Eteplirsen Data Still Strong: Treated Boys with DMD Stable at 120 Weeks

Sarepta Therapeutics presented new favorable safety and efficacy results for its experimental exon-skipping drug eteplirsen, designed to treat Duchenne MD caused by specific dystrophin mutations

Results at 120 weeks into a phase 2b trial of DMD drug eteplirsen continue to support the drug's safety and stabilizing effect on walking distance.
Article Highlights:
  • Sarepta Therapeutics, developer of Duchenne MD exon-skipping drug eteplirsen, presented 120-week results of its phase 2b eteplirsen trial via a conference and press release on Jan. 15, 2014; the intravenously administered drug targets exon 51 of the dystrophin gene.
  • Trial participants treated with eteplirsen for the full 120 weeks (continuous treatment group) showed a decline in their six-minute walk distance of 14 meters from baseline, which is much less than the 122-125 meters seen for 104 weeks in natural history studies.
  • Trial participants treated with a placebo for the first 24 weeks and then with eteplirsen (placebo/delayed treatment group) showed a decline in their six-minute walk distance of 79 meters from baseline, which is still less decline than natural history studies have shown for this time frame.
by Margaret Wahl on January 16, 2014 - 3:48pm

Update (Feb. 5, 2014): An analysis of pulmonary function tests at 120 weeks (2.3 years) found boys treated with eteplirsen showed a stabilization of respiratory function over a time period and in an age group where a decline would have been expected. Sarepta announced these results in a Feb. 5, 2014, press release.


Sarepta Therapeutics, developer of the experimental exon-skipping drug eteplirsen to treat Duchenne muscular dystrophy (DMD), has announced favorable 120-week results related to efficacy and safety from its phase 2b eteplirsen trial. The announcements were made Jan. 15, 2014, at the J.P. Morgan Healthcare Conference in San Francisco and via a Jan. 15 press release.

"We are happy to see that, after 120 days of treatment, the eteplirsen data still look strong," said Jane Larkindale, MDA's vice president of research. "The drug appears safe, and there are indications that it might be helping to stabilize walking ability in the small cohort of patients in the trial. MDA is waiting anxiously to hear what the next steps will be for this drug."

MDA has funded the development of exon skipping as a strategy to treat DMD since the 1990s. It provided supplemental funding to help defray costs for participants' travel and other expenses associated with the phase 2 trial.

The supporting materials (slides) from the J.P. Morgan conference presentation, delivered by Sarepta CEO Chris Garabedian, are available on the Sarepta website at Events & Presentations.

Highlights from the Jan. 15 presentation and press release follow.

About the phase 2b eteplirsen study

The phase 2b eteplirsen study involves weekly intravenous infusions of eteplirsen, a drug designed to coax cells to "skip" (leave out) exon 51 (section 51) of the gene for the dystrophin protein and create smaller-than-normal, but functional, dystrophin protein molecules in muscle tissue.

The study includes boys with DMD who were 7 to 13 years old at its start; have a dystrophin gene mutation potentially treatable by skipping exon 51 of the dystrophin gene; were able to walk 200 to 400 meters (656 to 1,312 feet) in six minutes at the start of the study; and were receiving treatment with a stable dose of oral corticosteroids for at least 24 weeks prior to study entry.

The main outcome measures for this study are production of new dystrophin protein — the protein that's needed but missing in DMD-affected muscles — and the distance walked in six minutes, known as the "six-minute walk test."

At the start of the trial, there were 12 boys with DMD who met the criteria. Eight were assigned to a "continuous treatment" eteplirsen group and received weekly infusions of eteplirsen at either 30 milligrams per kilogram of body weight (four boys) or 50 milligrams per kilogram of body weight (four boys). These two groups are later referred to in summaries of results as the "continuous treatment" group.

Also at the start of the trial, four participants were assigned to receive placebo infusions for the first 24 weeks, after which two were assigned to the 30 milligrams per kilogram eteplirsen group, and two were assigned to the 50 milligrams per kilogram eteplirsen group. These two groups, combined, are later referred to in summaries as the "placebo/delayed treatment" group.

Early in the study, two participants lost the ability to walk and therefore could not undergo further testing on the six-minute walk test. They did stay in the trial, however, and were evaluated on other measures. Summaries of six-minute walk test data therefore include only 10 participants.

Six-minute walk test results

New data about the distance participants could walk at the 120-week (2.3 years) point in the phase 2b study were presented yesterday (Jan. 15, 2014). The data show:

  • At 120 weeks, study participants in the continuous treatment group at either dosage level declined in their six-minute walking distance by an average of 14 meters (46 feet) from their baseline walking distance; this represents a less than 5 percent decline from baseline to 120 weeks.
  • Two studies of "natural history" (usual course) of DMD, both published in 2013, found that the average decline in walking distance in six minutes over 104 weeks (two years) is 122 to 125 meters (400 to 410 feet), much more than the 14 meters seen in the continuously treated eteplirsen group.
  • At 120 weeks, the placebo/delayed treatment group had declined in six-minute walking distance by 79 meters (259 feet) from baseline; this is less decline than the natural history would have predicted but more than the 14-meter decline seen in the continuous treatment eteplirsen group.
  • On average, the continuous treatment group walked 65 meters (213) feet farther at 120 weeks than the placebo/delayed treatment group.
  • From week 36 through week 120 of this study, no participant declined more than 15 percent on the distance walked in six minutes.

Safety results

The safety and tolerability of eteplirsen appear very good so far:

  • There were no clinically significant treatment-related adverse events, no hospitalizations or discontinuations of treatment, and no clinically significant treatment-related changes in lab values.
  • Three participants experienced temporary elevations in urinary protein excretion, but these resolved without treatment.

Dystrophin results

Dystrophin protein production was evaluated by analysis of muscle biopsy samples taken at 12, 24 and 48 weeks (no further biopsies were done after 48 weeks):

  • Dystrophin protein production in this trial appears to begin between 12 and 24 weeks after starting treatment with eteplirsen.
  • The dystrophin protein produced after treatment with eteplirsen is not completely normal; it is shorter than normal and is similar to what is observed in some patients with Becker muscular dystrophy (BMD).
  • Muscle biopsy samples taken at 48 weeks looked more like either healthy muscle tissue or tissue from BMD patients than muscle tissue from DMD patients.

Sarepta's DMD drug development plans

In his Jan. 15 presentation, Sarepta CEO Chris Garabedian said that the active part of the eteplirsen molecule (the chemical sequence that interacts with the dystrophin genetic instructions) and the molecule's "backbone" (based on "PMO" chemistry) are, in Sarepta's view, different from and better than those proposed for exon-skipping DMD drugs from other companies. He also said:

  • Sarepta is fine-tuning the chemistry for their exon-skipping compounds and is developing "next-generation" PMO chemistries.
  • Sarepta has in development compounds to treat DMD that skip exons 53, 45, 50, 44, 52, 55 and 8.
  • Sarepta expects to have plans for a large confirmatory trial of eteplirsen in place by the end of March 2014; it is waiting for more guidance from the U.S. Food and Drug Administration (FDA), following the agency's November 2013 statement that an accelerated approval pathway for eteplirsen was premature.
  • Sarepta plans to administer eteplirsen to the first patient in the confirmatory trial by the end of June 2014.
  • The company expects to meet with the FDA about conducting a trial of SRP-4053, its experimental compound targeting dystrophin exon 53, by the end of March 2014.
  • It expects to have the chemical sequences selected for experimental compounds targeting dystrophin exons 52, 55 and 8 by the end of June 2014.
  • It expects to submit requests to the FDA to test at least two new DMD exon-skipping compounds in clinical trials during the second half of 2014.
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