SS-31 (Elamipretide)

Also known as: Elamipretide, FORZINITY, Bendavia, MTP-131, elamipretide hydrochloride

Evidence: Clinical

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Overview

Mitochondria-targeted tetrapeptide that binds cardiolipin. FDA granted accelerated approval on 2025-09-19 as FORZINITY, 40 mg subcutaneously once daily, to improve muscle strength in Barth syndrome.

Elamipretide (SS-31, MTP-131, formerly Bendavia) is an aromatic-cationic tetrapeptide, D-Arg-Dmt-Lys-Phe-NH2, that concentrates in the inner mitochondrial membrane and binds cardiolipin. FDA granted accelerated approval on 2025-09-19 as FORZINITY for Barth syndrome, at 40 mg subcutaneously once daily in patients weighing at least 30 kg, on an intermediate endpoint of knee extensor strength, with continued approval contingent on a confirmatory trial. The trial record elsewhere is largely negative: the Barth crossover trial missed both primary endpoints and the gains appeared only in the open-label extension (Thompson 2021, 2024), the phase 3 MMPOWER-3 trial in 218 primary mitochondrial myopathy patients missed both primaries (Karaa 2023), and two heart failure trials failed to improve left ventricular end-systolic volume (Daubert 2017; Butler 2020).

Benefits

Improved knee extensor muscle strength in Barth syndrome (basis of the FDA accelerated approval, n=12 plus extension), sustained 6-minute walk gains in that extension, reduced oxidative stress and better mitochondrial function (rodent and cell). Anti-aging claims are rodent-only

Dosing reference

Research dose: 40 mg subcutaneously once daily, the approved dosage for patients weighing at least 30 kg; 20 mg once daily in adults with eGFR under 30 mL/min not on dialysis
Range: 20000 to 40000 mcg, 1x daily
Reconstitution: 2 mL bacteriostatic water
Common vial sizes: 20 mg, 40 mg

Subcutaneous injection into the abdomen at least 2 inches from the navel, or the outer thigh, rotating sites daily; the approved product is a ready-to-use 280 mg/3.5 mL solution (80 mg/mL) needing no reconstitution, and each 0.5 mL dose delivers 40 mg. Vials are discarded 8 days after first opening. Trial doses: 40 mg/day subcutaneously in Barth syndrome and in MMPOWER-3; 4 mg and 40 mg/day for 28 days in PROGRESS-HF; single 4-hour infusions at 0.005 to 0.25 mg/kg/h in the earlier heart failure study. Research-grade lyophilized vials require reconstitution and are not the approved product.

Mechanism

FDA's label describes elamipretide as a mitochondrial cardiolipin binder that localizes to the inner mitochondrial membrane and improves mitochondrial morphology and function. Its alternating aromatic-cationic structure drives accumulation there. Mechanistic work refines this: the peptide binds lipid bilayers and modulates membrane surface electrostatics, which the authors propose as the key component of its action rather than a specific protein target (Mitchell 2020), and a genome-wide CRISPR screen identified phospholipid scramblase 3 as a biological target in kidney cells, reported in 2024. In Barth syndrome, treatment moved the monolysocardiolipin to cardiolipin ratio in a direction that tracked clinical outcomes (Thompson 2024). Effects on reactive oxygen species are reported in cell and rodent models.

Evidence

Clinical: at least one published human trial or an approved drug

TAZPOWER, a randomized double-blind placebo-controlled crossover trial of 40 mg/day in 12 Barth syndrome patients, missed both primary endpoints (6-minute walk distance and symptom score); in the open-label extension, 6-minute walk distance improved by a cumulative 96.1 m at week 168 and knee extensor strength rose, which became the basis of the accelerated approval (Thompson et al., 2021; Thompson et al., 2024)
MMPOWER-3, a phase 3 randomized trial of 40 mg/day for 24 weeks in 218 primary mitochondrial myopathy patients, missed both primary endpoints; the 6-minute walk difference was -3.2 m and the fatigue score difference was not significant, graded Class I evidence of no effect (Karaa et al., 2023)
PROGRESS-HF randomized 71 patients with reduced ejection fraction to placebo, 4 mg or 40 mg daily for 28 days: left ventricular end-systolic volume and ejection fraction did not differ from placebo (Butler et al., 2020)
An earlier ascending-dose trial of single 4-hour infusions in 36 patients with reduced ejection fraction found reduced left ventricular end-diastolic and end-systolic volumes at end of infusion with no serious adverse events, and plasma levels undetectable by 24 hours (Daubert et al., 2017)
ReCLAIM-2, a randomized phase 2 trial in age-related macular degeneration with geographic atrophy, evaluated lesion growth, visual function and ellipsoid zone preservation (Ehlers et al., 2025)
Human-trial status: FDA granted accelerated approval on 2025-09-19 for Barth syndrome only, on an intermediate endpoint, with continued approval contingent on a confirmatory trial. The approval rests on 12 patients and their extension. Trials in primary mitochondrial myopathy and heart failure were negative

References

Side effects

Injection-site reactions dominate. In the placebo-controlled crossover period, all 12 patients on elamipretide had a local administration reaction against 8 of 12 on placebo: injection-site erythema 12 of 12 versus 3 of 12, induration and pruritus 8 of 12 versus 2 of 12, pain 9 of 12 versus 5 of 12, bruising and urticaria 3 of 12 versus 0. Eosinophil counts rose frequently when dosing ran 30 days or longer, peaking around day 90 at a mean increase of 0.5 to 0.6 times 10 to the ninth per litre and returning to baseline after 6 to 12 months or on stopping, with no clinical consequence reported. No clinically significant QTc prolongation at 3 times the peak concentration of the approved dose.

Storage

Storage: Refrigerate 2-8°C (36-46°F)
Lyophilized: 2+ years at room temp, 3+ years refrigerated
Reconstituted: Approved product: not reconstituted; the opened vial is discarded 8 days after first use and may be held at 2 to 8 C or at 20 to 25 C in that window. Research lyophilized powder: 28 to 30 days refrigerated after reconstitution is vendor guidance

Pharmacology

Half-life: Not stated in the FDA label. Peak concentration 0.5 to 1 h after subcutaneous dosing, minimal accumulation on daily dosing, and about 100% of the dose recovered in urine as parent plus the inactive M1 and M2 metabolites by 48 h. After a 4-hour infusion, plasma levels were undetectable by 24 h
Bioavailability: Subcutaneous: approximately 92% absolute bioavailability, with comparable exposure from thigh or abdomen; volume of distribution about 0.5 L/kg and plasma protein binding about 39% (FDA label)
Molecular weight: 639.8 Da
Sequence: D-Arg-Dmt-Lys-Phe-NH2