Eteplirsen, an experimental exon-skipping drug designed to treat Duchenne muscular dystrophy (DMD) caused by specific mutations in the dystrophin gene, continues to show sustained benefit on walking distance through week 84 of a phase 2b, 12-person study.
Eteplirsen is designed to skip exon 51 of the dystrophin gene.
Results were announced by Cambridge, Mass.-based Sarepta Therapeutics in a June 19, 2013, press release, and on the same day at the Wells Fargo Securities 2013 Health Care Conference, held in Boston.
A webcast of the conference presentation, with supporting materials, is available on the Sarepta website.
"We now have demonstrated stability of walking for over a year and a half in the original eteplirsen treatment cohort in boys who are now 11 years old on average, an age when many DMD boys have lost the ability to walk," said Chris Garabedian, president and chief executive officer of Sarepta Therapeutics.
Walking distance, dystrophin production evaluated
After 84 weeks (1.6 years), walking ability stabilized in all trial participants, although those treated with eteplirsen for all 84 weeks stabilized at a higher level (longer walking distance) than those who were on a placebo for the first 24 weeks and then treated with eteplirsen.
Walking distance was measured by the six-minute walk test— how far a trial participant can walk in six minutes.
Participants treated with weekly intravenous infusions of eteplirsen for the entire study period at either of two dosage levels are designated the continuous treatment group. Participants treated with placebo infusions for the first 24 weeks, followed by eteplirsen infusions, are designated the placebo/delayed treatment group.
Muscle biopsies to assess production of dystrophin— the muscle protein that's needed but missing in DMD — were performed at week 48 in all participants. Results reported earlier showed all participants were producing dystrophin at the 48-week time point.
Two participants from the continuous treatment group lost walking ability by week 24 and therefore could not be evaluated on the six-minute walk test after that point.
One participant from the placebo/delayed-treatment group temporarily lost walking ability due to an ankle fracture and could not perform the six-minute walk test at week 84. He has since regained the ability to walk.
Walking stabilized despite advancing age
The investigators found the following:
- From baseline (week 0) to week 84, the average decline in six-minute walking distance in the continuous treatment group was 21 meters (69 feet).
- From baseline to week 84, the average decline in six-minute walking distance in the placebo/delayed treatment group was 67 meters (221 feet).
- The continuous treatment group walked, on average, 46 meters (152 feet) farther at week 84 than the placebo/delayed-treatment group, a difference that was considered statistically significant.
- Six-minute walk distance in the placebo/delayed-treatment group began to stabilize at week 36, which is the time when dystrophin protein production may have begun.
- Between weeks 36 and 84, all participants in the continuous treatment group declined in walking ability, but by less than 10 percent. The average age in this group at 84 weeks was 11 years, a time when walking ability in DMD-affected children usually declines markedly.
- Between weeks 36 and 84, three participants in the placebo/delayed-treatment group actually increased their walking distance, while a fourth showed a decline of 2.5 percent. The average age at 84 weeks in this group was 10.4 years, a time when boys with DMD can be expected to experience significant declines in walking ability. (Note: One participant reported to have experienced a very small increase in walking distance was not evaluated on walking at 84 weeks because of an ankle fracture; results are presumed to be based on previous six-minute walk distance data.)
- There were no clinically significant treatment-related adverse events, no serious adverse events and no discontinuations of treatment.
- There were no clinically significant treatment-related changes on any laboratory test related to the safety of the drug.
- Two participants experienced temporary elevations of urinary protein, but these resolved without intervention and caused no apparent ill effects.
Sarepta's regulatory path forward
In his presentation at the Wells Fargo conference, CEO Chris Garabedian said the following:
- Sarepta hopes to meet with the U.S. Food and Drug Administration (FDA) about next steps toward approval for eteplirsen by the end of July 2013. (The company had originally hoped to meet with the FDA in June.)
- Sarepta hopes to begin a confirmatory trial of eteplirsen during the first quarter of 2014. (The company appears to be working under the assumption that a confirmatory trial will be required.)
- The company hopes the FDA will consider production of dystrophin protein, as measured in muscle biopsy samples, as a surrogate endpoint, a measurement "reasonably likely to predict clinical benefit." If the FDA considers dystrophin protein production a valid endpoint, the agency may allow Sarepta to submit an application for accelerated approval of eteplirsen. That could mean access to eteplirsen for patients prior to final approval of the drug.
For more information
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