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Dr. John Lynn Jefferies, including 25 additional physicians who serve as key opinion leaders (KOLs) in the care of Barth syndrome, undersigned a letter to FDA in October 2020. In their appeal, they asked the Agency to encourage the sponsor to submit a new drug application (NDA) for elamipretide for the treatment of Barth syndrome and that FDA commit to promptly reviewing the NDA. 

Dear Dr. Donohue, 

We, the undersigned physicians, are specialists knowledgeable about the care of Barth syndrome, an ultra-rare genetic mitochondrial disease that affects less than 130 individuals in the United States, or are cardiovascular clinical trialists. Given the multisystem impact of Barth syndrome, we are medical geneticists, cardiologists, doctors in physical therapy, and neurologists. Barth syndrome invariably leads to shortened lifespans due to the devastating cardiomyopathy that presents in almost all cases. During their truncated lifespan, these young men are severely limited in their activities of daily living by debilitating skeletal muscle weakness, exercise intolerance, fatigue, and neutropenia. Time is of the essence in identifying a therapy to stabilize cardiac and skeletal muscle function and hopefully delay an otherwise inevitable progression to early mortality. 

In the last 12 months, the ultra-rare global Barth syndrome population has lost 7 patients to complications of the disease. Given that there are only 255 individuals in the world living with Barth syndrome, this means that nearly 3% of the world’s cohort has succumbed in the last year, predominantly from cardiac-related causes. The unmet need is therefore immediate, severe, and urgent. While we hope for a cure for Barth syndrome, in the meantime a therapy which has the potential to delay progression would be of tremendous benefit. 

The Barth Syndrome Foundation has shared with us the data from the SPIBA-201 clinical trial and open-label extension, the first clinical trial ever conducted in Barth syndrome in which the investigational product, elamipretide, was assessed as a potential treatment. Although the trial did not show statistically significant changes in the prespecified primary endpoints during the double-blind placebo-controlled treatment period, early signals of efficacy emerged during that time-period, including objective biomarker evidence. The improvements thereafter observed during a two-year open-label extension across multiple functional endpoints assessing skeletal muscle function, patient and clinician reported outcomes assessing fatigue and quality of life, and echocardiographic endpoints assessing cardiac function, are not expected in the natural course of the disease, as those of us who have treated patients with this disease can also personally attest. 

Many of us who are cardiac clinical trialists are familiar with large trials in heart failure which necessarily comprise thousands of patients to be adequately powered to achieve statistically significant outcomes on endpoints such as survival, functional assessments (including six-minute walk test), and quality of life assessments. Therefore, the changes observed in this very small data set, albeit during an open label treatment arm, are impressive. Moreover, these changes are meaningful – an over 100-meter improvement in distance walked in 6 minutes in young men presenting at baseline with a level of impairment akin to septuagenarians with Class II/III heart failure is generally unprecedented for patients with this clinical presentation. In fact, this change (albeit not placebo-corrected) far exceeds that seen in trials of highly successful interventions in adult heart failure patients with interventions such as cardiac resynchronization therapy. Most importantly, these patients have characterized the meaningfulness of these improvements relative to how they feel and function on a day-to-day basis in interviews collected by the sponsor as part of a patient and caregiver perception of change interview protocol, in testimonials offered to the Barth community at the Patient Focused Drug Development meeting in 2018 and, more recently, during weekly webinars hosted by the Barth community, and, with respect to some of us, during their visits to our clinics. 

The safety profile of elamipretide in Barth syndrome appears to be acceptable. Most adverse events were injection site related and characterized as mild or moderate in nature, and there were no Suspected Unexpected Serious Adverse Reactions. This is consistent with the safety profile of elamipretide as observed during what we understand to be over 100-patient years of exposure collected to date. As physicians, we view the potential benefit afforded by elamipretide relative to the favorable safety profile exhibited to date as supporting a decision to make this drug immediately available to patients and prescribing physicians. 

Given the progressive cardiac manifestations during adolescence for Barth syndrome patients and the considerable unmet need, we would want to have the current opportunity to prescribe elamipretide to our patients with Barth syndrome while more definitive efficacy studies, if these are deemed required, are conducted. The young men affected by Barth syndrome do not have years to wait for the sponsor to enroll, conduct and read out upon a second clinical trial, recruitment of which would be highly challenging even in ordinary times due to the ultra-rare nature of the disease. Indeed, during the current pandemic, it is highly unlikely that such a trial could initiate within a reasonable time frame, as the medical community has now advised against unnecessary travel for this immune-compromised population. 

In conclusion, as doctors familiar with and in many cases actively treating patients with Barth syndrome, relying upon our best ability and medical judgment of the clinical and basic science data collected to date, we ask that you encourage the sponsor to submit a new drug application for elamipretide for the treatment of Barth syndrome, and that you undertake to promptly review that application. 

We also want to take this opportunity to whole-heartedly thank you and your colleagues at the FDA for all the work you are doing through the current crisis to respond to the urgent demands the pandemic has imposed. We admire and thank you for your continued commitment to the young men affected by Barth syndrome, even as you battle a broader public health crisis. 


John Lynn Jefferies, MD, MPH, FAAP, FACC, FAHA, FHFSA 

University of Tennessee Methodist Le Bonheur Healthcare System 

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