- Sarepta Therapeutics plans to soon file for a speedy U.S. approval of an experimental treatment for Duchenne muscular dystrophy, reporting Thursday interim results from a late-stage trial that the company says could support an application for the drug, called casimersen.
- Casimersen works in a similar fashion to Sarepta's first drug for DMD, Exondys 51, which was controversially approved in 2016. Muscle biopsy data from study participants show treatment with casimersen led to increased production of a protein missing in patients with DMD, who are almost always boys.
- Sarepta is currently awaiting a decision from the Food and Drug Administration on approval of another related therapy, called golodirsen. If golodirsen and casimersen pass regulatory muster, the biotech estimates nearly one-third of DMD patients in the U.S. could be treated with its RNA-based medicines.
Recently, much of the attention to Sarepta has focused on the biotech's advancing research in gene therapy, including a particularly promising candidate for DMD.
Yet Sarepta also has a pipeline of RNA-targeted therapies aimed at expanding on the success the biotech found with Exondys 51 (eteplirsen), its first approved drug.
Golodirsen and casimersen rely on the same approach Sarepta used with Exondys 51, binding to specific sections of the cellular instructions produced by a gene that encodes for the crucial dystrophin protein. In patients with DMD, mutations in that gene disrupt dystrophin production, causing progressive muscle weakness that eventually leads to death before the age of 30.
By binding to dystrophin pre-mRNA, Sarepta's drugs can cause mRNA processing to "skip" specific coding regions known as exons, resulting in some production of a shortened dystrophin protein.
Sarepta's leading exon-skipping drug candidates
|Exon skipped||% of DMD population amenable to treatment||Status|
|Exondys 51||Exon 51||13%||Conditionally approved|
|golodirsen||Exon 53||8%||FDA decision set for Aug. 19|
|casimersen||Exon 45||8%||Potential submission to FDA by mid-2019|
SOURCE: Sarepta, CureDuchenne
Sarepta is currently running a Phase 3 study of both casimersen and golodirsen in patients who are amenable to skipping exons 45 and 53, respectively.
Interim data from that study showed mean dystrophin production in the 27 patients treated with once-weekly casimersen increased from baseline, rising from 0.925% of normal to 1.736% of normal by week 48 of treatment. That increase, while small, was statistically greater than what was observed in the 16 patients given placebo.
By comparison, treatment with Exondys 51 was shown to result in dystrophin levels of 0.93% of normal after 180 weeks.
With this early data on casimersen in hand, Sarepta plans to meet with the FDA and work toward filing the drug by the middle of 2019.
"This is the third exon-skipping agent to have shown a statistically significant increase in dystrophin production, and reinforces our confidence in the exon-skipping approach for treating Duchenne patients with amenable mutations," said Francesco Muntoni of the University College London, in a statement provided by Sarepta. Muntoni was the principal investigator of an earlier Sarepta study.
Not all DMD patients are amenable to exon-skipping, however, and approval of Exondys 51 was initially met with considerable skepticism of whether Sarepta sufficiently proved the drug worked.
Sarepta has since expanded its research efforts into gene therapy, partnering with Nationwide Children's Hospital on treatment candidates that could hold greater potential for treating DMD.
Early data from four boys, published last year, showed the company's most advanced gene therapy candidate helped study participants stand up, walk and climb stairs more quickly than would normally be expected.
And previously disclosed results found the therapy, called AAVrh74.MHCK7.micro-dystrophin, led to protein levels between 38% and 54% of normal.
As Sarepta's gene therapy efforts progress, approvals for golodirsen and casimersen would expand the percent of DMD patients who could be treated with its medicines beyond the 13% currently amenable to Exondys 51.
"Whereas we continue to view microdystrophin gene therapy as a potentially revolutionary therapeutic option for DMD patients in the long run, we currently view the exon skipping drugs as a meaningful revenue contributor to [Sarepta]," wrote SVB Leerink analyst Joseph Schwartz in a March 28 note to clients.