Monthly Research Briefing

Two peptides expanding the research toolbox.

Last month we surveyed the multi-agonist incretin pipeline. This issue widens the lens: a fixed-dose combination that pairs an amylin analog with semaglutide, and the first FDA-approved cardiolipin-binding mitochondrial peptide. Different mechanisms, different therapeutic spaces, both with fresh 2024–2025 readouts worth tracking.

CagriSema

cagrilintide 2.4 mg + semaglutide 2.4 mg · Novo Nordisk

Fixed-Dose Combination Amylin · GLP-1 Phase 3

Mechanism

Once-weekly subcutaneous fixed-dose combination of cagrilintide (a long-acting amylin analog) and semaglutide (a GLP-1 receptor agonist). Amylin signaling slows gastric emptying and reinforces meal-ending satiety in brainstem and hypothalamus; GLP-1R agonism suppresses appetite and improves glycemic regulation. Investigated for additive effects on weight and cardiometabolic endpoints versus either monotherapy.

Trial Status

Phase 3 REDEFINE program: REDEFINE 1 (NCT05567796, obesity without T2D, n=3,417, peer-reviewed June 2025), REDEFINE 2 (NCT05394519, obesity + T2D, peer-reviewed June 2025), REDEFINE 3 (cardiovascular outcomes, ongoing). Separate REIMAGINE Phase 3 program covers T2D indications.

Key Finding · REDEFINE 1 (Obesity)

Phase 3 in adults with overweight/obesity without T2D: mean body-weight change at 68 weeks was −20.4% vs −3.0% placebo (treatment-policy estimand). Trial-product estimand: −22.7% (CagriSema) vs −11.8% (cagrilintide alone), −16.1% (semaglutide alone), −2.3% (placebo). AEs predominantly mild-moderate GI.

Garvey WT, et al.; REDEFINE 1 Study Group. N Engl J Med 2025;393(7):635–647. PMID: 40544433. NCT05567796.
pubmed.ncbi.nlm.nih.gov/40544433

Key Finding · REDEFINE 2 (Obesity + T2D)

In adults with overweight/obesity and T2D: mean weight change of −15.7% vs −3.1% placebo at 68 weeks (trial-product estimand). 73.5% reached HbA1c ≤6.5% on CagriSema vs 15.9% on placebo. First Phase 3 evidence for an amylin + GLP-1 combination in T2D.

Davies MJ, et al.; REDEFINE 2 Study Group. N Engl J Med 2025;393(7):648–659. PMID: 40544432. NCT05394519.
pubmed.ncbi.nlm.nih.gov/40544432

Why it matters for researchers First Phase 3 readout for an amylin + GLP-1 combination peptide therapy. REDEFINE 1's direct head-to-head against each monotherapy is the cleanest available reference for understanding amylin's incremental contribution to weight regulation in a research context.

Elamipretide

SS-31 · MTP-131 · Stealth BioTherapeutics

Mitochondrial Cardiolipin Binder FDA Approved (2025)

Mechanism

Water-soluble, cell-penetrating aromatic-cationic tetrapeptide (D-Arg-2',6'-Dmt-Lys-Phe-NH₂) that selectively concentrates in the inner mitochondrial membrane and binds cardiolipin. The interaction is reported to stabilize cristae architecture, preserve electron-transport-chain supercomplex assembly, and reduce mitochondrial ROS through electrostatic / hydrophobic (non-enzymatic) interactions.

Trial Status

FDA accelerated approval September 19, 2025 as FORZINITY for Barth syndrome — first FDA-approved mitochondria-targeted peptide drug. Confirmatory 4TAZPower Phase 3b/4 trial (NCT07531251) ongoing. Separate geographic atrophy program continues following ReCLAIM-2 (NCT03891875).

Key Finding · Barth Syndrome OLE

168-week open-label extension of TAZPOWER in genetically confirmed Barth syndrome: ~96 m cumulative gain on 6-minute walk test vs OLE baseline, plus signals of improved cardiac function. Sustained tolerability over >3 years. These data underpinned the eventual FDA accelerated approval.

Thompson WR, et al. Genet Med 2024;26(7):101138. PMID: 38602181. NCT03098797.
pubmed.ncbi.nlm.nih.gov/38602181

Key Finding · Geographic Atrophy (Mixed)

ReCLAIM-2 Phase 2 RCT in dry AMD with non-central GA: 48-week subcutaneous elamipretide 40 mg daily missed primary endpoints (LL-BCVA, sqrt-GA area), but showed ~43% less progression of macular ellipsoid-zone attenuation and higher proportion of ≥10-letter visual-acuity gainers (14.6% vs 2.1%).

Ehlers JP, et al. Ophthalmol Sci 2024;5(1):100628. PMID: 39605874. NCT03891875.
pubmed.ncbi.nlm.nih.gov/39605874

Why it matters for researchers First FDA-approved cardiolipin-binding mitochondrial peptide and a foundational research tool for mitochondrial-membrane pharmacology. The contrast between positive Barth-syndrome and mixed GA outcomes is instructive for tissue-specific mitochondrial-targeting research design.