Weekly injections of the exon-skipping drug drisapersen in boys with Duchenne muscular dystrophy resulted in a significant difference in walking distance compared to a placebo
Update (May 16, 2013): This story has been updated to reflect new information received from GSK indicating that the “phase 3” trial of drisapersen planned for the U.S. is not actually a phase 3 trial but a treatment IND protocol. The U.S. Food and Drug Administration (FDA) defines a treatment IND protocol as a mechanism for providing eligible subjects with investigational drugs for the treatment of serious and life-threatening illnesses for which there are no satisfactory alternative treatments.
Update (May 8, 2013): In a May 6 webinar co-sponsored by MDA, CureDuchenne and Parent Project Muscular Dystrophy, John Kraus from GlaxoSmithKline (GSK) said the earliest the company would file an application for approval of drisapersen in the United States or Europe would be the first quarter of 2014.
He also said:
The webinar is not archived. Data similar to that presented at Cold Spring Harbor was presented at the MDA Scientific Conference in Washington, D.C., in April. This story was also updated May 8 to reflect that the 48-week results from the continuous drisapersen group were clinically meaningful but not statistically significant.
After 48 weeks of treatment, the study found a 117-foot difference in the distance walked in six minutes by those who received the drug every week and those who received a placebo.
In addition, the “continuous treatment” group (which received weekly injections of drisapersen) walked farther in six minutes than those who received drisapersen on a different ("intermittent") dosing schedule.
The study did not find changes in muscle strength in any group. Researchers report the drug was well-tolerated and all participants completed the trial.
Assessments of production of dystrophin protein — the protein missing in DMD-affected muscles — were not reported.
John Kraus from GSK presented the trial results April 11, 2013, at the RNA and Oligonucleotide Therapeutics meeting at Cold Spring Harbor Laboratory in Cold Spring Harbor, N.Y.
A presentation is also planned for MDA's April 21-24, 2013, Scientific Conference in Washington, D.C.
The 53-person trial compared two drisapersen dosing regimens — "continuous" and "intermittent" — to placebo regimens. It was conducted in Australia, Belgium, Germany, Israel, Spain, Turkey and the United Kingdom between September 2010 and September 2012.
Participants were required to be boys with DMD, to be at least 5 years old, to be able to walk and to rise from the floor in seven seconds or less, and to have a dystrophin gene mutation that could potentially be helped by skipping exon 51, as well as meeting many other study criteria.
The primary outcome measure was the distance that a trial participant walked in six minutes (six-minute walk test, or 6MWT) 24 weeks into the trial.
Secondary outcome measures included the 6MWT at 48 weeks, various timed function tests, the North Star Ambulatory Assessment, muscle strength and safety.
The continuous drisapersen treatment group included 18 participants who received 6 milligrams per kilogram of body weight of drisapersen once weekly, by subcutaneous (under the skin) injection.
The intermittent drisapersen treatment group included 17 participants who received injections of drisapersen at 6 milligrams per kilogram of body weight on an intermittent schedule: 10-week cycles of nine doses of 6 milligrams per kilogram over six weeks and four weeks off the drug.
Eighteen participants — nine associated with each treatment group — received placebo injections on the same schedule as the drisapersen-treated patients.
At 24 weeks, the continuous treatment group showed a clinically meaningful and statistically significant difference of 35 meters (115 feet) from the placebo group on the 6MWT. In other words, the drisapersen-treated boys walked an average of 115 feet farther in six minutes than the boys given a placebo.
At 24 weeks, there also were some positive trends toward a difference between the continuous drisapersen group and the placebo group in other timed function tests and the North Star Ambulatory Assessment, a standardized way to measure motor function that looks at activities such as standing, walking, climbing steps, rising from the floor and hopping.
A difference on the 6MWT between the continuous treatment group and the placebo group was maintained at 48 weeks, with the continuous treatment group walking an average of 35.8 meters (117 feet) farther than the placebo group at this second time point. This difference did not reach statistical significance but was what GSK called "clinically meaningful."
In the intermittent treatment group, at 24 weeks, drisapersen-treated participants did not walk farther than the placebo group. However, at week 48, there was a clinically meaningful — but not statistically significant — difference of 27 meters (89 feet) between the intermittently treated drisapersen group and the placebo group.
Also at 48 weeks, there were trends toward differences between the participants in the intermittent drisapersen and the placebo group in timed function tests and the North Star Ambulatory Assessment.
There was little change in muscle strength at either time point for either treatment group. (The method of evaluating muscle strength was not described.)
GSK's written summary stated that drisapersen was generally well-tolerated, with the majority of adverse events related to injection site reactions and excretion of protein in the urine (proteinuria).
All participants completed the study.
GSK's written summary of the results said that drisapersen "may represent an important treatment option for boys with DMD having mutations correctable by exon 51 skipping."
Drisapersen is designed to change the way muscle cells interpret instructions for the dystrophin protein by causing the cell to skip (omit) a section of the dystrophin gene called exon 51 from the final instructions for this protein.
The hoped-for result is that children with specific dystrophin mutations that have the potential to be helped by skipping exon 51 will produce shorter-than-normal, but still functional, dystrophin protein that can improve muscle function.
For drisapersen trial information, see:
MDA has supported the development of exon skipping for DMD since the 1990s, leading to the development of drisapersen and another experimental drug, eteplirsen, now being tested by Sarepta Therapeutics.
More reporting of results of exon-skipping drug trials and discussion of the strategy will take place at the April 21-24, 2013, MDA Scientific Conference in Washington, D.C.
To learn more about drisapersen and exon skipping, read: