Editor's note (Oct. 26, 2012): This story has been modified to note that it's possible for the U.S. Food and Drug Administration to give conditional approval to a promising rare-disease drug prior to a larger confirmatory trial being performed.
The experimental exon-skipping drug eteplirsen, in development by Sarepta Therapeutics (formerly AVI BioPharma) to treat approximately 13 percent of boys with Duchenne muscular dystrophy (DMD), has been found to have significant functional and biochemical benefits in a phase 2b trial.
This is the first trial of a treatment for DMD that has showed a reversal, not just a slowing, of disease symptoms. However, an important caveat is that the trial was very small, involving a total of only 12 participants.
"Despite the small size of the trial, the results are very promising and provide hope for the families for whom exon skipping is a viable treatment option,” said Sanjay Bidichandani, MDA vice president of research.
MDA has been supporting exon skipping as a potential strategy for treating DMD since the 1990s. The strategy modifies genetic instructions so that a functional protein can be produced despite the presence of a genetic mutation.
In addition, the Association supplied supplemental support for the current eteplirsen trial through a grant to neurologist Jerry Mendell at Nationwide Children's Hospital in Columbus, Ohio. Mendell is a longtime MDA research grantee and co-directs the MDA neuromuscular disease clinic at Nationwide.
Sarepta, headquartered in Cambridge, Mass., announced results of the 48-week, phase 2b trial of the drug in a press release on Oct. 3, 2012.
Trial participants were required to have a mutation potentially treatable by skipping the exon 51 section of the dystrophin gene, to be ambulatory and to meet other study criteria. ("Skipping" exon 51 means leaving out exon 51 from the final genetic instructions for the dystrophin protein, with the goal of producing a functional protein instead of a nonfunctional one.)
The trial included 12 boys with DMD ages 7 to 13 who met these criteria. It was divided into two parts: a 24-week, placebo-controlled part and a 24-week extension part.
During the placebo-controlled part, eight boys received weekly intravenous infusions of eteplirsen. Four of the eteplirsen-treated participants received the drug at 30 milligrams per kilogram, and four received it at 50 milligrams per kilogram. In addition, four boys received placebo infusions.
This initial phase resulted in increased dystrophin in the muscle fibers of those receiving eteplirsen, but no significant improvement in walking ability compared to the placebo group.
During the 24-week extension part of the study, all 12 participants received eteplirsen infusions. Those who received it initially continued to receive it at the same dosage level. Two of those who had been on the placebo infusions began receiving eteplirsen at 30 milligrams per kilogram, and two began receiving it at 50 milligrams per kilogram. (The extension study was "open label," meaning investigators and trial participants were aware of the dosage being given.)
Those who received the placebo for the first 24 weeks and then eteplirsen for the second 24 weeks are referred to by Sarepta as the placebo/delayed treatment group.
Below are details of the main findings of the eteplirsen phase 2b trial at 48 weeks.
All participants, including those who initially received a placebo, showed a significant increase in production of the needed dystrophin protein in sampled muscle fibers at the 48-week time point.
In DMD, fewer than 5 percent of fibers produce dystrophin. (In a person without DMD, 100 percent of muscle fibers produce dystrophin.)
The eight boys who received eteplirsen infusions for all 48 weeks showed an average of 47 percent of their muscle fibers producing dystrophin.
In addition, the four boys in the placebo/delayed treatment group showed an average of 38.3 percent of sampled muscle fibers producing dystrophin at the 48-week mark.
The four boys who were in the 50-milligram eteplirsen group for all 48 weeks increased the distance they walked in six minutes (the "six-minute walk test") by an average of 21 meters (68.9 feet) between their first (baseline) test and their final test at 48 weeks.
This is the first known instance of a trial of a DMD treatment resulting in an actual reversal, rather than simply a slowing in the decline of walking ability.
In contrast, the four participants in the placebo/delayed treatment group showed an average decline of 68.4 meters (224.4 feet) between their baseline and their final six-minute walk tests.
Participants who were in the 30-milligram eteplirsen group for all 48 weeks showed a decline in walking distance similar to those in the placebo/delayed treatment group.
(The company reported that its analysis of the six-minute walk test results excluded two of the four participants in the 30-milligram eteplirsen group who showed signs of "rapid disease progression" within weeks of enrollment in the study, because they could not perform the required walking tests after 24 weeks.)
There were no serious adverse events or treatment-related adverse events, and no one discontinued treatment. No significant treatment-related changes were detected on any laboratory tests, including those for kidney function.
Sarepta President and CEO Chris Garabedian said in a webcast on Oct. 3 that the company is "exploring a variety of possibilities" for moving eteplirsen toward U.S. Food and Drug Administration (FDA) approval.
The current small study will continue, and a larger study will be designed. Although the FDA usually requres a placebo-controlled confirmatory study, Garabedian said he thought the DMD community might not "tolerate" a study in which some participants received a placebo instead of eteplirsen. He said that there are alternatives to placebo-controlled studies, such as using an untreated group for comparison, and emphasized that Sarepta will be "having conversations" with the FDA.
Under the FDA's Accelerated Approval mechanism, it's possible for a rare-disease drug to receive conditional approval prior to a larger confirmatory study being performed.
To learn more about accelerated approval, see the FDA's Fast Track Accelerated Approval and Priority Review and MDA Urges Legislators to Speed Approval of Rare Disease Drugs.
Geneticist Louis Kunkel, a longtime MDA research grantee at Boston Children's Hospital and Harvard University and part of the team that initially identified the dystrophin gene in 1986, was enthusiastic but cautious in his assessment of the data.
"It's great to see this day coming after all the work that has been done by so many investigators over many years," he said, adding that "it would not have been possible without MDA support."
Kunkel said he and others proposed as far back as the late 1980s, shortly after the dystrophin gene was identified, that the course of DMD could be improved by taking out some of the genetic instructions for the dystrophin protein — a strategy that later became known as exon skipping.
However, Kunkel also encouraged caution: "This looks good, but it's preliminary data. There were a small number of patients, and more patients need to be studied." He also emphasized that eteplirsen will only treat a minority of people with DMD.
Eteplirsen targets exon 51 of the dystrophin gene, as does another experimental drug, drisapersen, being tested in clinical trials. Drisapersen, in development by GlaxoSmithKline, is now in a phase 2 trial in the U.S. and a phase 3 trial outside the U.S.
Although approximately 13 percent of the DMD population can be treated by drugs that target exon 51, Sarepta's website says approximately 85 percent of individuals with DMD potentially could benefit from an exon-skipping drug, although different errors in the dystrophin gene will require different compounds. Sarepta has drugs targeting other dystrophin exons in its pipeline, and other researchers are working on the "block skipping" of multiple exons in mice.
MDA has awarded approximately $4 million in grants to support research in exon skipping for DMD since 1996 and continues to support this strategy.
To learn more about exon skipping: