FDA Okayed Life Saving Drug for Baby, Yet Access for 129 Young Americans with Same Ultra-Rare Disease Hangs in the Balance as FDA Declines Review.
I’ve spent the last 20 years of my medical career caring for patients with rare genetic mitochondrial diseases, including some afflicting only a few Americans. I’m excited to see potential new therapies emerging, including a potential therapy for Barth syndrome – an ultra-rare disease in which cardiolipin, a key building block necessary to make the energy needed to sustain life, is severely depleted. Affected children have life-threatening cardiac dysfunction, severe exercise intolerance, muscle weakness, debilitating fatigue, increased risk of infection and reduced life expectancy. Most do not survive their fifth birthday. There are fewer than 130 affected individuals living in the United States.
In 2021, the Food and Drug Administration (FDA) refused to review data for the first and only therapy currently in development for the disease. Now, with two years of additional data showing sustained improvements, FDA is still unwilling to review the therapy. FDA’s intransigence leaves doctors like me with our hands tied when an acutely ill child is hospitalized.
Earlier this year, an 11-month-old boy was admitted to the intensive care unit at the Children’s Hospital of Philadelphia. He was in acute heart failure, and genetic testing confirmed a diagnosis of Barth syndrome. He was placed on an extracorporeal membrane oxygenation machine (ECMO), which pumped the blood outside of his body to remove carbon dioxide and infuse oxygen, and then on a ventricular assist device (VAD), which helped pump blood from the heart to the rest of his body. He was listed for a heart transplant.
I was familiar with the clinical data for elamipretide, a cardiolipin-targeted mitochondrial therapeutic that showed benefit in Barth syndrome patients treated with drug compared to both a natural history control and to patients’ pretreatment baseline. In both analyses, the results were compelling, with improvement in exercise tolerance, sustained strength, heart function and cardiolipin ratios across a four-year period. Most patients tolerated the therapy well.
My first thought was whether I could facilitate compassionate use of elamipretide through an expanded access program – which allows patients with a serious or life-threatening disease to try unapproved drugs if the potential benefit justifies the potential risks. I spoke with cardiac experts, who cautioned that there has been no case in which a VAD was successfully removed from a child with Barth syndrome without a heart transplant. Since extending time to transplant for a critically ill infant is important, there was consensus that elamipretide might help. The FDA approved my emergency request within a day.
After three months, my patient’s heart structure and function improved. After six months, the VAD was successfully removed. The child came off the transplant list because his native heart had recovered sufficiently to sustain his life. His mother says he is thriving.
It is incomprehensible to me that FDA can determine that a drug for an ultra-rare disease –one with no approved therapies from which very young children frequently die – is safe enough and has enough potential benefit for me to dispense it to my patient, while also determining that the data for this drug is not worth FDA’s time and resources to even review. I question the ethics of FDA’s refusal to act, knowing that the other 129 Americans living and dying with this devastating disease may never have equal access to the only potential therapy.
Ten percent of the global Barth syndrome patient population has died since FDA first declined to review elamipretide five years ago. If the FDA doesn’t correct its error soon, that number will only continue to grow, and patients like mine will lose their only foreseeable chance at full, productive lives.
There has to be a path forward. It's unconscionable to ignore these pleas.
Amy Goldstein, MD, Director of the Mitochondrial Medicine Program at the Children’s Hospital of Philadelphia