As Sarepta (formely AVI) 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. For quick reference, this group includes out-of-frame deletions in exons 45-50, 47-50, 48-50, 49-50, 50, and 52.

But for 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 intractable. 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.

Not feeling altruistic? Keep in mind that:

• There are two drugs in the “healthy volunteer” phase of testing that increase the amount of utrophin, a protein that can stand-in for the loss of dystrophin (Summit PLC, Pfizer) and another two that are in the preclinical lead-up phase to a human study in Duchenne (PTC Therapeutics, Tivorsan).
• There are two drugs in development that may be able to produce the positive effects of prednisone without the side effects, one in testing in healthy volunteers (Catabasis) and one that has been partnered by the National Institutes of Health to move it toward clinical testing (Reveragen).
• Idebenone, a strong antioxidant, is in phase III clinical testing for Duchenne (Santhera).
• Nationwide Children’s Research Institute is testing the ability of a gene called follistatin to increase muscle mass in Becker muscular dystrophy via gene therapy.
• None of these approaches are mutation-dependent.

Not fast enough? The good news is that it looks like there may be a number of existing approved drugs that may be useful in slowing the progress of Duchenne.

• Currently in clinical testing are phosphodiesterase inhibitors Sildenafil (Viagra®) and Tadalafil (Cialis®), which may overcome the reduced blood flow experienced by people with Duchenne when the muscles contract and may do other helpful things that aren’t clearly understood yet.
• Following impressive improvements in strength in mouse models of muscular dystrophy, a class of cardiac drugs called aldosterone inhibitors (including spironolactone and eplerenone) are in clinical testing now.
• Another study, supported by Charley’s Fund, is evaluating the potential benefits of insulin-like growth factor.

Parent Project Muscular Dystrophy’s mission is to support all those affected by the lack of dystrophin—boys and girls, Duchenne-like symptoms and Becker-like symptoms. We will continue to fund a wide portfolio of research projects that includes both mutation-specific and non-mutation-specific approaches. And we will support the back-up approaches to those approaches. This strategy dovetails with our research plan characterized by the phrase “Better, Faster, Now!”  We will put better drugs into clinical testing, we will improve the speed of clinical testing and we will test approved drugs in parallel now. And we will still be in this business until meaningful treatments are available for all of those with Duchenne.

Blog by Sharon Hesterlee, Ph.D.
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