I have said unkind things about Sarepta’s drug for Duchenne muscular dystrophy, Exondys (eteplirsen). That’s because I did not think that there was enough information to approve it at the FDA, and I had trouble believing that its biochemical effects were enough to be meaningful in general. I have no reason to modify those opinions, but I do have reason to modify my opinions about Sarepta itself, because they have just presented startlingly good data for Duchenne MD via a completely different approach.
The key to helping Duchenne patients seems to be production of functional dystrophin protein, which they lack. Exondys was an attempt to do this by changing the way the protein was expressed, via a
small molecule antisense oligo, restoring a functional reading frame and producing a less-ruined dystrophin protein. This new method, though, is out-and-out gene therapy, using an AAV vector to insert a new gene. The dystrophin gene itself is far too large a payload, as it turns out, so this uses a “micro-dystrophin”, a truncated form of the protein that should nonetheless be functional (or at least far more functional than the mutated forms that patients themselves produce).
The results in the initial dosing of three children appear to be dramatic. The levels of dystrophin protein increase strongly, and the levels of creatine kinase (an enzyme marker of the disease, involved in destruction of muscle tissue) drop strongly as well. It seems that the patients themselves are experiencing equally strong clinical benefit, if the video (at that first link) of one of them running up a flight of stairs is at all representative. No complete scientific presentation has been made, I need to add, but what we can see is very interesting indeed.
Sarepta is starting a 12-patient placebo-controlled crossover trial, which should help out evaluating this technique. Twelve patients is not a lot, but with an effect size this large, it could be convincing. Meanwhile, Pfizer started dosing their own mini-dystrophin gene therapy in April, and Solid Biosciences, after a clinical hold, is back dosing their version as well. Encouraging word has leaked out concerning a single patient on the latter therapy, for what that’s worth.
In general, though, there has never been a more encouraging time for Duchenne MD patients and their families. Here are three very strong shots at corrective therapy well into the clinic. The thing to hold the breath about, as usual, is safety. AAV is currently of huge interest as a method for gene therapy, and so far seems relatively safe, but the field is young. There’s also a potential problem of antibody formation: everyone’s immune system is different, and some patients may find their own attacking the viral capsid proteins that are delivering the gene. No one’s sure how large a problem this might be yet, or how it might vary across patient populations in clinical practice.
But these questions – efficacy and safety – are finally being sorted out in real patients, and we can hope for the best. Gene therapy has obviously – in theory – been the sovereign remedy for many genetic disorders ever since we understood how these worked in the first place (which would be 1949, and Linus Pauling’s demonstration of the molecular basis of sickle cell anemia). But turning that into reality has been a very long and very hard process – see Jesse Gelsinger for the first example, and not the last. Although Gelsinger’s case is definitely the clearest connection, there have been numerous deaths in subsequent gene therapy trials (although it’s also true that many of these patients have been very sick indeed, trial or not). If we’re closer to getting this to work reliably, the world will be a better place for a lot of patients who have nowhere else to turn (note Bluebird’s recent data on sickle cell and beta-thalassemia). We shall see.