Amycretin · Pep IQ

Origin & What It Is

One molecule, two pathways — and an oral option

Amycretin is Novo Nordisk's most structurally ambitious obesity compound: a single peptide backbone that simultaneously activates both GLP-1 receptors and amylin/calcitonin receptors. The comparison point is CagriSema — Novo's fixed-dose combination of cagrilintide (long-acting amylin analogue) plus semaglutide. Amycretin aims to deliver the same dual receptor engagement as CagriSema, but in one molecule rather than two co-injected compounds.

The molecule is acylated with a C18 diacid at position K37 — the same chemical engineering used in semaglutide to extend half-life through albumin binding. This gives amycretin a once-weekly SubQ profile. A separate oral formulation (once-daily tablet) has also been developed, using the same transcellular gastric absorption technology as oral semaglutide — and the Phase 1 oral data (13% weight loss at 12 weeks vs 6% for semaglutide at the same timepoint) was striking enough to convince Novo to develop both formulations simultaneously into Phase 3.

The Phase 1 Lancet paper (July 2025, Gasiorek et al.) and the Phase 1b/2a Lancet paper (July 2025, Dahl et al.) published simultaneously represent the most up-to-date peer-reviewed amycretin data. Phase 3 (REDEFINE programme for obesity) initiated in 2025 with results expected 2026–27. Phase 3 T2D programme also announced.

Phase 1

First-in-human

✅ Complete · Lancet 2025

Phase 1b/2a

Proof-of-concept

✅ 22% loss · Lancet 2025

Phase 3

REDEFINE

🔄 Ongoing · 2025–27

FDA

Submission

⏳ Est. 2027–28

Science & Mechanism

GLP-1 + amylin — complementary, not redundant

Dual Mechanism — Why Amylin Adds to GLP-1

1

GLP-1 receptor (appetite, insulin): Central appetite suppression via hypothalamic GLP-1Rs. Glucose-dependent insulin secretion. Delayed gastric emptying. The proven mechanism behind semaglutide and tirzepatide's efficacy — amycretin's GLP-1 component replicates this baseline.

2

Amylin receptor (satiety timing, glucagon): Amylin is co-secreted with insulin from pancreatic beta cells in response to meals. It reduces appetite independently of GLP-1 pathways, slows gastric emptying through a separate mechanism, and suppresses postprandial glucagon. The amylin component adds satiety signalling that operates via different neural circuits — explaining why the combination produces greater weight loss than either alone.

3

No weight plateau at 36 weeks: In the Phase 1b/2a study, weight loss had not plateaued at the end of the maintenance period — both the 20mg and 60mg cohorts showed continued downward trajectory. This is unusual in obesity pharmacology and suggests the dual mechanism may sustain weight loss longer than single-target GLP-1 agonists.

4

Oral bioavailability via transcellular gastric absorption: The oral formulation exploits the same mechanism as oral semaglutide (Rybelsus) — a carrier molecule enables transcellular absorption through the gastric mucosa. The oral amycretin Phase 1 data (13% weight loss at 12 weeks vs 6% for semaglutide at the same point) was described as exceeding expectations.

The key data from Dahl et al. (Lancet, July 2025): once-weekly subcutaneous amycretin in 125 adults with overweight/obesity (BMI 27–39.9). The highest-dose groups: 60mg reached 24.3% weight loss at 36 weeks; 20mg reached 22.0%. All doses showed significantly greater weight loss than placebo (p<0.0001). Safety profile consistent with GLP-1 and amylin agonists — GI adverse events predominantly mild to moderate. No novel safety signals. No deaths. Weight loss still descending at end of maintenance — no plateau observed. Phase 3 T2D data (Phase 2 published): subcutaneous up to 14.5% at 36 weeks; oral up to 10.1% at 36 weeks; HbA1c reductions up to 1.8%.

How amycretin compares: Semaglutide at 36 weeks: ~15% weight loss (STEP 1). Tirzepatide at 36 weeks: ~20% (SURMOUNT-1). Retatrutide Phase 3: 28.7% at 68 weeks. Amycretin 20mg at 36 weeks: 22.0% — still descending. Direct Phase 3 head-to-head comparisons will be the decisive test. The oral formulation, if it reaches 15–20% weight loss in Phase 3, would be genuinely transformative for obesity treatment.

Benefits & Evidence to Date

What the data shows

⚖️

Weight loss — 22–24% at 36 weeks

Phase 1b/2a (n=125): 22.0% at 20mg and 24.3% at 60mg over 36 weeks. No weight plateau observed. Oral Phase 1: 13% at 12 weeks (vs 6% for semaglutide). Published Lancet July 2025.

● Moderate — Phase 1b/2a · Phase 3 underway

🩸

Glycaemic control (T2D)

Phase 2 T2D: HbA1c reduced up to 1.8% (SubQ), 1.5% (oral). 77.6% reached HbA1c <7%; 62.6% reached ≤6.5%. Phase 3 T2D programme now initiated.

● Moderate — Phase 2 data

💊

Oral formulation

First oral amylin + GLP-1 dual agonist. Phase 1 oral: 13% weight loss at 12 weeks — 2× semaglutide oral at same timepoint. Daily tablet vs weekly injection as an alternative delivery route.

● Limited — Phase 1 only · Phase 3 oral ongoing

Safety to Date

Safety profile — consistent with GLP-1 class

Moderate

GI adverse events — nausea, vomiting, diarrhoea, constipation. Most common (81% of those reporting any AE had GI events). Mild to moderate severity. Consistent with incretin class profile. Higher frequency than observed in Phase 1 vs later-stage trials is expected.

Unknown

Long-term safety not yet established — no Phase 3 safety data yet. Phase 3 trials will characterise long-term safety across diverse populations. Same class warnings as GLP-1 agonists apply (thyroid C-cell, pancreatitis, etc.) until proven otherwise.