Sarepta’s Data Are First in Rush for Duchenne Gene Therapy

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an average of 76.2 percent of muscle fibers with dystrophin. And patients have had an average 87 percent decrease, after 60 days, of CK levels. Very high CK levels are evidence of muscle damage and a hallmark of patients being diagnosed with Duchenne. The level of CK decline in the three patients shows “how much the micro dystrophin that we’re seeing is protecting the muscle fibers,” says Mendell. Sarepta reported no major safety issues in these three patients.

Sarepta has only disclosed indirect measurements. It hasn’t yet reported any data on functional improvements—such as whether patients’ ability to climb stairs or walk has improved. But the indirect measurements of the disease, via proteins in the blood, are still important because the FDA approved Sarepta’s own Duchenne drug, eteplirsen (Exondys 51), in September 2016 largely based on changes in dystrophin levels in just 12 patients. The FDA said the amount of dystrophin eteplirsen helped produce was “reasonably likely to predict clinical benefit.” At the time, there were no approved drugs for Duchenne, a devastating disease that affects an estimated 15,000 boys in the U.S., 300,000 worldwide, putting them in wheelchairs by their teenage years and typically killing them at an early age. The FDA approval was so controversial it caused an internal rift at the agency. (Eteplirsen is only meant for a form of Duchenne carried by 13 percent of patients. Since its approval, the FDA has also given the nod to a muscle-boosting steroid for all patients called deflazacort (Emflaza). Neither are cures.)

It’s unclear at this point whether the FDA would consider a surrogate marker approvable for the gene therapy. “We’re going to have to sit and talk with the FDA about this,” says CEO Doug Ingram.

But Ingram is pursuing an “ambitious timeline” for the gene therapy. Sarepta will report more detailed data from all six patients enrolled in this part of the study at the World Muscle Society meeting in October. And by the end of the year, the company hopes to enroll 24 patients in a new, placebo-controlled arm of the trial in which half the group would get the gene therapy initially, and the other half after a year. The hope is Sarepta could file for FDA approval off of that data, he says, though he cautions, “We need to meet with the FDA and ensure it aligns with us on that process.” Sarepta will meet with the agency sometime in the next 90 days, he says.

These patients and others enrolled will get several physical examinations over the next few years to help accrue data on micro dystrophin expression, CK levels, and muscle function to see how much the gene therapy benefits patients and how long its effects hold up.

While the data being reported today are from just three patients, small sample sizes so far have been the norm in gene therapy trials for rare diseases. The first gene therapy approved in Europe, Glybera for a rare metabolic disease, was tested in just 27 patients before European approval in 2012. Late last year, the FDA approved the gene therapy voretigene neparvovec (Luxturna), for a rare inherited vision loss, after it was tested in just 41 people.

Small sample sizes aside, an important question hangs over Duchenne gene therapy: is it safe? The FDA halted a study of a gene therapy from Sarepta’s rival Solid Bio (NASDAQ: SLDB) after a patient’s platelet and red blood cell counts dropped dangerously low. The news came weeks after gene therapy pioneer James Wilson—who resigned from Solid’s scientific advisory board in January—and his colleagues at the University of Pennsylvania published a paper sounding an alarm about gene therapy for diseases like Duchenne. Their concerns stemmed from animal tests of a potential gene therapy for the rare disease spinal muscular atrophy.

Wilson and colleagues called for more “careful monitoring” when infusing into the bloodstream a high dose of adeno-associated viruses (AAV)—the leading method of gene delivery for certain gene therapies, such as those from Sarepta, Solid, and Pfizer.

The FDA on Monday cleared Solid to resume testing of its Duchenne gene therapy SGT-001 with a modified protocol that included closer monitoring.

So far, Sarepta has not reported serious problems. The company reported today that two patients saw levels of a particular enzyme spike, a common gene therapy reaction, but extra steroids helped lower those levels. Patients had temporary nausea from the steroids.

Back in January, Mendell, told Xconomy that it was important to see if the “micro” version of dystrophin being packed into Sarepta’s gene therapy would behave in the same way as regular dystrophin. With the new data, Mendell is already confident that these results are real and could provide a lasting benefit for those who have been treated. He wants to see if patients continue to get better beyond seven years of age, which is when Duchenne patients tend to see their muscle function start to significantly decline.

“We expect [the gene therapy] to improve function,” Mendell says. “Otherwise we’re not doing better than steroids or eteplirsen.”

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