Barth syndrome (BTHS) is a paediatric-onset, ultra-rare disease characterised by cardiac abnormalities that can result in various health challenges, including an enlarged and weakened heart, heart failure, exercise intolerance, fatigue, and short stature.
Currently, BTHS has no cure and can only be treated with medications to help manage symptoms and prevent complications. With an eye to fill this unmet medical need, Stealth BioTherapeutics Inc (Stealth) developed elamipretide hydrochloride injection, a new molecular entity and mitochondrial protective agent. The firm’s resubmitted new drug application (NDA) was recently reviewed at a meeting of the US Food and Drug Administration’s (FDA’s) Cardiovascular and Renal Drugs Advisory Committee (CRDAC) and garnered broad support by the panel to introduce a new treatment option for BTHS.
Approximately (~) 250 individuals worldwide and ~130 people in the US live with BTHS, and cardiomyopathy is considered the leading cause of death. The X-linked condition is caused by mutations in the TAFAZZIN gene and is inherited as a recessive allele. The National Library of Medicine of the National Institutes of Health (NIH) notes in MedlinePlus that the tafazzin protein is located in mitochondria and is responsible for altering a lipid called cardiolipin. Cardiolipin maintains mitochondrial shape, energy production, and protein transport. TAFAZZIN mutations can lead to decreased levels of adenosine triphosphate, a molecule that stores and provides energy for cells. Elamipretide functions by distributing to and improving the function of cardiolipin-deficient mitochondria in patients with BTHS.
Clinical Evidence for Rare Diseases
The US Orphan Drug Act defines a rare disease as any disease or condition that either affects <200,000 people in the US or affects >200,000 people and “there is no reasonable expectation that the cost of developing and making available in the United States a drug for such disease or condition will be recovered from sales.” Section 115(a) of the Food and Drug Administration Modernization Act allows the FDA to determine if data from a single adequate and well-controlled clinical trial plus confirmatory evidence are sufficient to establish effectiveness. However, particular clinical circumstances (e.g., unmet medical need) can impact the degree of certainty supporting the conclusion that substantial evidence of effectiveness has been demonstrated.
At the CRDAC meeting in October 2024, the committee reviewed evidence provided by Stealth for its NDA resubmission in the form of clinical study results and nonclinical findings. The sponsor originally submitted its NDA for elamipretide in August 2021 and subsequently received a refusal-to-file letter from the FDA. Stealth proceeded to develop the needed data to suitably support the efficacy of the drug to treat BTHS, leading it to resubmit the NDA in early 2024.
While the majority of the CRDAC found data from the animal models and echocardiography to be “disappointing and unclear,” several panelists supported the efficacy assessment after listening to testimonies shared during the open public hearing (OPH) of positive experiences with elamipretide. The OPH is a staple of FDA advisory committee meetings that gives the panelists a chance to receive input from members of the public on the topic at hand. Given the rarity of BTHS, many CRDAC members commented on the importance of the OPH.
The majority of patients, caregivers, and healthcare providers who spoke during the OPH stated that they witnessed a marked improvement in quality of life after they, their loved ones, or their patients began treatment with elamipretide. Before the OPH, several CRDAC panelists emphasised how the data were insufficient to support efficacy and stated they looked forward to hearing from patients directly. Afterward, most of the committee members noted that the OPH made “a huge difference” to their viewpoints and said the patient experiences with elamipretide were “hard to ignore” and “compelling.” As a result, the panel majority agreed that the drug was shown to be effective and even went as far as to recommend its approval.