Sarepta Therapeutics, maker of the lone drug approved in the U.S. for Duchenne muscular dystrophy, may soon have another competitor with which to contend.
Wave Life Sciences, a Cambridge, Massachusetts-based biotech, expects to disclose fresh study results by the end of year for its experimental DMD drug suvodirsen, a potential rival to Sarepta's Exondys 51. If sufficiently strong, Wave could take the data to the Food and Drug Administration by next year in hopes of securing an expedited OK.
Expectations are mixed, however. An update from an earlier part of the trial raised questions on suvodirsen's dosing and safety, triggering a stock slide for Wave.
But the next cut of data, which comes from an open-label extension of the Phase 1 study, will describe for the first time how much of a critical protein treated patients with DMD produce. This protein, called dystrophin, is missing in boys with DMD and leads to progressive muscle weakness.
"We'll have this open-label extension data this quarter, which gives us a signal for protein and will be our trigger to do an accelerated approval filing next year, if positive," said Paul Bolno, CEO of Wave Life Sciences, in an interview.
"Importantly, behind that is coming this much larger study where we are going to have both dystrophin measurement and outcome measurement," he added, referring to a a Phase 2/3 study that began enrolling patients during the third quarter.
Wave is one of many biotech and pharma companies that are developing drugs for DMD, a disease that until Exondys 51's controversial OK in 2016 had no treatment options specifically approved to treat it.
Since then, though, the conversation around treating DMD has swung more decisively toward gene therapy, an approach pursued by Sarepta as well as Pfizer, Solid Biosciences and, much further out, Vertex.
By contrast, Wave's suvodirsen is an exon-skipping therapy, designed to alter genetic expression to spur production of dystrophin protein and, hopefully, improve muscle function.
"We know that the functional dystrophin created with skipping is actually restoring the protein that derives clinical benefit," said Bolno.
"To this date, you can't compare the Solid micro-dystrophin, to the Bamboo mini-dystrophin, to the Sarepta target. They've all cut out various parts of the protein." (Pfizer acquired Bamboo to access, in part, the company's DMD gene therapy program.)
Suvodirsen's direct comparator will be Exondys 51, both of which are designed for patients with DMD amenable to exon 51 skipping. The idea behind exon-skipping is to use an oligonucleotide — essentially a strip of nucleic acid — to compel cells to "skip over" exon 51 on the DMD gene, thereby allowing production of partially functional dystrophin protein.
Exondys 51's approval was based on data showing the drug led to production of between about 0.5% and 1.0% of the dystrophin in a healthy person — a increase small enough to spark internal division at the FDA over whether Sarepta's therapy should be approved at all.
Evercore ISI's Salim Syed and Stifel's Paul Matteis, two sell-side analysts that cover Wave, have both set 3% as the threshold production level above which suvodirsen might be considered a clear alternative to Exondys 51. Five percent would be an "unequivocal win," wrote Matteis in a recent investor note.
Dystrophin production above 3%, they argue, could mean patients' disease trajectory resembles a more mild muscular dystrophy known as Becker's.
It's a conclusion that has some basis in past FDA deliberations.
"DMD experts, including those involved with the development of eteplirsen, have stated that levels < 3% are generally associated with the typical DMD phenotype, and no patient has been found to have or produce a level of Becker-type dystrophin > 3% in response to treatment," wrote Ellis Unger, director of the FDA's Office of Drug Evaluation 1, using Exondys 51's nonproprietary name in a 2016 decisional memo.
It's unclear whether the FDA's views have changed since, however. Another Sarepta drug, this time targeting patients amenable to exon 53 skipping, was recently rejected by the agency over infection risk tied to the drug's delivery and preclinical kidney toxicity. The decision was a surprise and spurred reevaluations of what might be necessary to prove an adequate benefit-risk profile.
The rejection also opened the door for Japan's NS Pharma. Its drug viltolarsen was recently submitted to the FDA and, if approved, would be the first drug cleared to treat patients amenable to exon 53 skipping.
Bolno, however, believes NS Pharma's case won't have much bearing on suvodirsen, should it be advanced to regulators.
"As it relates to the exon 51 space, we know what the threshold standard of care looks like in Exondys 51," said Bolno. "These different exons — just as there are different drugs in development — will have different thresholds."
Safety will be critical as well, particularly given the concerns earlier this year about incidents of fever, accelerated heartbeat and vomiting seen in two patients given a high dose of suvodirsen.
If Wave shows strongly positive data, some of the roughly $300 million a year Sarepta now earns from Exondys 51 could be at risk. More mixed results, however, would further cement Sarepta's leading position in the DMD space, at least until the gene therapies in development have more data.