Cagrilintide
High EvidenceA long-acting amylin analog studied for appetite regulation; NDA filed for CagriSema (cagrilintide + semaglutide) combination in December 2025, with FDA review expected in 2026.
What It Is
Cagrilintide is a long-acting analog of the hormone amylin, which is naturally co-secreted with insulin from pancreatic beta cells. It works by slowing gastric emptying, promoting satiety, and reducing glucagon secretion. It is the amylin component of CagriSema, a once-weekly fixed-dose combination of cagrilintide 2.4 mg and semaglutide 2.4 mg. On December 18, 2025, Novo Nordisk submitted a New Drug Application (NDA) to the FDA for CagriSema for chronic weight management — making it the first GLP-1/amylin combination to reach NDA stage. Both pivotal Phase 3 trials were published in the New England Journal of Medicine in 2026. In REDEFINE-1, CagriSema achieved 20.4% mean weight loss at 68 weeks, with 60% of participants losing ≥20% and 23% losing ≥30% body weight. In REDEFINE-2 (adults with obesity and T2D), CagriSema achieved 13.7% mean weight loss and 73.5% of participants reached HbA1c ≤6.5% vs 15.9% with placebo. Gastrointestinal AEs affected 79.6% of the CagriSema group but were mostly transient and mild-to-moderate. CagriSema initially fell short of an internal 25% weight loss target, which briefly pressured Novo Nordisk's stock price, though the 22.7% on-treatment weight loss still exceeds most competitors. The FDA is expected to render a decision by approximately October 2026 under standard review timelines. In April 2026, Novo Nordisk announced positive headline results from REIMAGINE-2, a Phase 3 trial in adults with overweight or obesity and type 2 diabetes. CagriSema 2.4 mg/2.4 mg demonstrated superior HbA1c reduction of 1.91 percentage points versus 1.76 with semaglutide 2.4 mg alone (from a baseline of 8.2%), and superior weight loss of 14.2% versus 10.2% with semaglutide alone (from a baseline of ~101 kg) at 68 weeks. These results confirm CagriSema's incremental benefit over its GLP-1 component alone in the T2D population.
Proposed Mechanisms
- Activates amylin receptors in the area postrema to reduce appetite and caloric intake
- Slows gastric emptying, prolonging post-meal satiety signals
- Reduces post-prandial glucagon secretion, improving glycemic control
- Complements GLP-1 agonism through an independent anorexigenic pathway
- Long-acting albumin-binding design extends half-life to once-weekly dosing
Evidence Snapshot
| Study Type | Model | Outcome | Link |
|---|---|---|---|
| Human (Phase 3) | REDEFINE-1: Adults with obesity, no T2D (n=3,417) | 20.4% mean weight loss at 68 weeks vs 3.0% placebo | Source |
| Human (Phase 3) | REDEFINE-2: Adults with obesity + T2D (n=1,507) | 13.7% mean weight loss at 68 weeks vs 3.4% placebo | Source |
| Human (Phase 2) | Healthy adults with overweight/obesity | Dose-dependent weight loss, well-tolerated GI side effects | Source |
Commonly Discussed Benefits
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Safety & Cautions
- NDA filed December 2025; FDA decision expected ~October 2026
- Gastrointestinal side effects observed in 79.6% of CagriSema group (mostly mild-to-moderate and transient)
- Missed internal 25% weight loss target in REDEFINE-1 — achieved 22.7% on-treatment
- Primarily studied in combination with semaglutide, not as standalone
- Not yet FDA-approved
- Context (June 2026): interest in lean-mass-sparing weight loss is widening beyond amylin agonists. A small early-stage trial of the endocannabinoid-system peptide Pep19 reported visceral-fat reduction without lean-mass loss — a different mechanism worth distinguishing from amylin-based approaches like cagrilintide.
Comparisons
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Citations
- [1] Novo Nordisk — CagriSema NDA filing announcement. December 2025 PubMed
- [2] REDEFINE-1 — Cagrilintide-Semaglutide in Adults with Overweight or Obesity, NEJM 2026 PubMed
- [3] REDEFINE-2 — Cagrilintide-Semaglutide in Adults with T2D, NEJM 2026 PubMed
- [4] Novo Nordisk submits NDA for CagriSema — PharmExec, April 2026 PubMed
- [5] Novo Nordisk — REIMAGINE-2 Phase 3 headline results, April 2026 PubMed
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CagriSema
High EvidenceA fixed-dose combination of cagrilintide (amylin analog) and semaglutide (GLP-1 agonist) studied for enhanced weight loss through dual hormonal pathways.
Pep19
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ALV-200
Low EvidenceALV-200 is Alveus Therapeutics' highly selective amylin receptor 3 (AMYR3) peptide agonist in IND-enabling development for obesity, designed to capture amylin's weight-loss and lean-mass-preserving benefits while avoiding the nausea and aversion tied to calcitonin-receptor activation. It is engineered for once-weekly dosing.
ASC39
Low EvidenceASC39 is Ascletis Pharma's investigational once-daily oral small-molecule amylin-selective amylin receptor agonist for obesity. In head-to-head preclinical assays it matched Eli Lilly's injectable peptide eloralintide on amylin-receptor potency, selectivity over the calcitonin receptor, and weight loss in diet-induced obese rats. Ascletis plans to file a U.S. FDA IND for ASC39 - and for a fixed-dose combination with its oral GLP-1 agonist ASC30 - in the third quarter of 2026.
MET-233i
Medium EvidenceMET-233i is a first-in-class, once-monthly ultra-long-acting amylin analog for obesity, originally developed by Metsera and now a Pfizer asset. In its Phase 1 trial it produced up to 8.4% placebo-subtracted weight loss after five weekly doses and showed a roughly 19-day half-life - the most durable of any reported amylin analog - supporting once-monthly subcutaneous dosing. It is engineered to be combined with Metsera's monthly GLP-1 agonist MET-097i in a single once-monthly injection.