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Safety questions linger as Pfizer preps Duchenne gene therapy for final test.

Pfizer is adding fresh details to a growing body of evidence suggesting that gene therapy might help change the trajectory of Duchenne muscular dystrophy, a deadly genetic disease with no cure. New study results from Pfizer, to be presented Friday at the American Society of Gene and Cell Therapy's yearly meeting, come with important caveats, however.

The data are from a handful of patients in an early-stage, uncontrolled study that's meant, first and foremost, to make sure the gene therapy is safe. To that point, two patients experienced potentially dangerous immune reactions after treatment. Some patients appear to have improved motor function after a year of follow-up, but it's unclear how long those effects will last and whether the gene therapy is doing all the work.

Still, Pfizer believes the data are good enough to take the experimental gene therapy, called PF-06939926, into a late-stage study that should begin later this year, according to Michael Binks, Pfizer's vice president of rare disease clinical research. That would put the pharma close behind rival Sarepta Therapeutics, whose gene therapy SRP-9001 is already in the first of two final tests and should produce results early next year.

Duchenne is a genetic disease that afflicts some 300,000 people, mostly boys, worldwide. They lack a key muscle-protecting protein, dystrophin, which causes their muscles to slowly waste away. They're typically in wheelchairs by adolescence and die at a young age from lung or heart problems. The only treatments are steroids, and, for two small subsets of patients, two drugs from Sarepta called Exondys 51 and Vyondys 53. At best, these treatments can slow the march of the disease, but they don't change its course.

The hope is that gene therapy can do much better. Pfizer, Sarepta and Solid Biosciences are all developing one-time treatments that shuttle genetic instructions into the body to produce, in perpetuity, a shortened form of dystrophin capable of functioning like the real protein.

The differences between each treatment involve which gene therapy tools are used to deliver the dystrophin blueprints into patients. The studies also have some key differences that make them difficult to compare to one another: Sarepta's results to date are in boys 4 to 7 years old, while Pfizer is testing its gene therapy in 6 to 12 year olds, who are more likely to have started declining from the disease. Both are using different methods to measure levels of dystrophin in the muscles.

Ideally, according to Binks, gene therapy could slow or "hopefully stop" the progression of Duchenne. That could mean patients get extra years walking, or without breathing support, or ultimately alive. It's too early to say whether any of that is possible, or even whether producing shortened versions of dystrophin is truly helpful.

"The extent to which we'll see improvements in function, we don't know whether that's going to happen," Binks said.

Over the past two years, dribs and drabs of data have emerged from studies of each treatment suggesting that there's a chance it will. None of the results are from placebo-controlled trials, and the tests involve treatment with steroids, which could make it difficult to judge how much the gene therapies are helping.

Clinical trials have also borne out the difficulties in bringing a gene therapy to Duchenne patients all at once. It's likely that some patients won't be able to get the treatments, if they reach market, due to manufacturing bottlenecks and other issues.

"A couple of years ago it was, 'this is the silver bullet,' so many families thought this was going to be the cure. We've had to become very sober about the realities of gene therapy for Duchenne," said Debra Miller, the CEO of the nonprofit group CureDuchenne, in an interview.

But the early data — first from Sarepta in 2018, and then from Pfizer last year — suggested a clinical benefit, based on positive changes seen on the North Star Ambulatory Assessment scale that measures motor function in patients with Duchenne.

Pfizer provided its most detailed results yet on Friday, primarily from six patients who received the gene therapy over a year ago. Three of those patients got a low dose of Pfizer's gene therapy; the other three a high dose.

When disclosing initial results last year, Pfizer had reported serious side effects in two patients, including one who had kidney damage from a dangerous immune response and had to spend 11 days in the hospital. That patient has since recovered, but Pfizer has now seen a second instance of a potential immune reaction to the gene therapy.

In the most recent case, the patient experienced low platelet counts on a blood test a week after getting treated, and was given a platelet infusion and the drug Soliris before things got worse. "We believe it's most likely a result of antibodies forming" against the gene therapy, Binks said. Since the first worrisome immune response, Pfizer has been monitoring patients more closely right after getting treated, he added.

But the disclosure separates Pfizer's gene therapy from Sarepta's program, which hasn't had any serious safety problems as of yet. Rival Solid has, and the FDA has halted its program as a result.

According to Miller, the safety issues seen thus far haven't dampened patients' enthusiasm for gene therapy. "There's a belief that we're learning as we go," she said. 

Author: Benthe Fidler

Published: May 15, 2020

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