DMD: Experimental Exon-Skipping Drug Drisapersen Disappoints

Drisapersen, designed to treat boys with Duchenne MD with mutations near exon 51 of the dystrophin gene, showed no benefit in a phase 3 trial

Article Highlights:
  • The experimental drug drisapersen, in development to treat boys with DMD who have mutations near exon 51 of the dystrophin gene, did not show benefit on tests of walking distance or motor function in a 48-week, phase 3 trial that included 186 participants.
  • A phase 2 trial had shown encouraging results with respect to walking distance and dystrophin protein production.
  • Families whose children are currently in drisapersen clinical trials should contact their local study team.
  • A Sept. 20, 2013, conference call is available for replay on the Prosensa website.
by Margaret Wahl on September 20, 2013 - 12:55pm

Update (Dec. 19, 2013): In a communication today to patient groups, GlaxoSmithKline (GSK) said that, together with Prosensa, it is continuing to analyze the phase 3 drisapersen trial and other aspects of the drisapersen clinical program, and that it anticipates having results of this analysis in January 2014. Until then, GSK said, dosing of drisapersen in ongoing studies will continue to be held. The GSK Global Patient Relations team expressed appreciation for how difficult this situation is for DMD-affected families and thanked them for their patience.

In a Dec. 19, 2013, press release, Prosensa summarized the GSK communication. In addition, Prosensa CEO Hans Schikan commented, "Given the devastating impact of DMD on boys and their families, it is of critical importance that this robust dataset is understood in its entirely and no stone is left unturned." He continued, "The driaspersen program represents one of the largest datasets in this disease to date, and we continue to collaborate with patient groups and other key stakeholders to help patients with DMD."

A large-scale, phase 3 trial of the experimental exon-skipping drug drisapersen, in development to treat Duchenne muscular dystrophy (DMD), found no statistically significant differences on tests of walking distance or motor function between trial participants treated with the drug and those treated with a placebo.

The results were jointly announced in a Sept. 20, 2013, press release from drisapersen's developers, multinational pharmaceutical company GlaxoSmithKline (GSK) and Dutch biotechnology company Prosensa.

"Today’s news is very disappointing," said neurologist Valerie Cwik, executive vice president and chief medical and scientific officer at MDA. "We’re eager to see the data to better understand why the drug failed in this trial."

A Sept. 20, 2013, conference call, available for replay on the Prosensa website, provides further details. In the approximately 30-minute call, Prosensa's CEO Hans Schikan and Giles Campion, chief medical officer at Prosensa, noted that today's announcement represents "top-line" (preliminary) results and that full results of the phase 3 trial of drisapersen will be presented at upcoming medical conferences in October.

The conferences are the World Muscle Society meeting to take place Oct. 1-5, 2013, in Asilomar, Calif., and the Oligonucleotide Therapeutics Society meeting, which will take place in Naples, Italy, Oct. 6-8.

MDA says DMD drug portfolio is deep

MDA has been supporting the development of exon skipping for DMD since the 1990s, largely through basic science research.

"MDA remains committed to a deep and comprehensive portfolio of experimental drugs in the pipeline for DMD, including other exon-skipping drugs," Cwik said. "Drisapersen results do not affect the prospects for other Duchenne drug candidates in clinical trials or early development. While the setback for this trial is unfortunate, we remain hopeful that breakthroughs are on the horizon."

Phase 3 trial found drisapersen not better than placebo

The phase 3 trial of drisapersen took place at some 50 sites (none of which were in the U.S.) and involved 186 boys (125 on the drug, 61 on a placebo) with DMD who were more than 5 years old, able to walk, and had mutations in the dystrophin gene that potentially could be treated by coaxing cells to skip exon (section) 51 of the dystrophin gene.

Trial participants received weekly injections of drisapersen at a dosage level of 6 milligrams per kilogram of body weight or weekly injection of a placebo for 48 weeks (nearly a year).

Results for this 48-week, phase 3 trial showed that:

  • The distance drisapersen-treated participants could walk in six minutes (the "six-minute walk distance") was not significantly different from the distance that placebo-treated participants could walk in the same test.
  • There was no statistically significant difference between drisapersen and placebo groups in assessments of motor function on the 10-meter (33-foot) walk/run test or four-stair climb.
  • There was no statistically significant difference between the drisapersen and the placebo groups on the North Star Ambulatory Assessment, a test of motor functions such as standing, walking, rising from a chair and climbing.
  • Injection-site reactions and protein in the urine — both considered "adverse events" — were more common in the drisapersen-treated trial participants than in the placebo-treated participants.

Phase 2 results had been encouraging

A smaller, phase 2 trial of drisapersen in boys with DMD had shown some encouraging results in of the six-minute walk distance and production of the dystrophin protein.

"These results demonstrate that the clinical trial process works," Cwik said. "Researchers will gain valuable insight from this trial that will shape future trials."

Next steps

In a Sept. 20, 2013, email to patient groups, Rohit Batta, global medical affairs leader for GSK's neuromuscular disorders unit, said the following:

  • GSK will be working closely with the patient advocacy community to arrange a webinar about the phase 3 results; the webinar will provide an opportunity for boys and their families to ask questions.
  • GSK will be consulting with experts in the field before deciding on next steps for drisapersen.
  • For now, GSK will withhold dosing with drisapersen in all ongoing studies, although safety monitoring and other relevant assessments will continue.
  • Study investigators have been notified about the phase 3 results, and GSK recommends that patients currently participating in drisapersen trials contact their local study team.

For more information

To learn more about drisapersen and exon skipping, read A Snapshot View: Drisapersen and Eteplirsen and DMD: Exon-Skipping Timeline.

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