SS-31 Clinical Research: An Overview
Since the early 2010s, SS-31 (Elamipretide) has been under extensive clinical investigation. Research programs are investigating its potential in a variety of conditions linked to mitochondrial dysfunction. SS-31 is a man-made tetrapeptide (D-Arg-Dmt-Lys-Phe-NHâ‚‚).
It targets cardiolipin on the inner mitochondrial membrane and represents a unique approach to tackling mitochondrial pathology at its source.
Clinical investigations of SS-31 have produced encouraging findings in some indications while yielding mixed or negative results in others.
In 2024, 18 clinical trials of SS-31 in humans were reviewed systematically in Mitochondrion. These trials provide a comprehensive review of both positive and negative outcomes across different research settings.
This article reviews the main results of these investigations.
If you would like to learn more about how SS-31 works, its interaction with cardiolipin, and its effects on mitochondrial bioenergetics in laboratory research, read our complete guide: How SS-31 Works: Understanding Cardiolipin and Mitochondrial Function.
Barth Syndrome Treatment and SS-31: A Major Breakthrough
Barth syndrome is a rare X-linked genetic disease characterized by mutations in the TAFAZZIN gene. The TAFAZZIN (TAZ) gene provides instructions for making the tafazzin protein, an essential mitochondrial enzyme involved in cardiolipin metabolism. A mutation in this gene leads to mitochondrial dysfunction and improper cardiolipin remodeling.
This mutation occurs rarely in about 1 in 1,000,000 males and is estimated to affect about 150 people in the USA. Until 2025, no medications had been developed for this serious disease.
TAZPOWER Trial
The double-blind, placebo-controlled, cross-over Phase 2/3 study was performed at Johns Hopkins University in 12 patients diagnosed with Barth syndrome. The treatment included the administration of 40 mg of elamipretide once daily for 12 weeks, followed by a 4-week washout phase. After that, the cross-over to another arm of the study occurred.
Primary Endpoints: Primary endpoints of changes in the 6-minute walk test (6MWT) and Barth Syndrome Symptom Assessment Scale were not achieved during the initial 12 weeks of the placebo-controlled study.
Findings of the Open-Label Extension Period: In total, ten patients entered the open-label extension, and eight reached the 36-week mark. At this point, notable improvements appeared:
| Endpoint | Improvement | Statistical Significance |
| 6-Minute Walk Test | +95.9 meters | p = 0.024 |
| BTHS Symptom Assessment | -2.1 points | p = 0.031 |
| Knee Extensor Strength | Significant improvement | — |
| Cardiac Parameters | Significant improvement | — |
The open-label extension study carried out for 168 weeks also revealed that the treated individuals exhibited significantly improved cardiac function relative to matched natural history controls, including greater than 40% increased left ventricular stroke volume.
Accelerated Approval by the FDA
The US Food and Drug Administration approved the use of elamipretide, marketed as Forzinityâ„¢, for the treatment of Barth syndrome on September 19, 2025. It became a historic event when the FDA approved the very first drug that may be used for the treatment of Barth syndrome.
- Grounds for Approval: The drug was approved due to improvement in the strength of knee extensor muscles, which was considered by the FDA to predict future clinical benefits.
- Restrictions of Weight and Age: The drug was approved for people with a weight of at least 30 kilograms. It happened because primary clinical trials were performed mostly on adolescents and adults.
- Requirement of a Confirmatory Trial: As a part of the accelerated approval process, Stealth BioTherapeutics is required to perform a confirmatory trial after the drug is sold, such as a Phase 3 NuPOWER trial to prove the clinical benefits of the drug.
- Safety Data: In clinical trials for Barth syndrome, the most common adverse effects of the drug were local reactions at the injection site. Overall, the safety profile of this drug was quite positive.
Primary Mitochondrial Myopathy: The MMPOWER Trials
The largest clinical development program in SS-31 is the MMPOWER clinical trials, where the drug has been used to treat several genetic disorders characterized by mitochondrial dysfunction, known as primary mitochondrial myopathies (PMM).
MMPOWER-3 Study
The MMPOWER-3 study was a phase 3 randomized controlled clinical study of the effects of subcutaneous injection of elamipretide in patients suffering from PMM. This study included 231 patients, where the changes in the 6-minute walk test and the PMMSA Total Fatigue Score were considered.
| Metric of Evaluation | Clinical Outcome | Key status |
| 6-Minute Walk Test (6MWT) | No noticeable distance increase vs. placebo | Missed Endpoint |
| Total Fatigue Score of PMMSA | No statistical separation from placebo | Missed Endpoint |
| Tolerability and Safety | Mostly mild injection site reactions, but overall it showed good tolerability | Favorable Profile |
- Primary Outcome: Elamipretide therapy did not produce significant overall improvement in a genetically diverse, broad group of adult patients with PMM.
Post-hoc Analysis Based on Genotypes
Due to high heterogeneity of PMM, an important post-hoc analysis published in the Orphanet Journal of Rare Diseases in 2024 explored the impact of genotypes on the response to treatment with SS-31. It was found that the nature of the mitochondrial defect played a significant role in patients’ reaction to SS-31 therapy:
- Large-Scale mtDNA Deletions: Patients with single large-scale mitochondrial DNA deletions appeared to demonstrate greater clinical responsiveness to elamipretide than some other genetic subgroups.
- nDNA Mutations: Patients with nDNA mutations (POLG, TK2) showed a different reaction, thus emphasizing the importance of selecting patients according to their unique genetic profile for all future studies. Dose-proportional exposure to the drug was observed during pharmacokinetics analysis, with peak plasma concentration reached at the end of infusion and clearance within 24 hours.
Age-Related Macular Degeneration (AMD) and Other Uses
ReCLAIM and ReCLAIM-2 Studies (Dry AMD)
SS-31 has been tested in the treatment of non-exudative (dry) Age-Related Macular Degeneration (AMD) in ReCLAIM and ReCLAIM-2 studies. The results have been mixed. Though it has not met the conventional structural endpoints needed for regulatory approval, SS-31 showed very promising visual signal effects in a specific subpopulation of patients with Geographic Atrophy (GA):
- Low Luminance Visual Acuity (LLVA): Patients showed significant improvement in reading ability in low light conditions.
- Geographic Atrophy Lesion Growth Rate: Evidence suggests possible slowing down of GA lesion growth rate, confirming that bioenergetic stabilization could improve specialized ocular tissues.
Heart Failure With Preserved Ejection Fraction (HFpEF)
Phase I-II clinical studies were conducted to see the possible effect of the drug on mitochondrial function biomarkers. The results obtained from a phase 1/2 clinical study for the intravenous administration of elamipretide showed that the concentration of the drug increased dose-dependently in the range from 0.005 to 0.25 mg/kg/h, with achievement of its peak plasma level upon completion of administration without alterations in either blood pressure or heart rate in heart failure patients. Currently, the clinical trial of the drug in HFpEF has not shown any positive results.
Rationale for Clinical Trials Based on Preclinical Data
The proposed clinical trials rely on a large amount of preclinical data:
- Mesenchymal Stem Cells: The use of SS-31 in aged bone marrow mesenchymal stem cells resulted in a significant improvement in mitochondrial function, which allowed for a 35% increase in ATP and a 40% decrease in the level of ROS (reactive oxygen species).
- Spinal Cord Injury Models: Recent experiments in animals with injury of the spinal cord demonstrated the success of using SS-31 in maintaining mitochondrial bioenergetics and neuronal remodeling.
- Neurological Data: SS-31 is known to be successful in reducing the levels of lipid peroxidation and reactive oxygen species in the hippocampus of epileptic rats.
Clinical Research Program: Key Findings
From the combined SS-31 clinical trial findings, key trends can be observed as follows:
- Variable Efficacy: Although the drug did not have the anticipated efficacy in the general population of PMM, it proved very efficacious in the selected subgroup of Barth syndrome.
- Importance of Long-Term Exposure: In both Barth syndrome and PMM patient populations, significant benefit was only observed in patients who took the drug for a prolonged time period (36 to 168 weeks).
- Importance of Selecting Suitable Patients: Considering that patients with mitochondrial disorders exhibit considerable variability, precise identification of genetic subtypes (specific mtDNA deletions) is essential in proving the efficacy of the drug.
- Safety Profile: There are no serious systemic adverse events associated with SS-31 clinical trials among different disease models. Localized injection site reaction is the sole issue faced by the subjects.
FAQs
1. What is the regulatory status of SS-31 (Elamipretide)?
The FDA granted accelerated approval on September 19, 2025, for SS-31 for the treatment of Barth syndrome in patients weighing 30 kg or more, under the trade name Forzinityâ„¢. It is being studied for the treatment of diseases including primary mitochondrial myopathy, age-related macular degeneration, and heart failure.
2. What were the main findings in the MMPOWER-3 study?
MMPOWER-3 was a phase 3 clinical trial to assess the efficacy of SS-31 in patients with primary mitochondrial myopathy (231 subjects). The trial did not show statistically significant improvements in the 6-minute walk test and the PMMSA Total Fatigue Score.
3. What information led to the FDA approval of Forzinityâ„¢ in Barth syndrome?
The FDA approved it based on the phase 2/3 study and a subsequent open-label extension trial. The 12-week placebo-controlled trial did not reach its primary endpoints, but the 36-week open-label extension trial showed significant improvements in 6-minute walk distance (+95.9 m, p=0.024), symptom scores, and knee extensor muscle strength.
4. Is there any study of SS-31 under other conditions?
Yes, studies in a clinical setting for SS-31 have been done under other conditions, including age-related macular degeneration (ReCLAIM studies), heart failure with preserved ejection fraction, and various mitochondrial conditions. The results have been inconsistent, as some of the studies have shown signs in certain sub-populations without overall approval.
5. What is the safety profile of SS-31 in clinical studies?
In several clinical studies conducted on SS-31, the drug shows a safe safety profile. The common side effects of the drug include injection site reactions. There have been no significant effects on blood pressure, heart rate, or electrocardiogram measurements.
Research Disclaimer
SS-31 (Elamipretide), available at OrionPeptide.com, is solely for laboratory research uses. The information contained within this article is compiled from various scientific publications and does not serve as medical advice, nor is it to be used for any application other than Barth Syndrome.
References
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