For families in the Barth syndrome community, the search for effective treatments has been a long and arduous journey. Despite efforts and advancements, Barth syndrome remains one of the 95% of rare diseases without an FDA-approved treatment.

A promising therapy called elamipretide, developed by biopharmaceutical company Stealth BioTherapeutics, has offered the community a glimmer of hope.

The U.S. Food and Drug Administration (FDA) recently extended the Prescription Drug User Fee Act (PDUFA) action date for elamipretide’s New Drug Application (NDA) from January 29, 2025 to April 29, 2025.

But what does that mean, and how will it affect the Barth syndrome community? Read on to find out.

What is Barth Syndrome?

Barth syndrome is an ultra-rare genetic condition that primarily affects males. The inborn error of phospholipid metabolism is caused by TAZ gene mutations. This mutation disrupts the production of tafazzin, a protein essential for mitochondrial function. Unfortunately, Barth syndrome currently comes with a significantly reduced life expectancy; 85% of children with Barth syndrome die before age five.

However, there have been some medical advances that are life-preserving. The Barth Syndrome Foundation explains that:

with improved diagnosis, medical therapy and monitoring, survival has been extended, with many survivors now into their adult years. Survivors of BTHS, however, almost always live with extremely compromised physical health, and those few who enjoy relatively good health live every day with medical conditions that can become life-threatening with little or no warning. 

Characteristics of Barth syndrome may include:

• Exercise intolerance
• Debilitating fatigue
• Cardiomyopathy
• Muscle weakness
• Heart failure
• Neutropenia (low neutrophil count)
• Delayed growth
• Feeding problems such as difficulty swallowing, textural aversions

Though Barth syndrome was first described in the 1980s, research into the condition has been limited due to its rarity. Barth syndrome affects approximately 150 people across the United States. Current treatments focus on symptom management, but not the underlying mitochondrial dysfunction. This is why identifying targeted therapies like elamipretide is so crucial.

What is Elamipretide?

Elamipretide is an investigational peptide compound that binds reversibly to cardiolipin, a key lipid in the mitochondrial membrane that plays a role in energy production. By stabilizing cardiolipin, elamipretide aims to restore mitochondrial function. This could potentially alleviate the systemic energy deficits that cause symptoms of Barth syndrome. According to Stealth BioTherapeutics:

 In preclinical or clinical studies, we have observed that elamipretide increases mitochondrial respiration, improves electron transport chain function and ATP production and reduces formation of pathogenic ROS levels. This elamipretide-cardiolipin association has been shown to normalize the structure of the inner mitochondrial membrane, thereby improving mitochondrial function. Functional benefit is achieved through improvement of ATP production and interruption and potential reversal of damaging oxidative stress.

Admittedly, the clinical trial findings have been promising in many ways. Yet it’s important to note that some of these findings have associated complexities.

For example, the Phase 2/3 TAZPOWER study set out to explore the safety and efficacy of elamipretide for Barth syndrome. The trial demonstrated improvements in key functional measures, such as increased exercise capabilities and reduced fatigue. Many patients also reported improvements in quality-of-life metrics.

Yet despite the noticeable benefits that families saw, the study failed to meet its primary endpoint. This is a challenge that frequently emerges in rare disease research given the small patient populations and variability in clinical outcomes. Still, Stealth BioTherapeutics submitted the NDA for elamipretide in 2024. The NDA included clinical data and input from patient advocacy groups, many of whom hope to see elamipretide advance to an approved treatment.

Outside of Barth syndrome, elamipretide is also being evaluated as a potential therapy for conditions like dry age-related macular degeneration (dry AMD) and primary mitochondrial myopathies.

Decoding the PDUFA Action Date Extension

First created by Congress in 1992, the Prescription Drug User Fee Act allows the FDA to collect fees from pharmaceutical companies to expedite the review process for new drugs. Each NDA is assigned a PDUFA action date by which the FDA must issue a decision on the drug’s approval or denial.

PDUFA action date extensions, like the one for elamipretide, are not uncommon, per se. Sometimes the FDA requires additional time to review data or analyses submitted by the drug’s sponsor.

According to a press release regarding the extension:

Stealth [BioTherapeutics] was notified last week that the Agency requires additional time to conduct a full review of supplemental information provided in response to recent FDA requests that were received following the positive Cardiovascular and Renal Drugs Advisory Committee (CRDAC) meeting on October 10, 2024.

In the same press release, Reenie McCarthy, Chief Executive Officer of Stealth BioTherapeutics, shared:

“We appreciate the FDA’s commitment to a thorough review of our NDA and the positive supplemental analyses submitted in response to its recent information requests, and remain confident in the robustness of this NDA package. We continue to work closely with the Agency as it completes its review of the elamipretide NDA and are actively preparing to support broad access to this therapy for individuals living with Barth syndrome as quickly as possible following potential approval.”

It’s important to note that the FDA has not identified any safety issues associated with elamipretide. The FDA’s decision underscores the agency’s commitment to a thorough evaluation to ensure that elamipretide’s benefits outweight its risks. Still, the extension may feel like a setback to patients or families.

Why Does This Matter?

As I mentioned earlier, only 5% of rare diseases have an FDA-approved treatment. This means that 95% of rare disease communities lack a pathway forward. For Barth syndrome, this very well could be the path towards better care, longer lifespans, and an actual disease-modifying treatment. The stakes truly could not be higher.

But until April, the Barth syndrome community will now be stuck in a familiar but frequently uncomfortable place: waiting. Waiting for more awareness. Waiting for treatment. Waiting for the medical community to care.

Still, amidst the fear, there is hope. All eyes now turn to April 29, 2025 to see if this day could be the historic one that the Barth syndrome community, and partners like Stealth BioTherapeutics, have been waiting for.

About Stealth BioTherapeutics

Stealth BioTherapeutics’ mission is to develop novel therapies to improve the lives of patients living with diseases of mitochondrial dysfunction. The company’s lead product candidate, elamipretide, is under review for Barth syndrome and in late-stage development for primary mitochondrial myopathy and dry age-related macular degeneration. Stealth BioTherapeutics is also evaluating a topical ophthalmic formulation of its second-generation clinical-stage candidate, bevemipretide (SBT-272), for dry age-related macular degeneration, and have a deep pipeline of novel compounds under evaluation for rare neurological and cardiac disease indications. Learn more about Stealth BioTherapeutics, or follow the company on LinkedIn or X.