.1% body weight at 12 weeks across all active doses vs −1.1% on placebo. The phase 1b/2a subcutaneous readout (Dahl 2025 Lancet^[2]) extended out to 36 weeks and reported up to −22.0% body weight at the highest dose. That puts amycretin in the same magnitude class as retatrutide and CagriSema — with the structural advantage of being a unimolecular co-agonist rather than two drugs in one pen. This article walks through the published data, the trajectory to phase 3, and how amycretin compares to everything else Novo and Lilly have in the pipeline.

The honest summary

• Amycretin is a unimolecular dual agonist. One molecule binds both the GLP-1 receptor and the amylin (calcitonin) receptor — not a co-formulation of two separate drugs. Both oral (tablet) and subcutaneous (weekly injection) formulations are in clinical development (Gasiorek 2025^[1], Dahl 2025^[2]).
• Oral amycretin phase 1: −13.1% body weight at 12 weeks across all active dose arms vs −1.1% on placebo (Gasiorek 2025 Lancet^[1]). The trial was a first-in-human single-ascending-dose and multiple-ascending-dose study, so the absolute magnitude at 12 weeks understates what longer dosing will likely produce.
• Subcutaneous amycretin phase 1b/2a: −22.0% body weight at 36 weeks at the top dose (Dahl 2025 Lancet^[2]). That number alone puts amycretin ahead of every approved obesity drug on a magnitude basis at the timepoints reported.
• Mechanism rationale: amylin — the peptide co-secreted with insulin from pancreatic beta cells — suppresses appetite via the area postrema and slows gastric emptying. GLP-1 adds satiety, insulin release, and glucagon suppression. Stacking the two mechanisms in one molecule is the entire bet (Khoo and Tan 2025 Lancet editorial^[3]).
• Phase 3 trajectory: Novo has guided to a large phase 3 program with first regulatory submissions in the 2027–2028 window. The most likely brand naming mirrors the REDEFINE family Novo is using for CagriSema.

What amycretin actually is, pharmacologically

Amycretin is a long-acting peptide engineered to bind two receptors simultaneously. The GLP-1 receptor side of the molecule shares its core mechanism with semaglutide, liraglutide, and tirzepatide’s GLP-1 component: glucose-dependent insulin secretion, glucagon suppression, delayed gastric emptying, and hypothalamic satiety signaling. The amylin (calcitonin-family) receptor side recapitulates what pramlintide (Symlin) and cagrilintide do: it activates amylin receptors in the area postrema and the dorsal vagal complex, which independently suppress appetite and slow gastric emptying through a separate central pathway from GLP-1.

The Khoo and Tan editorial in the same Lancet issue^[3] framed amycretin as a logical next step in the multi-receptor agonism program that produced tirzepatide (GLP-1 + GIP), retatrutide (GLP-1 + GIP + glucagon), and the CagriSema co-formulation (GLP-1 + amylin as two molecules). The key engineering question for amycretin is whether a single molecule can deliver balanced agonism at both receptors with adequate selectivity to avoid the dose-limiting nausea that often appears when amylin activity is high.

The phase 1 oral readout: Gasiorek 2025 Lancet

Gasiorek 2025^[1] reported the first-in-human phase 1 oral amycretin trial — a double-blind, randomized, placebo-controlled single-ascending-dose and multiple-ascending-dose study in adults with overweight or obesity. The headline magnitude readout was approximately −13.1% body weight at 12 weeks across the active dose arms vs −1.1% on placebo. That separation — roughly 12 percentage points in 12 weeks of phase 1 dosing — is substantially steeper than what STEP-1 (Wilding 2021^[5]) or SURMOUNT-1 (Jastreboff 2022^[4]) showed at comparable early timepoints. The safety signal was consistent with the GLP-1 class: gastrointestinal adverse events (nausea, vomiting, decreased appetite) were the most common and dose-related, with no unexpected signals.

The structural difference vs Rybelsus — the only currently approved oral GLP-1 — is that oral amycretin does not rely on Rybelsus’s SNAC permeation enhancer in the same way, and the molecule was optimized for oral bioavailability from the start rather than being a reformulated injectable. That matters for the consistency of plasma exposure at standard doses.

The phase 1b/2a subcutaneous readout: Dahl 2025 Lancet

Dahl 2025^[2] reported the subcutaneous amycretin phase 1b/2a trial — a longer-duration study running out to 36 weeks at the top dose. The headline number, −22.0% body weight at 36 weeks, is the key data point everyone cites. For magnitude reference, that is essentially identical to the SURMOUNT-1 tirzepatide 15 mg arm at 72 weeks (−22.5% body weight in Jastreboff 2022^[4]) — achieved in half the dosing duration. The dose response was clean and the safety signal again was consistent with class expectations.

The 36-week timepoint matters because most phase 1b/2a readouts stop earlier, and the curve had not visibly plateaued in the published data. Extrapolation to a full 72-week phase 3 readout is speculative — the trajectory could continue steeply or could flatten — but a reasonable upper-bound estimate for phase 3 subcutaneous amycretin is in the −25% to −30% range, putting it head-to-head with retatrutide.

Unimolecular vs bimolecular: why the structure matters

CagriSema is a co-formulation: two separate molecules (cagrilintide + semaglutide) delivered in one pen. The REDEFINE 1 trial (Garvey 2025 NEJM^[7]) reported 20.4% mean weight loss (22.7% adherent estimand) at 68 weeks in adults with overweight or obesity without diabetes; REDEFINE 2 (Davies 2025 NEJM^[8]) reported 13.7% vs 3.4% placebo in adults with type 2 diabetes. Amycretin achieves the same kind of dual GLP-1 + amylin agonism with a single peptide.

The practical advantages of a unimolecular co-agonist are manufacturing simplicity (one peptide instead of two), cleaner pharmacokinetics (one half-life, one exposure curve instead of two), and lower production cost at scale. The practical disadvantage is rigid dose ratios: a co-formulation like CagriSema can in principle be re-titrated to change the ratio of cagrilintide to semaglutide, while a unimolecular agonist has a fixed receptor-binding ratio baked into the molecule. Whether Novo can balance the amylin and GLP-1 receptor potency well enough to match what optimized bimolecular ratios achieve is the central uncertainty.

Magnitude: amycretin vs the approved and pipeline drugs

Safety profile and the amylin question

Published amycretin safety data so far look consistent with the broader GLP-1 class: the dominant adverse events are gastrointestinal (nausea, vomiting, decreased appetite, constipation), dose-related, and most pronounced during the titration period. The Gasiorek^[1] and Dahl ^[2] papers did not flag any unexpected signals attributable to the amylin component specifically. Pramlintide (the only currently approved amylin analog) has a long safety record including hypoglycemia risk when combined with insulin; amycretin is not currently positioned for use with insulin so that interaction is less relevant.

Two open safety questions remain. First, whether the amylin component adds meaningful nausea on top of what GLP-1 agonism alone produces; pramlintide’s label flags nausea as the single most common adverse event, and combined amylin + GLP-1 activation at full doses could be limiting. Second, whether long-duration amylin agonism produces any receptor desensitization that erodes efficacy — that question can only be answered in the phase 3 program.

Phase 3 trajectory and brand-name speculation

Novo has not yet published the full phase 3 program design for amycretin, but the public signaling and Capital Markets Day positioning suggest a large multi-trial program with both oral and subcutaneous arms. By analogy to the REDEFINE family used for CagriSema, amycretin phase 3 trials will likely use a similar naming convention. Likely composition: a non-diabetic adult-obesity trial (the STEP-1/SURMOUNT-1 analog), a type 2 diabetes weight-management trial (the STEP-2/SURMOUNT-2 analog), and a cardiovascular-outcomes trial (the SELECT/SUMMIT analog). First regulatory submissions are most plausibly in the 2027–2028 window, with commercial launch in 2028–2029.

Pricing speculation is exactly that — speculation — but the base case is launch parity with current Novo injectable obesity drugs (approximately $1,349 per month retail list price), with the eventual price compression driven by competition from Lilly’s pipeline (retatrutide, orforglipron) and the entry of generic and biosimilar semaglutide products after 2031–2032 patent expiry in the major markets.

How patients and clinicians should think about amycretin today

Amycretin is not prescribable, not compoundable from legitimate research-peptide sources, and not commercially available in any form. The compounded peptide market does not currently sell amycretin because the molecule is too early in development and the API is not available outside of Novo’s clinical supply chain. Anyone advertising “amycretin” in a research-peptide marketplace is almost certainly selling something else (frequently relabeled cagrilintide or retatrutide). The honest answer to “can I get amycretin?” in 2026 is no.

For current treatment decisions, the relevant drugs are the approved ones: Wegovy (semaglutide 2.4 mg, STEP-1^[5]), Zepbound (tirzepatide, SURMOUNT-1^[4]), and the soon-to-be-approved CagriSema (cagrilintide + semaglutide, REDEFINE 1 and REDEFINE 2^[7][8]). For patients tracking the pipeline, the head-to-head race that will define the late-2020s obesity-drug market is amycretin vs retatrutide (Jastreboff 2023 NEJM^[6]) — Novo’s unimolecular dual agonist vs Lilly’s unimolecular triple agonist, with phase 3 readouts expected in roughly the same window.

Related research and tools

• CagriSema REDEFINE trial results — the predecessor bimolecular amylin/GLP-1 combination, with the published phase 3 magnitude
• Retatrutide triple-agonist evidence — Lilly’s GLP-1/GIP/glucagon competitor and the phase 2 magnitude (−24.2% at 48 weeks)
• GLP-1 pipeline overview — the broader landscape including survodutide, maridebart-cafraglutide, and ecnoglutide
• Retatrutide vs tirzepatide head-to-head — the magnitude comparison most relevant for benchmarking amycretin’s phase 3 trajectory
• Wegovy (semaglutide 2.4 mg) — the STEP-1 reference standard for new obesity drugs
• Zepbound (tirzepatide) — the current best-in-class approved obesity drug