Eteplirsen trail results extremely encouraging
The exon-skipping drug eteplirsen showed extremely encouraging results in both an October and a December report from Sarepta Therapeutics. The experimental drug is in development to treat boys with DMD who have mutations that potentially can be treated by skipping exon 51 of the dystrophin gene (RJ is missing exons 22-29).
Exon skipping is an experimental strategy in which cells are coaxed to reinterpret genetic instructions by “skipping” certain sections (exons) of a gene and piecing together the remaining parts to create a functional protein. IN DMD, the protein is called dystrophin.
On Oct 3, Sarepta announced results of a 12-person trial in which boys treated with 48 weekly intravenous infusions of high-dose eteplirsen increased the distance they could walk in six minutes by about 69 feet. By contrast, boys who received placebo infusions for the first 24 weeks and then eteplirsen for the next 24 weeks declined in walking ability by a bout 224 feet over the same time period. A group that received a lower dose of eteplirsen fro the entire48 weeks declined similarly in walking distance.
All trial participants, including those who initially received placebo infusions, showed a significant increase in dystrophin protein in sampled muscle fibers at the 48-week time point. The boys who received eteplirsen for the entire 48-weeks showed an average of 47 percent of their muscle fibers producing dystrophin. Normally, 100 of muscle fibers produce dystrophin; in DMD, fewer than 5 percent do.
There were no serious adverse events and no one discontinued treatment.
“These data represent a significant milestone and a defining moment of progress and hope for patients with DMD and their families, as well as for those of us in the scientific community who have been pursuing potential treatments for this devastating and deadly disease for decades,” Dr. Mendell said.
On Dec. 7, Sarepta reported data from an additional 14 weeks of this trial. The 62-week results show continued stabilization of walking ability with eteplirsen.
Sarepta is continuing to follow the progress of the participants in this trail and plans to meet with U.S. Food and Drug Administration (FDA) to discuss next steps toward approval of eteplirsen.
Drisapersen in Phase 2 and 3 trials
In November, multinational pharmaceutical company GlaxoSmithKline (GSK) announced that its experimental drug drisapersen, which (like eteplirsen) targets exon 51 of the dystrophin gene, appears to be safe and to reach adequate blood levels after injection in nonambulatory boys with DMD. The trial included 20 boys who had been using a wheelchair full time for one to four years, and who had specific mutations in the dystrophin gene.
What does this mean for RJ?
As Sarepta announces promising results from its phase II interim data and GSK follows up its promising phase II data with a phase III study, things are looking good for an exon-skipping based therapy for Duchenne…if you happen to be in the 13% of those with Duchenne who have a mutation that can be improved by skipping exon 51. RJ is not in the 13% because he is missing exons 22-29.
Although RJ falls in the other 77% of families out there dealing with other types of mutations including other deletions, duplications or point mutations, what does an exon 51 success mean? From the big picture standpoint a success with a drug focused on exon 51 means that we will have, for the first time, a “proof of principle” that the course of the disease can be modified beyond the effect gained by steroids. It means that work on skipping additional exons to include a broader range of mutations will speed up dramatically. It also means that companies working on other types of therapy that are not mutation-specific and their investors will gain confidence from knowing that the disease is not inflexible. It means that there will have been established a “regulatory path” or roadmap that can be used by other companies to approve additional drugs. It means that new born screening will become ethically acceptable and we will identify all affected children earlier, which will in turn allow those children to participate in trials of new drugs at even earlier ages.
Bottom-line is that success with exon skipping 51 would hopefully lead to success with other exon skipping like RJ’s missing 22-29 exons!