Research Brief O25KX SS‑31 / Elamipretide: Mechanisms, Efficacy, Safety, and Translational Readiness

Kamil Khoury
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Prepared by: Kamil Khoury

Date: October 2, 2025
Intended Use: Research‑use only; not medical advice.

Disclaimer: Educational content for research‑use only. This document does not provide medical advice, diagnosis, treatment, or dosing guidance.

Executive Summary

What it is. SS‑31 (elamipretide; MTP‑131; Bendavia; Ocuvia) is a mitochondria‑targeted tetrapeptide (D‑Arg‑dimethylTyr‑Lys‑Phe‑amide) that binds cardiolipin in the inner mitochondrial membrane (IMM), stabilizing cristae/ETC supercomplexes and reducing cytochrome‑c peroxidase activity. Net effects: improved mitochondrial structure‑function, reduced lipid peroxidation, and better bioenergetic coupling.

Clinical signals (human first).

  • Barth syndrome (BTHS): Randomized crossover portion did not meet co‑primary endpoints, but the long‑term open‑label extension (OLE) showed sustained improvements in knee extensor strength and some cardiac/functional measures. In September 2025, the FDA granted accelerated approval (brand Forzinity) to improve muscle strength in BTHS ≥30 kg, based largely on knee extensor strength, with confirmatory trials required.

  • Primary mitochondrial myopathy (PMM): Phase 3 MMPOWER‑3 (40 mg SC daily, 24 weeks) was negative on 6‑minute walk test (6MWT) and fatigue (Class I evidence). Post‑hoc genotype‑focused analyses are exploratory.

  • Dry AMD / geographic atrophy: ReCLAIM‑2 randomized Phase 2 did not meet primary endpoints (LLVA, GA growth), though safety acceptable; a Phase 3 (ReNEW) program is underway.

  • Cardiovascular: EMBRACE‑STEMI (PCI) showed no reduction in infarct size; HFrEF PROGRESS‑HF did not improve LVESV at 4 weeks.

  • Renal: A small Phase 2a during renal artery stenting suggested improved renal oxygenation/flow and eGFR vs placebo (pilot).

PK/safety. SC bioavailability ≈92%; Tmax 0.5–1 h; Vd ~0.5 L/kg; primarily renal excretion; t½ ~3–4 h; dose reduction recommended in severe renal impairment; most common AEs are injection‑site reactions.

Bottom line. Mechanism‑strong with mixed/negative outcomes in broad indications; positive long‑term functional signals in BTHS underlie accelerated approval with confirmatory obligations. Human efficacy remains unproven in PMM, STEMI/HFrEF, and dry AMD.

Scientific Background & Mechanisms

Origin/chemistry. SS‑31 is a cationic–aromatic tetrapeptide that concentrates at the IMM by electrostatic and hydrophobic interactions with cardiolipin (CL).

Primary MoA.

  • Cardiolipin binding → cytochrome‑c peroxidase inhibition: SS‑31 binds CL, limiting cytochrome‑c’s peroxidase activity, thereby reducing CL peroxidation, preserving cristae, and maintaining ETC supercomplexes.

  • Mitochondrial structure‑function: Improves IMM biophysics/cristae and bioenergetics; lowers ROS and supports ΔΨm and ATP output.

Uncertainties. No single cell‑surface receptor; degree of BBB penetration remains unclear; some models show structural benefits without measurable changes in total CL content post‑injury.

Evidence by Indication (Human → Animal → Cell)

3.1 Barth syndrome (BTHS)

  • Human: TAZPOWER randomized crossover (12 weeks) did not meet co‑primary endpoints; OLE (to 168–192 weeks) showed sustained improvements in knee extensor strength and selected cardiac/functional metrics; safety/tolerability acceptable. FDA accelerated approval (Forzinity) to improve muscle strength ≥30 kg; confirmatory trial pending.

  • Preclinical/mechanistic: Rationale anchored in CL remodeling deficits in BTHS; SS‑31 stabilizes CL‑dependent mitochondrial functions.
    GRADE: B (functional OLE data; surrogate endpoint basis). TRL: 8–9 (U.S. accelerated approval with post‑marketing requirement).

3.2 Primary mitochondrial myopathy (PMM)

  • Human: MMPOWER‑3 (n≈200, 40 mg SC daily, 24 weeks) was negative on 6MWT and fatigue (Class I evidence). Exploratory genotype‑specific post‑hoc analyses suggest heterogeneity but are non‑confirmatory. Safety consistent with ISR profile.

  • Preclinical: Broad improvements in muscle bioenergetics in models.
    GRADE: B‑ (collectively negative RCT + supportive preclinical). TRL: 5–6.

3.3 Ophthalmology (Dry AMD / Geographic atrophy)

  • Human: ReCLAIM‑2 randomized Phase 2 did not meet co‑primary endpoints (LLVA, GA growth) over 48 weeks; ISRs were common; Phase 3 ReNEW launched (SC 40 mg daily, up to 96 weeks).

  • Preclinical/early human: Phase 1 in intermediate AMD established tolerability; ocular function signals were exploratory.
    GRADE: C (no efficacy on primary endpoints to date). TRL: 4–5.

3.4 Cardiovascular

  • STEMI (PCI): EMBRACE‑STEMI Phase 2a showed no infarct‑size reduction (CK‑MB AUC) vs placebo.

  • HFrEF: PROGRESS‑HF Phase 2 showed no LVESV improvement at 4 weeks.

  • Mechanistic/preclinical: Robust cristae/IMM preservation and improved mitochondrial function after cardiac I‑R in animals.
    GRADE: C. TRL: 4–5.

3.5 Renal

  • Human (pilot): During renal artery stenting (PTRA), IV elamipretide was associated with improved renal oxygenation/flow and eGFR over 3 months vs placebo. Small, single‑center Phase 2a; hypothesis‑generating.

  • Preclinical: Protection from I‑R tubular injury and improved mitochondrial integrity across models.
    GRADE: C+. TRL: 4–5.

3.6 Pulmonary/Critical care

  • Preclinical: Benefits reported in sepsis‑induced diaphragm dysfunction and LPS/ARDS models (reduced inflammation/pyroptosis, preserved mitochondrial function). Human interventional data are lacking.
    GRADE: C (preclinical only). TRL: 3–4.

3.7 Neurologic/CNS and other domains

  • CNS: Mixed preclinical neuroprotection; BBB delivery uncertain. Dermatologic/ischemic limb: Preclinical hindlimb ischemia suggests improved recovery. Oncology‑adjacent: Not an antineoplastic; no clinical efficacy data.
    GRADE: C. TRL: 2–4.

Human Genetics & Biomarkers

No SS‑31‑specific human genetics. Target engagement/PD options include mitochondrial respiration in PBMCs, 31P‑MRS phosphocreatine recovery (where feasible), and imaging/functional surrogates in organ‑specific studies. Mechanistic biomarkers (e.g., cardiolipin oxidation indices) are research‑grade and not standardized.

Pharmacokinetics (PK), Pharmacodynamics (PD), and Dosing

Approved dose (U.S., BTHS): 40 mg SC once daily (Forzinity). Bioavailability ≈92%; Tmax 0.5–1 h; Vd ~0.5 L/kg; minimal protein binding (~39%). Metabolism via stepwise C‑terminal cleavage to inactive M1/M2; excretion renal with ~100% recovery (parent + metabolites) ≤48 h. t½ ≈3–4 h. Reduce dose by half in severe renal impairment (eGFR < 30 mL/min, not on dialysis).

Common AEs: Injection‑site reactions (ISRs); eosinophilia noted without clinical sequelae in long‑term exposure; no meaningful QTc effects at 3× Cmax.

Exposure–response: Clinically validated surrogate in BTHS is knee extensor strength; no established exposure–response for PMM, STEMI, HFrEF, or AMD to date.

Safety Profile

Across programs, SS‑31 is generally well‑tolerated; the most frequent AE is ISR (erythema, pruritus, pain). Ophthalmic and systemic studies report low systemic serious AE rates; label carries benzyl alcohol warning (contraindicated in neonates). No hepatic metabolism; renal excretion drives exposure; monitor in severe CKD per label.

Regulatory & Policy Landscape

  • United States: Accelerated approval (Sep 19 2025) for Forzinity (elamipretide HCl) to improve muscle strength in BTHS patients ≥30 kg; priority review and rare pediatric disease voucher granted. Continued approval contingent on confirmatory trial(s).

  • Other jurisdictions: No approvals identified as of this writing.

  • Key prior programs: PMM Phase 3 negative; dry AMD Phase 2 negative on co‑primary endpoints; Phase 3 ReNEW ongoing. STEMI and HFrEF programs negative on primary imaging/functional endpoints.

Manufacturing, CMC & Quality

Peptide manufactured by solid‑phase peptide synthesis (SPPS); commercial U.S. product is a ready‑to‑use SC solution(pH 4.7–6.1) containing benzyl alcohol preservative. Identity/purity by LC‑MS and HPLC; related substances and endotoxin controlled per parenteral standards.

IP & Competitive Landscape

Foundational patents on composition of matter and CL‑binding use claims (Szeto‑Schiller family) underpin the program. Competitive field spans mitochondria‑targeted agents (e.g., SkQ1/Visomitin, MitoQ, idebenone), with differing MoAs and mixed clinical evidence; elamipretide is the first FDA‑approved mitochondria‑targeted therapeutic (accelerated approval in BTHS).

Strategy Comparison Table (T1)

Risk Register

Development & Experiment Plan (12–24 months)

  1. BTHS (post‑marketing confirmatory): Multicenter, randomized, placebo‑controlled study in ≥30 kg patients; co‑primary knee extensor strength and clinically meaningful functional endpoint (e.g., 6MWT or patient‑centered PRO), with cardiac imaging secondary.

  2. Renal ischemia (replication): Multicenter RCT during PTRA or other I‑R settings with renal oxygenation (BOLD‑MRI) and eGFR at prespecified timepoints.

  3. Phenotype‑enriched pilot in PMM: Target genotypes from post‑hoc signals with biomarker‑anchored endpoints (mitochondrial respiration in PBMCs, 31P‑MRS) and clear go/no‑go criteria.

  4. Ophthalmology: Proceed with ReNEW while pre‑specifying visual function endpoints with established MIDs; independent masked reading centers.

Gaps & Verification List

  • Verify confirmatory trial design requirements and timelines under Forzinity’s accelerated approval. Next step:FDA docket/label updates.

  • Harmonize strength measurements (device/technique) across sites in BTHS. Next step: central training & QC per protocol.

  • Establish robust exposure–response for strength/functional outcomes. Next step: pooled PK/PD modeling leveraging label PK and trial datasets.

  • Replicate renal PTRA findings in larger, blinded cohorts. Next step: multicenter RCT with standardized imaging/biomarkers.

References

  • Sabbah HN. Contemporary insights into elamipretide’s mitochondrial mechanisms. Front Cardiovasc Med. 2025. (cardiolipin/cristae).

  • Szeto HH. Cardiolipin‑protective action of SS‑31. Br J Pharmacol. 2014.

  • Birk AV et al. SS‑31 inhibits cytochrome‑c peroxidase and CL peroxidation. J Am Soc Nephrol. 2013.

  • Allen ME et al. Elamipretide mitigates cardiac I‑R structural‑functional deficits. Commun Biol. 2020.

  • FDA Label — Forzinity (elamipretide HCl). PK, dosing, safety (2025).

  • FDA Press Release (Sep 19 2025). Accelerated approval in BTHS.

  • Thompson WR et al. TAZPOWER (BTHS) randomized + OLE. Genet Med. 2021; OLE update 2024.

  • Karaa A et al. MMPOWER‑3: Class I evidence of no benefit in PMM. Neurology. 2023.

  • Ehlers JP et al. ReCLAIM‑2 randomized Phase 2 in GA. Ophthalmol Sci. 2024/2025.

  • Gibson CM et al. EMBRACE‑STEMI Phase 2a (no infarct‑size reduction). Eur Heart J Acute Cardiovasc Care.2016.

  • Butler J et al. PROGRESS‑HF Phase 2 (no LVESV benefit). J Card Fail. 2020.

  • Saad A et al. Renal PTRA pilot (improved oxygenation/eGFR). Circ Cardiovasc Interv. 2017.

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