SS-31 (Elamipretide) Advances to Phase 3 for Dry AMD
SS-31 (Elamipretide) is in Phase 3 trials ReNEW and ReGAIN for dry AMD with photoreceptor loss and extrafoveal geographic atrophy. This article covers mechanism, study design, and regulatory context as of March 5, 2026.
SS-31, also known as Elamipretide, is a mitochondria-targeted drug candidate with clinical programs in several indications. Phase 3 programs are ongoing for dry AMD with photoreceptor loss and extrafoveal geographic atrophy, and for Barth syndrome, Forzinity (Elamipretide) received accelerated FDA approval on September 19, 2025. This article reflects the status as of March 5, 2026. Sources: FDA, September 19, 2025, Stealth BioTherapeutics, March 13, 2025, ClinicalTrials.gov, ReNEW / NCT06373731.
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What is SS-31?
SS-31 is a small, cell-permeable tetrapeptide (D-Arg-Dmt-Lys-Phe-NH2) that targets the inner mitochondrial membrane. It binds to cardiolipin, a phospholipid important for the structure and function of mitochondrial cristae. Preclinical and clinical work investigates whether this approach can influence mitochondrial dysfunction in various disease contexts.
Mechanism of Action
The mechanism is most commonly described in the literature through interaction with cardiolipin:
- Cardiolipin binding - SS-31 binds to cardiolipin in the inner mitochondrial membrane and is proposed to stabilize membrane organization.
- Support of the electron transport chain - By stabilizing membrane architecture, more efficient electron transfer across complexes I through IV is thought to be maintained.
- Reduction of oxidative stress - The approach targets primarily a reduction in excessive generation of free radicals in dysfunctional mitochondria, rather than scavenging already-formed radicals.
- Cristae structure - Preclinical models have described effects on cristae structure; whether and to what extent this translates clinically depends on the indication.
Phase 3 Studies: ReNEW and ReGAIN for Dry AMD
Stealth BioTherapeutics is developing Elamipretide in two Phase 3 programs for dry AMD with photoreceptor loss and extrafoveal geographic atrophy. According to a company announcement from March 13, 2025, ReNEW had at that time reached 50 percent of its planned recruitment; the company also announced ReGAIN as a second global Phase 3 study. The primary endpoint was described as the rate of change of the macular area with photoreceptor loss at week 48. Sources: Stealth BioTherapeutics, March 13, 2025, ClinicalTrials.gov, ReNEW / NCT06373731.
Why Dry AMD?
AMD affects approximately 20 million people in the United States. Until recently, no approved therapies existed for late dry AMD with geographic atrophy. That has changed: Syfovre received approval in February 2023 and Izervay in August 2023 for GA secondary to AMD; in February 2025, Izervay received an expanded label without a time limit on dosing. Against this background, Elamipretide is not being developed as the first therapy for GA, but as a candidate with a different biological approach. Sources: NEI, December 12, 2023, Astellas, February 13, 2025.
The clinical approach of Elamipretide differs from the already-approved complement inhibitors: instead of directly intervening in the complement cascade, the program targets mitochondrial function and photoreceptor integrity.
Study Design
ReNEW (NCT06373731) and the sister program ReGAIN announced by Stealth were described with substantially the same basic design:
| Parameter | Details |
|---|---|
| Patients per study | 360 |
| Randomization | 2:1 (active : placebo) |
| Duration | 96 weeks |
| Dosing | 40 mg/day subcutaneous self-injection |
| Primary endpoint | Rate of change of macular area with photoreceptor loss at week 48 |
| Open-label extension | ReTAIN study |
ClinicalTrials.gov additionally lists secondary endpoints at weeks 72 and 96 as well as low-luminance BCVA measurements for ReNEW. The choice of the photoreceptor-based endpoint aligns with the hypothesis that structural photoreceptor changes could be relevant to disease progression. Whether this translates into clinically meaningful benefits remains to be demonstrated in Phase 3. Sources: ClinicalTrials.gov, ReNEW / NCT06373731, Stealth BioTherapeutics, March 13, 2025.
FDA Approval: Barth Syndrome Since September 2025
Forzinity (Elamipretide) received accelerated FDA approval on September 19, 2025 for Barth syndrome in patients weighing 30 kg or more. The FDA characterizes the decision as the first approval of a treatment for Barth syndrome. Source: FDA, September 19, 2025.
The FDA also notes that accelerated approval is contingent on a confirmatory post-approval study. For other indications such as dry AMD, the Barth syndrome approval primarily means that regulatory, safety, and pharmacokinetic experience in humans is already available for Elamipretide; it is not, however, evidence of efficacy for ophthalmic applications.
Clinical Dosing: What is Publicly Documented
The clinically documented doses differ depending on indication and study design. For the AMD context relevant here, study registry entries and company disclosures are the most reliable sources.
Study Doses in the Publicly Documented AMD Program
- Phase 3 for dry AMD (ReNEW / ReGAIN): 40 mg/day subcutaneous
- Earlier cardiac study programs: Lower and higher dosing regimens were also investigated, depending on indication and study design
For the assessment of the AMD program, the registered daily dose and study design are primarily relevant. This article therefore relies on publicly traceable study registries and company announcements, not on unsubstantiated details from third-party descriptions.
Further Investigated Indications
The mitochondrial mechanism of SS-31 has led to programs in several disease areas:
- Barth syndrome - furthest advanced regulatorily; FDA approval since September 19, 2025
- Dry AMD with photoreceptor loss and extrafoveal geographic atrophy - Phase 3 development with ReNEW and ReGAIN
- Primary mitochondrial myopathies - clinically investigated
- Cardiac and other mitochondrial indications - addressed in earlier study programs
This breadth of development is relevant to researchers primarily because it points to a compound with multiple clinical datasets in different tissues and endpoint logics.
Relevance for Researchers
From a research perspective, SS-31 is interesting primarily because several levels come together here: a clearly formulated mitochondrial mechanism, an FDA approval in a rare disease, and ongoing late-stage clinical development in an ophthalmic indication. This keeps Elamipretide relevant for research groups working on mitochondrial biology, bioenergetics, and age-associated degenerative processes.
At the same time, the assessment should remain sober. The Barth syndrome approval does not demonstrate benefit in dry AMD, and the Phase 3 program in this AMD subgroup was still ongoing at the time of this article, without definitive efficacy data.
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