Deanna Tucker, PharmD, is the medical science liaison team leader at Sarepta Therapeutics. Credit: Larry Luxner

Six years ago, Sarepta Therapeutics of Cambridge, Massachusetts, became the first drug company to win US Food and Drug Administration (FDA) approval for a therapy to treat Duchenne muscular dystrophy (DMD).

That medication, eteplirsen (Exondys 51), was specifically aimed at the 13% of patients with DMD who have a confirmed mutation of the dystrophin gene amenable to exon 51 skipping.

Since eteplirsen’s rollout in September 2016, Sarepta has won FDA approval for two more DMD therapies: casimersen (Amondys 45TM), for DMD patients amenable to exon 45 skipping, and golodirsen (Vyondys 53TM), for those with an exon 53 deletion.

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But the latest drug in Sarepta’s pipeline could be a real game-changer: the first-ever experimental gene therapy to treat Duchenne.

Read more about gene therapy for DMD

In July, the company announced it would ask the FDA to grant accelerated approval for delandistrogene moxeparvovec (SRP-9001) specifically for Duchenne patients who can still walk.

“Based on the feedback we received following a thorough and in-depth review, we intend to submit a [Biologics License Application] for our SRP-9001 gene therapy this fall,” Sarepta president and CEO Doug Ingram said in a press release. “We look forward to a collaborative review commencing this year and running through the first half of 2023.”

EMBARK Trial Now Enrolling Patients

That would represent a major victory for Sarepta and its Swiss-based partner, Roche, which are racing to develop a DMD gene therapy in competition with Pfizer and Solid Biosciences.

Deanna Tucker, PharmD, is Sarepta’s medical science liaison team leader. In an exclusive interview with Rare Disease Advisor, Dr. Tucker outlined her company’s approach to treating—and ultimately curing—the rare fatal and progressive neurological disease.

“We have three different programs for developing therapies for Duchenne. The first is our RNA platform, which designs exon‑skipping therapies. Our first generation has already produced three FDA‑approved exon‑skipping therapies for exons 45, 51, and 53,” said Dr. Tucker, speaking on the sidelines of CureDuchenne’s 2022 Futures Conference in Orlando, Florida.

“We are also developing a second-generation or a next-generation technology we refer to as PPMO [peptide phosphorodiamidate morpholino oligomer],” she explained. “We’ve taken that exon‑skipping molecule and added a peptide conjugate. That gets it into the muscle cell a little bit quicker. We hope this will produce more dystrophin in a faster period of time.”

But Sarepta is clearly focusing most of its attention on the third prong of its Duchenne pipeline: gene therapy. According to a report in TheStreet—an online newsletter for investors—Sarepta’s DMD portfolio alone is expected to generate $825 million in 2022 net revenue. And, of the company’s 37 products in the pipeline, 21 are in gene therapy.

Sarepta has already dosed 80 patients in clinical trials for SRP-9001, ranging from 3 to 19 years of age, with varying levels of ambulation. Its phase 3 trial, known as EMBARK, is enrolling 120 patients in the US and overseas. Later this year, Sarepta hopes to launch its second phase 3 study, ENVISION, for boys older than 8 years of age—both those who can walk and those who cannot.

For EMBARK, Sarepta is including only boys ages 4 to 8, and those with mutations 18 to 79. The one exception in that 18-79 range is exon 45, which is being excluded, as well as all boys with mutations in exons 1 to 17.

Key Barriers to DMD Gene Therapy

Several conditions must be met, however, for gene therapy to have any hope of being effective in treating Duchenne.

“Patients must be on a daily, stable dose of steroids. We also have to make sure they don’t have too many antibodies,” Dr. Tucker said. “We have to run that test prior to them getting the dose of gene therapy, because if you have too many antibodies, the body will keep it from going into the muscle cell.”

She added: “Fortunately, many of us have developed protocols that will allow for older, nonambulatory patients, because we still need to understand how we can modify their disease.”

The biggest challenge in developing a gene therapy for DMD has always been dystrophin’s size; it’s the largest gene in the human body.

“The vector we use—basically our vehicle that gets that new gene into the body—is very small. Oftentimes, I’ll tell people it’s like going on a very long trip and only being able to take a carry‑on suitcase,” Dr. Tucker explained. “We have this tiny little suitcase that we have to put this big gene into. With some diseases, the gene is small enough that you can put the entire gene into that very small vehicle. With Duchenne, we’re just not able to do that.”

Another challenge is that viral capsids currently used in drug development often trigger strong immune reactions. In a recent seroprevalence study of 101 boys aged 4 to 18 years with Duchenne, Sarepta found that 14% had antibody levels that were too high, a rate Dr. Tucker said “has been very consistent with the literature.”

The other big obstacle in gene therapy is the sky-high high price of raw materials, even though no one knows how much SRP-9001 will cost. For example, onasemnogene abeparvovec-xioi (Zolgensma®), a one-time gene therapy for spinal muscular atrophy (SMA), retails for $2.1 million.

“With gene therapy, it is very time-intensive to develop enough of the vector. Then, you’ve got to package it in the gene, and the cost of goods to manufacture it is much higher than your traditional type of medication,” she said. “Other therapies that have been approved definitely tell us that it’s probably going to be expensive.”