SS-31 (elamipretide)

01Key questions

02Overview

SS-31 (Elamipretide) is a mitochondria-targeting pentapeptide that selectively binds to cardiolipin — a lipid found exclusively on the inner mitochondrial membrane — and in doing so, normalizes mitochondrial structure, improves electron transport chain function, increases ATP production, and reduces pathological reactive oxygen species (ROS).

Developed by Dr. Hazel Szeto at Weill Cornell Medical College, SS-31 has undergone the most extensive clinical trial program of any therapeutic peptide in this category. On September 19, 2025, the FDA granted accelerated approval of Elamipretide (marketed as FORZINITY™) for improving muscle strength in Barth syndrome patients weighing ≥30 kg — making it the first FDA-approved mitochondrial peptide therapy.

Evidence Level: Strong — Multiple Phase 1, 2, and 3 clinical trials. FDA accelerated approval for Barth syndrome (Sep 2025). Extensive preclinical data. 168-week open-label extension shows sustained functional gains.

03Mechanism of Action

Primary Target: Cardiolipin Binding

Cardiolipin is a phospholipid exclusively expressed on the inner mitochondrial membrane that plays a critical structural role: - Organizes electron transport chain components into "supercomplexes" for efficient oxidative phosphorylation - Interacts with cytochrome c to regulate its electron-carrying function vs. apoptotic signaling - Maintains mitochondrial membrane potential - Required for inner-membrane cristae architecture

SS-31's Effects on Cardiolipin

1. Binds reversibly to cardiolipin — stabilizes its molecular structure
2. Modulates cytochrome c interaction — promotes electron carrying function over apoptotic signaling
3. Normalizes inner mitochondrial membrane structure — restores cristae architecture
4. Inhibits mitochondrial permeability transition pore (mPTP) opening — prevents mitochondrial swelling and apoptosis
5. Reduces MLCL/CL ratio — increases mature cardiolipin relative to monolysocardiolipin (a direct downstream effect in tafazzin-deficient BTHS cells)

Downstream Effects

• Increased ATP production — improved oxidative phosphorylation efficiency
• Reduced ROS generation — less oxidative stress
• Anti-apoptotic — prevents cytochrome c release and caspase activation
• Anti-fibrotic — reduces tissue fibrosis in multiple organs
• Improved mitochondrial dynamics — better fission/fusion balance

Tissue Distribution

After subcutaneous administration, SS-31 concentrates in: - Kidney (highest) - Heart, liver, skeletal muscle, lungs - Brain (low but detectable — crosses BBB)

04Primary Uses & Applications

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05Clinical Evidence

FDA Accelerated Approval — September 19, 2025

FORZINITY™ (Elamipretide HCl injection) — NDA 215244, Stealth BioTherapeutics Inc., Needham MA - Indicated to improve muscle strength in adult and pediatric patients with Barth syndrome weighing ≥30 kg (≥66 lb) - Barth syndrome: ultra-rare X-linked mitochondrial disorder (estimated prevalence 1/400,000–500,000 live births; ~150 patients in the U.S.) caused by TAFAZZIN mutations that impair cardiolipin remodeling, leading to cardiomyopathy, neutropenia, skeletal myopathy, and ~85% mortality by age 5 in severe forms - Pathway: Accelerated approval under FDCA §506(c) / 21 CFR 314.510 - Approval basis (intermediate clinical endpoint): Improvement in knee extensor muscle strength by handheld dynamometry (HHD) during the TAZPOWER 168-week open-label extension (NCT03098797; n=12 randomized → n=10 OLE → n=8 reached week 168) - Primary endpoints of the randomized crossover were NEGATIVE for the FDA's two co-primary endpoints (6-minute walk test, Total Fatigue Score) — the approval rests on the HHD signal that emerged in the open-label extension - Labelled dose: 40 mg subcutaneously once daily (same time each day; skip missed doses — do NOT double) - Renal adjustment required in adults with severe renal impairment - Most common AE: injection-site reactions (mild-to-moderate); rare serious reactions including hypersensitivity - Pediatric exclusion: safety/efficacy NOT established for patients <30 kg (the most severely affected infants). As of April 2025, ~35 patients worldwide had received elamipretide via expanded/emergency access including infants on ECMO/Berlin Heart support — case-series data, not in label - Adcomm history: Oct 2024 advisory committee voted 10–6 in favor; some "no" voters later changed position after seeing clinical responses - Source: FDA approval letter (NDA 215244, 9/19/2025); FDA Integrated Review; FDA Press Announcement (9/19/2025)

Required Post-Marketing Studies (PMRs)

Per the FDA approval letter, Stealth must complete:

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Source: FDA Approval Letter, NDA 215244, 9/19/2025

TAZPOWER 168-Week Open-Label Extension (PMID 38602181)

Publication: Thompson WR et al. Long-term efficacy and safety of elamipretide in patients with Barth syndrome: 168-week open-label extension results of TAZPOWER. Genet Med. 2024. DOI 10.1016/j.gim.2024.101138. PMID 38602181.

Design: 28-week randomized double-blind placebo-controlled crossover → 168-week OLE. Patients on elamipretide 40 mg daily. n=10 entered OLE; n=8 reached week 168.

Key results (vs OLE baseline): - 6-minute walk test: +96.1 m cumulative improvement at week 168 (P=.003) — far exceeds the published MCID range of 25–35 m for cardiopulmonary outcomes - Muscle strength (HHD): significant improvements at all visits (P<.05); range 37.9–60.3 N improvement - BTHS-SA Total Fatigue: improved at all measured timepoints (cumulative -1.21 at week 168; P=.21) - SWAY balance: significant at weeks 72 and 168 (P<.05) - 3D echocardiography: significant improvement in LV stroke volume, end-diastolic volume, and end-systolic volume over 168 weeks - MLCL/CL ratio: substantial reductions correlated with functional and cardiac improvements — a candidate biomarker for future trials - Safety: no new safety signals through 192 weeks of treatment; injection-site reactions most common; 3 serious AEs in OLE considered unlikely/unrelated to drug

Critical interpretation: The signal emerged during open-label, unblinded, long-term treatment — not in the randomized portion. BTHS natural history shows 6MWT and lower-extremity strength do NOT improve spontaneously, so within-patient pre/post comparison is informative, but the FDA's accelerated-approval letter explicitly accepts "more uncertainty than we would for less rare diseases." The 168-week OLE data is what converted a failed Phase 2 into a label.

Other Major Clinical Trials

Heart Failure (Phase 2, n=71): 28-day treatment with SS-31 (4 or 40 mg/day). Well-tolerated. Some adverse events reported but mostly mild. Butler et al., 2020

Primary Mitochondrial Myopathy (MMPOWER-2, Phase 2 crossover, n=30): 40 mg/day for 4 weeks. Majority of adverse events were mild. Karaa et al., 2020

Phase 3 in primary mitochondrial myopathy (n=218): Terminated — did not meet primary endpoints. Significant setback that drove the strategic pivot to Barth syndrome.

Preclinical Neuroprotection

• Aged mice exposed to isoflurane: SS-31 (5.0 mg/kg IP) protected cognitive function and mitochondrial Complex I activity Wu et al., 2016
• Improved mitochondrial function, decreased ROS, increased ATP production
• Prevented mPTP opening in hippocampal neurons

06Doses in studies

⚠️ Note: SS-31 is now FDA-approved for Barth syndrome. Below includes both approved and research dosing.

Doses in studies

• Studies used 40 mg subcutaneously once daily for patients ≥30 kg
• Dose at the same time each day; if missed, skip — do NOT double
• Renal adjustment required in adults with severe renal impairment (see FDA label Table 1)
• Each 0.5 mL contains 40 mg elamipretide (46.8 mg elamipretide HCl), 10 mg benzyl alcohol (preservative), 2.07 mg monobasic sodium phosphate monohydrate
• NOT approved for IV use; benzyl alcohol caution — fatal "gasping syndrome" reported in low-birth-weight and preterm neonates given IV benzyl-alcohol-containing drugs (FORZINITY contains BA but is only and not approved in <30 kg patients)

Pharmacokinetics

• Half-life: ~4 hours (dogs, IV)
• BBB permeability: Yes (low brain concentrations)
• Bioavailability: Good subcutaneous absorption

07Safety Profile

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08Source & Origin

• Discovered by: Dr. Hazel Szeto, Weill Cornell Medical College
• Development: Stealth BioTherapeutics (clinical development; Needham MA)
• Mechanism class: First-in-class mitochondrial cardiolipin binder
• Milestone: First FDA-approved therapy targeting mitochondrial membrane lipids (Sep 19, 2025)
• FDA designation: Orphan drug, Priority Review, Rare Pediatric Disease designation (with priority review voucher)

09Where to get it

What studies and practitioners report

Amounts as reported in the cited sources: trial doses with the population studied, and practitioner-reported ranges marked as such. Not medical advice.

• Trial 40 mg/day · Elamipretide (MMPOWER-3) adults with primary mitochondrial myopathy, n=218 PMID 37268435
• Trial 40 mg/day · Elamipretide, 168-week extension patients with Barth syndrome PMID 38602181

10Connections

11Sources

1. NCT03098797NCT03098797
2. Thompson WR et al. (2024). "Long-term efficacy and safety of elamipretide in patients with Barth syndrome: 168-week open-label extension results of TAZPOWER." Genet Med . DOI 10.1016/j.gim.2024.101138 . PMID 38602181 — the open-label data underpinning approvalPubMed 38602181 · DOI 10.1016/j.gim.2024.101138
3. Tung C et al. (2025). "Elamipretide: A Review of Its Structure, Mechanism of Action, and Therapeutic Potential." Int J Mol Sci . PMC11816484PMC11816484
4. "Elamipretide: First Approval." Drugs Ther Perspect (AdisInsight). PMID 41335372 — approval record, ≥30 kg indication detailPubMed 41335372
5. Zhao C, Zhuang X, Gao J. (2025). "Elamipretide: The first cardiolipin-directed mitochondrial therapeutic for Barth syndrome approved under accelerated approval." Drug Discov Ther 19(6):435–436. PMID 41260682PubMed 41260682

12Entry history

Heretic informs and never prescribes. Where amounts appear, they describe what published studies used. Talk to a qualified clinician before acting on anything here.