An expert panel convened by the U.S. Food and Drug Administration (FDA) recently voted against granting accelerated approval to the novel Duchenne muscular dystrophy (DMD) drug candidate, eteplirsen. The vote came after a review of clinical trial data and 11 hours of hearing testimony that focused on the drug’s efficacy, but — says a mother of a DMD boy — wholly missed “the complexity of the Duchenne situation.”
Reuters news service reported that only five of the 13 panelists were convinced that eteplirsen’s developer, Sarepta Therapeutics, had produced persuasive evidence that the drug increases levels of the muscle protein dystrophin to a degree likely to provide clinical benefit. Seven voted against eteplirsen’s accelerated approval.
Coalition Duchenne, a Newport Beach, California-based nonprofit corporation committed to raising DMD awareness and funding for research, participated in the April 25 FDA advisory committee hearing on the efficacy of eteplirsen.
Coalition Duchenne’s founder and executive director, Catherine Jayasuriya, reported that the meeting at the Marriott Conference Center in Hyattsville, Maryland, was attended by over 1,000 people — patients, parents, patient advocates, scientists, doctors, politicians, and caregivers, as well as companies with an interest in Duchenne developments.
She notes that the FDA will now decide how much emphasis will be afforded patient advocacy and experiential testimony —compared to the information presented to the committee. Following the vote, she said that Dr. Janet Woodcock, the regulatory agency’s top drug evaluator, took the time to talk with several parents, and boys and young men with Duchenne.
“In my opinion, at times Monday’s meeting felt more like a cross examination in a criminal case than a discussion about the efficacy of a promising treatment for Duchenne,” Jayasuriya said in a release. “As the clinical data on Eteplirsen was scrutinized, minor details became exaggerated and were considered to be relevant by the panel. Examples were the doubts expressed about validity of the Six Minute Walk Test (6MWT), and one panelist’s claim that ‘boys with Duchenne can walk if they put their minds to it.'”
“I felt that some of the panel misunderstood the complexity of the Duchenne situation,” Jayasuriya added. “I advocate for the generation of boys who
have lived the natural progression of the disease. When Duchenne is left untreated, the progression is cruel and relentless. My 23-year-old son, Dusty Brandom, will not benefit from Eteplirsen, but would benefit from the follow-on drugs targeting other exons once approval is made. Dusty has been waiting for this treatment ever since we funded Dr. Steve Wilton’s oligos [antisense oligomers] work at the University of Western Australia through the Dusty Brandom Fellowship in 2004.”
Duchenne muscular dystrophy is a devastating, genetic degenerative muscle disease that afflicts roughly 1 in every 3,600 boys born in the United States, caused by a defective gene that inhibits the production of dystrophin, which plays a key structural role in muscle fiber function. Boys and young men with DMD produce little or no dystrophin in their muscles, the lack of which causes the regenerative potential of dystrophic muscle fibers to diminish over time. Duchenne eventually affects all voluntary muscles, and the heart and breathing muscles in later stages. Currently incurable, life expectancy for DMD patients typically ranges from the late teens to the mid-20s.
Eteplirsen is designed to skip an exon — exon 51 — in the dystrophin pre-mRNA to enable synthesis of a functional shorter form of the dystrophin protein. Candidates for exon 53 skipping (SRP-4053) and for exon 45 skipping (SRP-4045) are in clinical development, with other drug candidates designed to skip exons 44, 52, 50, 43, 55, 8, and 35 in discovery and preclinical development.
The Wilton research team is collaborating with Sarepta, and currently working on extending the therapeutic applications of antisense oligomers to other inherited and acquired conditions, including spinal muscular atrophy, cystic fibrosis, multiple sclerosis, Alzheimer’s, Pompe’s disease, congenital muscular dystrophy, Huntington’s, and asthma.
Dr. Wilton says the concept of dystrophin exon skipping to treat Duchenne muscular dystrophy evolved during his development of diagnostic screening for neuromuscular diseases at the Australian Neuro-muscular Research Institute (now Western Australian Neurosciences Research Institute, or WANRI, in Perth, Western Australia) in 1991. He notes that his research group has been at the forefront in developing exon skipping as a DMD therapy, was among the first to report specific dystrophin exon skipping in the mdx mouse model (1999), and published the only panel of splice switching oligomers for every dystrophin exon (2007). The Wilton group designed the sequence of the morpholino
oligomer (eteplirsen). Dr. Wilton was appointed director of WANRI in February 2013, and the Foundation Chair in Molecular Therapies at Murdoch University in Perth in March 2013, where he is head of Molecular Genetic Laboratory in the Centre for Comparative Genomics.
“It feels like Dusty has been hanging on to a cliff, but now it is just by his fingertips,” Jayasuriya said. “We risk losing a generation of boys including my precious son. We really are running out of time. The judgment made at the 11th hour literally felt like a series of bullets that wounded our Duchenne community.
“But we don’t fall easily. In spite of my sadness and disappointment, I do have hope, because Dr. Woodcock, in her opening remarks, reminded the panel of the harm that could be done by failing to approve a drug that does work. She seemed empathic. After the meeting I thanked her and gave her a copy of my documentary, ‘Dusty’s Trail: Summit of Borneo,’ and she said that she would watch it. This is just one young man’s story — we must help the tens of thousands of boys and young men like Dusty,” Jayasuriya concluded. She added that Sen. Marco Rubio, a Florida Republican, called on the FDA to approve eteplirsen in a speech to the U.S. Congress on April 28 (https://youtu.be/pczSwOj8-Bc).
Coalition Duchenne was founded by Catherine Jayasuriya in 2011 to raise global awareness for Duchenne muscular dystrophy, and to fund research in eventual pursuit of a cure.
Coalition Duchenne has several research initiatives that are making advances in potential cardiac and pulmonary treatments for Duchenne muscular dystrophy, including a collaboration with a research team at Cedars-Sinai Medical Center in Los Angeles, California, led by Eduardo Marbán MD, PhD. That team is working on cardiac-derived stem cells and exosomes in Duchenne — technology that has been licensed by Capricor Therapeutics of Beverly Hills, California, which has launched an FDA-approved trial.
Coalition Duchenne was also instrumental in advancing into early development a novel therapy, Carmeseal by Phrixus Pharmaceuticals, for DMD and acute decompensated heart failure.
The company says that in multiple preclinical models, Carmeseal-MD, also known as Poloxamer-188 NF or P-188 NF, has been shown to seal the tears that characterize cellular membranes in DMD, leading to improved cell performance and prolonged survival and, subsequently, improved function of the heart, the diaphragm and skeletal limb muscle.
Phrixus recently announced a preclinical study showing that Carmeseal protected both skeletal and cardiac muscle in Duchenne. Carmeseal-MD is under development as a once-a-day subcutaneous injection, with an initial focus on the treatment of cardiac and respiratory deficits and upper body strength in non-ambulatory boys and young men with DMD.
For more information about Coalition Duchenne, visit coalitionduchenne.org.
Sarepta Therapeutics, Inc.
U.S. Food and Drug Administration