Yesterday, Sarpeta (NASDAQ: $SRPT) announced that its gene therapy for Duchenne Muscular Dystrophy failed to improve muscle function in a study of 40 boys, despite achieving impressive expression of micro-dystrophin (at least in the short term). However, you spin it – and this company is world-class at spinning a story – that represents a serious blow.
Sarepta is no stranger to controversy, following the decision of the US regulator to approve the company’s earlier product, eteplirsen, which induces exon-skipping to improve expression of dystrophin protein in individuals who carry the mutant gene, as Exondys 51 back in 2016. That decision was controversial precisely because the company offered no robust evidence of clinically-relevant efficacy, and even the data showing increased dystrophin expression was unimpressive. But backed by the vociferous, if largely unscientific, support of patients and their families, the FDA took the unusual step of granting approval for an agent that, on the balance of probability, was likely to be no more effective than placebo, on the proviso that the company provided post-marketing evidence to support the efficacy claims.
Four years later, and more than a billion dollars of total revenues from Exondys 51 later, no such data has ever been presented – and now we learn that a “next-generation” strategy for increasing dystrophin, using a gene-therapy approach, increased dystrophin levels to a much greater extent than does Exondys 51, but still yields no significant clinical benefit.
The study is relatively small, and cannot exclude the possibility of a small benefit. But a consistent picture is clearly emerging: boosting dystrophin levels, even substantially, does not offer the curative potential that Sarepta and others have been promising.
On the face of it, that looks like a surprise. Here is a disease that is caused by the lack of functional dystrophin in the muscles of these boys. So surely one would expect raising levels to improve function… Sarepta scored massive investments on that simple hypothesis. Only it was always likely to fail.
To understand why, we need to look at the biology of skeletal muscle degeneration in DMD. But before doing so, its worth reading a few paragraphs from a Commentary on gene therapy that DrugBaron wrote in 2001, marking the first publication of the completed human genome sequence, just to remind us that the central flaw in the Sarepta story was well-known two decades ago. Anyone still backing this particular horse thoroughly deserved to lose half their money when the US stock market opened Friday morning.
“The underlying assumption of most gene …
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