For genetic conditions like Duchenne muscular dystrophy, there is little doctors can do to slow or treat the condition other than trying to manage symptoms, since only addressing the genetic changes responsible can help halt the disease.
Earlier today (June 22), the U.S. Food and Drug Administration (FDA) approved the first such intervention, a gene therapy called Elevidys, from Sarepta Therapeutics, a Massachusetts-based biotech company. The approval applies only to children ages 4 and 5, which reflects the conflicting opinions within the agency about the quality of data supporting the gene therapy’s effectiveness, which delayed the decision from the original anticipate date, May 29.
Duchenne is an inherited genetic disorder, more common among males, that affects the muscles, including those not only in the limbs but in the heart and respiratory system as well, causing them to progressively weaken and waste away. The disease is caused by a genetic variant in the dystrophin gene that reduces the amount of dystrophin protein in muscles, making them stiffer and less pliable, eventually causing muscles to contracted too tightly and become less mobile. Over time, scarring and fibrosis further limit muscle function.
Most people born with the inherited genetic disorder start to show symptoms of muscle weakness as early as age 2, and as the disease worsens, typically lose their ability to walk and eventually to breathe on their own. There is no cure, but doctors can prescribe medications to improve muscle strength, particularly for the heart and lungs, or recommend surgery to treat severe contractions that can affect posture to help patients live to their 20s or 30s.
A new pioneering gene therapy
Elevidys works by replacing the Duchenne variant of dystrophin with man-made version based on a version found in a patient with a milder form of the disease, called Becker muscular dystrophy. That patient remained mobile and ambulatory into his 60s. His dystrophin gene was significantly shorter than normal versions, a key feature that made the gene therapy possible, since the dystrophin gene is the largest human gene, making it nearly impossible to pack into small enough molecular vehicles to deliver it into cells safely.
Dr. Jerry Mendell, a neurologist at Nationwide Children’s Hospital, and Dr. Louise Rodino-Klapec, then a post doctoral fellow in Mendell’s lab and now chief scientific officer at Sarepta, spent years figuring out which parts of the Becker dystrophin gene were essential to conserving muscle function. That genetic construct is the backbone of Sarepta’s gene therapy for Duchenne, which patients receive in a single injection.
Before the researchers could license the technology to the company, they had to solve the problem of how to deliver the carefully selected, improved version of the dystrophin gene to as many muscles throughout the body as possible. They eventually settled on a cold virus vector that can easily find muscle cells, and added a genetic sequence that was activated when it bound to muscle cells, ensuring the genetic payload was preferentially delivered to muscles and not to other types of cells.
In the first human studies of the gene therapy, in four boys ages 4 to 6 years old in 2018, the new dystrophin gene found its targets and the amount of healthier dystrophin they produced was “higher than we anticipated,” says Mendell. “We are at the five year mark for those kids and they haven’t declined; that’s very encouraging.”
Inconclusive results in a larger study
In the next, larger study of patients however, the results were less conclusive. Mendell faults the study design, which involved a broader range of patients including those who might have been too far along in their disease to show benefit from the therapy. Some FDA officials questioned whether the increased dystrophin levels seen in lab tests translated to real-world benefits such as greater muscle strength, or extended time during which the patients could walk independently.
That uncertainty is likely the reason why the FDA decided to limit its approval to 4- and 5-year old patients.
But for boys that age, the results look good: that data, says Dr. Barry Byrne, chief medical advisor for the Muscular Dystrophy Association (MDA) and director of the Powell Gene Therapy Center at the University of Florida, show “that are doing things that untreated boys could never do. One of the simplest things is to run. Boys who are not treated have trouble putting even one foot on the floor, [much] less both feet which is required to run. And running is a fundamental part of childhood and playing.”
Indeed, the first patients who received the gene therapy appear to have stabilized—which “buys time,” says Sharon Hesterlee, chief research officer at MDA, since there are other drugs in development that can reduce other disease processes, such as muscle scarring. And if the gene therapy can keep muscles functioning longer, some people who receive it early enough may never develop the more severe forms of the condition.
A potential price tag of more than $1 million
The next challenge for patients and their families will be access. While Sarepta has not priced the treatment, some analysts say that, given it is a one-time therapy, it could cost more than $1 million.
And of course, the current age requirement means access could become challenging if insurers strictly enforce the FDA approval recommendations for four- and five-year olds only, and families find themselves racing against an age deadline as affected children approach their sixth birthday.
While the treatment currently has an age-limited approval, Rodino-Klapec, Sarepta’s chief scientific officer, says in the future it could lead to options for Duchenne patients of all ages. “The mechanism of action applies to all patients with Duchenne muscular dystrophy regardless of age or disease status,” she says. “We may see differences in functional outcomes based on where they are in the course of their disease because it targets the muscle they have, but we believe it is applicable to all patients.” Rodino-Klapec says there are studies currently underway that could provide data to support that by the end of this year.
Gene therapy is still a nascent technology, and approvals like this one will help more patients to take advantage of it, and allow researchers to learn more about how to optimize it and apply those lessons to other genetic conditions as well. For Duchenne patients, it’s the beginning of a new era of potentially life-changing therapy. “This is the opening event,” says Mendell, “the pioneering event,”
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