# SS-31 (elamipretide)

Rating: Promising — Some human trials, or consistent animal work with a clear mechanism
Type: Compound
Updated: 2026-10-14
Canonical: https://heretic.bio/articles/ss-31-elamipretide-cardiolipin-targeted-mitochondrial-peptide.html

> SS-31 (elamipretide, FORZINITY) is a pentapeptide that binds cardiolipin on the inner mitochondrial membrane to stabilize electron transport and reduce ROS. It received FDA accelerated approval in September 2025 for Barth syndrome in patients weighing at least 30 kg, the first approval of its kind, but the basis was narrow: the randomized trial's co-primary endpoints were negative and approval rested on strength gains in a 168-week open-label extension with 8 completers. A confirmatory randomized trial is required by 2029-2030, and a phase 3 in mitochondrial myopathy previously failed.

> **Aliases:** Elamipretide®, Bendavia®, MTP-131, FORZINITY™ (FDA-approved for Barth syndrome), SS-31 **Sequence:** D-Arg-dimethylTyr-Lys-Phe-NH2 (5 amino acids, with D-Arg and methylated Tyr) **Molecular Weight:** 639.8 Da **Origin:** Designed by Dr. Hazel Szeto at Weill Cornell Medical College

## Overview

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.

## Mechanism 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)

## Primary Uses & Applications

Application | Evidence Level | Notes  
---|---|---  
**Barth syndrome** | FDA APPROVED (Sep 2025, accelerated) | FORZINITY™ — first mitochondrial therapy for this ultra-rare disease  
**Primary mitochondrial myopathy** | Phase 2/3 data | MMPOWER trials; Phase 3 did not meet primary endpoint  
**Heart failure** | Phase 2 data | Improved mitochondrial function; modest clinical benefit  
**Age-related macular degeneration** | Phase 2 data | ReVIVA trial  
**Myocardial infarction** | Phase 2a data | Cardioprotective during reperfusion  
**Renal artery stenosis** | Phase 2a data | Renoprotective  
**Ischemia-reperfusion injury** | Preclinical | Multiple organ systems  
**Neurodegeneration** | Preclinical | Cognitive improvement in aged mice  
**Dry AMD (Phase 3)** | ReNEW trial | Fully enrolled; readout expected **late 2027**  
**Bevemipretide (next-gen)** | Phase 1 eye drop | Phase 2 targeted by end-2026 — ophthalmic indications  
  
## Clinical 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](https://clinicaltrials.gov/study/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:

PMR | Study | Timeline  
---|---|---  
**4802-1** | Randomized, double-blind, placebo-controlled confirmatory trial in BTHS patients ≥5 years to verify clinical benefit predicted by HHD knee extensor strength | Protocol: 03/2028; Completion: 09/2029; Final report: 03/2030  
**4802-2** | 26-week GLP carcinogenicity study in TgRasH2 mice  | SPA: 11/2024; Final report: 02/2026  
**4802-3** | 2-year GLP carcinogenicity study in rats  | Protocol: 07/2026; Completion: 10/2029; Final report: 01/2030  
**4802-4** | Drug-drug interaction: effect of repeat-dose Forzinity on metformin (MATE1 substrate) PK | Protocol: 03/2026; Completion: 03/2027; Final report: 09/2027  
  
Source: FDA Approval Letter, NDA 215244, 9/19/2025

### TAZPOWER 168-Week Open-Label Extension (PMID [38602181](https://pubmed.ncbi.nlm.nih.gov/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](https://doi.org/10.1016/j.gim.2024.101138). PMID [38602181](https://pubmed.ncbi.nlm.nih.gov/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



## Doses 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



## Safety Profile

Aspect | Assessment  
---|---  
**Overall safety** | Good — well-characterized through 192 weeks in OLE; no new signals  
**Serious adverse events** | Rare; hypersensitivity reactions reported post-approval  
**Long-term safety** | Established up to 192 weeks (TAZPOWER OLE); carcinogenicity studies pending  
**Carcinogenicity** | Unknown — TgRasH2 mouse study due 02/2026, 2-yr rat study ongoing  
**Drug interactions** | Metformin (MATE1 substrate) DDI study pending 03/2027  
**Contraindications** | None established beyond hypersensitivity  
**Pregnancy** | Insufficient data  
**Pediatric <30 kg** | Safety/efficacy NOT established; not approved  
  
## Source & 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)

## Sources

1. NCT03098797 (NCT03098797)
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 approval (PubMed 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 . PMC11816484 (PMC11816484)
4. "Elamipretide: First Approval." Drugs Ther Perspect (AdisInsight). PMID 41335372 — approval record, ≥30 kg indication detail (PubMed 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 41260682 (PubMed 41260682)