With one exon-skipping therapy — Exondys 51 (eteplirsen) — approved for Duchenne muscular dystrophy (DMD) and others in clinical trials, it’s easy to envision Sarepta Therapeutics as the “exon-skipping company.”
But the idea of current exon-skipping treatments as the ultimate for DMD couldn’t be further from what Sarepta says it wants to achieve. In fact, Exondys 51 might just be the starting point in its goal of providing therapies for all Duchenne patients — and doing so quickly.
With partnerships in three different gene therapy development programs and a next-generation exon-skipping technology possibly just around the corner, the company has a clear vision, said Doug Ingram, who took over as Sarepta’s president and CEO in July.
“Our first goal, before any of our other goals, is to bring as many therapies to … the largest percentage of Duchenne muscular dystrophy children as possible,” he said in an interview with Muscular Dystrophy News.
An ‘agnostic approach’
Along with Ian Estepan, Sarepta’s executive director of corporate affairs, Ingram said that reaching this goal means adopting an “agnostic approach” to potential Duchenne treatments.
Sarepta, accordingly, is keen on partnering with others that have promising approaches. At the moment, the company is working with Catabasis of Cambridge, Massachusetts, on combining exon skipping with an experimental anti-inflammatory therapy called edasalonexent (CAT-1004).
And it is collaborating with French pharmaceutical firm Généthon and Nationwide Children’s Hospital of Columbus, Ohio, on three gene therapy projects, two of which are likely to reach clinical testing this year.
Nationwide Children’s researchers Jerry Mendell and Louise Rodino-Klapac are in advanced talks with the U.S. Food and Drug Administration (FDA) to bring a microdystrophin gene therapy into a clinical trial. Généthon is exploring this same method.
The dystrophin gene belongs to the top 10 largest human genes, making gene therapy in DMD particularly challenging. To get a new gene into the cells of a tissue, researchers must use some kind of carrier — often a harmless virus. But current carriers cannot hold the huge dystrophin gene.
Instead, researchers have developed micro-dystrophin — a shorter version of the gene that can fit into a virus. Preclinical data suggest that the smaller protein may be enough to have a significant impact.
At Nationwide Children’s, Sarepta is also collaborating with Kevin Flanigan on a Galgt2 gene therapy, a surrogate gene therapy that boosts other molecular processes in the muscle and may act to compensate for the lack of dystrophin.
In contrast to exon skipping, gene therapy can potentially help patients regardless of their specific mutation.
“We’re able to track a larger percentage of patients with one therapy,” Estepan said. “And that’s one of the reasons why we’re obviously extremely interested in this approach.”
If these treatments turn out to be effective, it might also be possible to combine them with others in the cocktail approach that has become standard in diseases like cancer, he added.
Sarepta, for its part, brings clinical expertise in DMD to the table. That’s the only disease field the company is now working in.
“From a clinical trial perspective, we’re the ones who eat, sleep and breathe Duchenne,” Estepan said. “Looking at clinical trials, looking at endpoints, developing endpoints, trying to validate them to be able to reliably track changes in progression. We can certainly help from that perspective.”
New treatment for exon 51 patients?
According to Ingram, Sarepta’s partnerships are also a strategic way to broaden its therapy pipeline while staying focused on its core approach — exon skipping.
While several exon-skipping drugs are in various stages of clinical trials, Sarepta is readying the clinical launch of a more advanced version of the method used, called PPMO. These compounds do exactly the same thing as current exon-skipping drugs like Exondys 51, but they have the potential of doing it much more efficiently.
The key is a tiny addition to the drug molecule — a small protein fragment that makes it easier for the drug to enter a cell. This translates to 10 to 30 times more exon skipping in animal models, Ingram said, and shows a broader reach, including to heart muscle.
“It allows exon skipping … essentially all over the body and in skeletal muscle, in the heart, in the diaphragm, in the esophagus,” he said. Sarepta is waiting for the results of a toxicology study before applying to test the compound in humans, he added.
As with first-generation exon-skipping, patients with exon 51 mutations will be at the forefront of tests of the new technology. If all goes according to plan, researchers will start treating the first child this year, Ingram said.
(An interview article with Estepan, focusing more on Exondys 51 and other exon-skipping treatments, is available here.)
Since the FDA granted accelerated approval to Exondys 51, Sarepta has been roundly criticized for pushing to move things quickly. Ingram made it clear this approach is not likely to change.
Building on his previous experience with Allergan, he spoke of the importance of acting with a sense of urgency.
“We have a lot of opportunity in front of us. We are a small group of human beings, less than 300” at Sarepta, he said. “We can move quickly and this mission that we were on is going to fuel us.”
He is well aware that such an approach includes risks and a large investment, as well as innovative thinking.
But it’s possible, he said. For innovation, Ingram and Estepan said Sarepta wants to be the first company to bring therapies to children with the most rare mutations in DMD, like those in exons 44, 52 or 50.
A goal, Estepan said, is finding a way to establish the effectiveness of exon-skipping for them. One possibility is extrapolating data from some patients with different and more common mutations to allow those with very rare mutations — who are too few to make up a clinical trial — to benefit from the treatment.
Such regulatory pathways have already been used with success, Estepan added. The FDA, for instance, recently granted Vertex Therapeutics expanded approval for a cystic fibrosis treatment, Kalydeco (ivacaftor), in patients for whom clinical trials were impossible.
Ingram also expects that Sarepta will one day work with other rare neuromuscular diseases besides DMD. But that change is not yet on the horizon.
“We want to ensure that we … bring in the therapy to DMD before we move into the next concept,” he said.
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