SS-31 (elamipretide) failed its biggest trial, then got FDA approval. Here is why.

In 2023 a 218-patient randomised trial found that elamipretide, also known as SS-31, did not help people with primary mitochondrial myopathy. In 2025 FDA approved it. The two facts are not a contradiction: the drug acts on one specific molecular target, and it was approved for the one disease in which that target is the defect.

What does SS-31 do inside a mitochondrion?

SS-31 (D-Arg-Dmt-Lys-Phe-NH2) is a four-amino-acid peptide developed by Hazel Szeto and Peter Schiller. It concentrates in mitochondria and binds cardiolipin, a lipid of the inner mitochondrial membrane.

Cardiolipin helps hold the complexes of the electron transport chain together and keeps cytochrome c in its normal role. When cardiolipin is damaged or abnormally formed, energy production becomes less efficient and more reactive oxygen species are produced. In preclinical studies, SS-31 stabilised cardiolipin and improved measures of mitochondrial function under conditions where cardiolipin damage was the main insult.

Why did it fail one trial and succeed in another?

MMPOWER-3. Published in Neurology in 2023, this trial enrolled 218 people with primary mitochondrial myopathy from many different genetic causes. Participants received elamipretide or placebo for 24 weeks. The difference in six-minute walk distance versus placebo was minus 3.2 metres, and neither primary endpoint reached significance. Most of the conditions enrolled do not involve cardiolipin remodelling as their main defect.

TAZPOWER. This trial enrolled 12 people with Barth syndrome, a rare inherited disease caused by mutations in the TAZ gene that directly impair cardiolipin remodelling. In the open-label extension, published in Genetics in Medicine in 2024, participants gained an average of 95.9 metres on the six-minute walk test at week 36, and muscle strength improved.

"The discordance between MMPOWER-3 and TAZPOWER illustrates a fundamental challenge in mitochondrial medicine: treating a heterogeneous syndrome with a mechanism-specific compound requires patient selection based on the target pathway, not the clinical syndrome."

Neurology, 2023 (MMPOWER-3 primary results)

How did it reach FDA approval?

An FDA advisory committee voted 10 to 6 in favour in October 2024, reflecting real disagreement about whether results from a small trial were enough. FDA granted accelerated approval in September 2025, under the brand name Forzinity, for Barth syndrome, using muscle strength as an intermediate endpoint. Accelerated approval requires a confirmatory trial to show clinical benefit. The approval covers Barth syndrome only; it is not an approval for mitochondrial disease in general, heart failure, ageing or any other use.

What about heart failure and healthy adults?

In heart failure, a phase 2 study published in Circulation: Heart Failure reported a short-term reduction in left ventricular end-systolic volume; a later, longer trial did not reproduce a benefit on its primary endpoint.

No randomised trial has tested elamipretide in healthy adults for ageing or performance. Cardiolipin composition changes with age in research, which makes the idea biologically interesting, but no study has shown that this translates into any measurable benefit for people without disease.

What safety data exists?

The TAZPOWER extension followed participants for 168 weeks. Local skin reactions were the most common adverse event, occurring in roughly a third of participants, and no serious systemic adverse events attributed to the drug were reported in that small group. A small group followed for three years is useful but cannot rule out rarer effects.

What is its regulatory status?

Elamipretide (Forzinity) is FDA-approved for Barth syndrome and is a prescription drug. For any other use it is unapproved. Products labelled "for research use only" are not for human use, and FDA treats them as unapproved drugs when they are marketed for people.

What genetics research says

The one genetic fact with clinical weight here is Barth syndrome itself: it is caused by TAZ mutations and diagnosed through clinical testing. It is not something a consumer DNA file can establish.

Mitochondrial haplogroups differ in mitochondrial DNA variants, and some, such as haplogroup J, have been linked to differences in oxidative stress in research. SOD2 rs4880 affects a mitochondrial antioxidant enzyme. No elamipretide trial has analysed results by haplogroup or by any nuclear gene variant, so no study has tested whether any of them changes response.