DMD: What's Next for Drisapersen?

Dutch biopharmaceutical company Prosensa outlined plans for drisapersen and other drugs for Duchenne MD in a Jan. 16, 2014, conference presentation and press release

Article Highlights:
  • Prosensa CEO Hans Schikan outlined the company's plans for further development of DMD exon-skipping drug drisapersen and other DMD exon-skipping drugs.
  • Schikan said the company's analysis of the recent phase 3 drisapersen trial, in which no benefit for the drug was shown, appears to have included particularly high numbers of participants who were older and had more advanced disease when it was compared with other drisapersen trials.
  • Prosensa plans to continue its development of drisapersen and other DMD exon-skipping drugs and is conducting a natural history study of DMD.
by Margaret Wahl on January 17, 2014 - 3:53pm

Update (Jan. 21, 2014): Both the Jan. 16, 2014, webcast from the J.P. Morgan conference and the Jan. 21 webcast for patient groups are available on the Prosensa site at Events & Presentations. The patient group webcast recaps many of the same themes as those summarized below from the J.P. Morgan conference presentation. However, the patient presentation was given by Giles Campion, Prosensa's chief medical officer. Campion thanked the DMD community for its input, confidence and patience with recent developments and recommends that families contact their treating physician with specific questions regarding the drisapersen trial's implications for their child. Prosensa hopes that the dosing of drisapersen in currently open extension trials can be restarted, but regulatory agencies will be making this decision.

Treatment with the experimental exon-skipping drug drisapersen to treat Duchenne muscular dystrophy (DMD) may be effective if started early in the disease course and given for long periods of time, according to Dutch biopharmaceutical company Prosensa, developer of this drug.

This analysis, based on results from several clinical trials, was presented by Prosensa Jan. 16, 2014, at the J.P. Morgan Healthcare Conference in San Francisco, and via a Jan. 16 press release.

"MDA lauds Prosensa for its commitment to DMD research," said Jane Larkindale, MDA's vice president of research. "As with any trial, it is very important to thoroughly analyze all data that comes out in order to maximize what we learn from each study. The hints of efficacy that Prosensa is seeing in some subgroups offers encouragement that exon-skipping technologies will be proven effective in the long term."

MDA has funded the development of exon skipping as a strategy to treat DMD since the 1990s.

A recording of the J.P. Morgan conference presentation, delivered by Prosensa CEO Hans Schikan, will be provided on the Prosensa website at Events & Presentations.

In the Jan. 16 press release, Schikan said Prosensa "will continue to work closely with patient groups, clinical experts and regulators to ensure that we leave no stone unturned to bring treatments to boys affected by DMD."

He also said, "We are encouraged by … results that suggest that treating earlier in the disease and treating longer shows a delay in the progression of the disease. These data encourage us … to explore a path forward for drisapersen, which includes the possibility of re-dosing." (Dosing of drisapersen in current trials has been halted, at least temporarily.)

About the drisapersen clinical trials

A large-scale, phase 3 trial of drisapersen in DMD recently showed no benefit for the drug when it was compared to a placebo over 48 weeks. The drug was administered weekly by subcutaneous (under the skin) injection at a dose of 6 milligrams per kilogram of body weight.

Drisapersen is designed to coax cells to "skip" (leave out) a section of the dystrophin gene instructions known as exon 51 (section 51).

This phase 3 trial took place at some 50 sites (none of which were in the U.S.) and involved 186 boys (14 on the drug and 61 on the placebo). It included boys with DMD who were at least 5 years old, able to walk, and had mutations in the dystrophin gene that potentially could be treated by skipping exon 51. As a result of this lack of demonstrated benefit, dosing of drisapersen to all participants in current trials has been halted.

Earlier studies of drisapersen had been encouraging in terms of their effect on the distance that participants were able to walk in six minutes (six-minute walk test). For instance, a phase 2, 53-participant trial of drisapersen, for which results were announced in April 2013, found that boys who received the drug continuously for 24 weeks walked significantly farther in six minutes than boys who received a placebo. (The results, however, did not reach statistical significance at the 48-week time point.)

Highlights of the Jan. 16 conference presentation and press release follow.

Six-minute walk test results

The six-minute walk test (distance walked in six minutes) has been used as an important indicator (outcome measure) of drisapersen's efficacy in DMD. Studies of boys with DMD published between 2010 and 2013 say they generally lose 40 to 60 meters (131 to 197 feet) of walking distance per year on this test.

Prosensa's analysis of trials of drisapersen showed that the distance a boy with DMD can walk in six minutes is influenced by his age and his baseline walking distance (distance walked when first evaluated for a study). Boys who are 7 years old and younger generally walk farther than those who are older than 7. Boys who walk farther on baseline testing generally continue to do better on the six-minute walk test.

Boys in the phase 3 trial who were 7 and younger showed a difference of 21 meters (69 feet) in their six-minute walk distance compared to the placebo group, while the group as a whole (all ages) showed a difference from the placebo group of 10.3 meters (34 feet); neither difference, however, was considered statistically significant.

Creatine kinase results

In the recent phase 3 trial, there was a statistically significant difference in serum creatine kinase levels — a possible marker of muscle integrity — favoring the drisapersen-treated versus the placebo group.

Participants in phase 3 trial older, more impaired, than in other trials

In the Jan. 16 presentation, Prosensa's Hans Schikan said that the recent phase 3 trial of drisapersen appears to have included more participants who were older and more advanced in their disease course than were included in other drisapersen trials.

Schikan said this may have accounted for the lack of apparent treatment benefit in the phase 3 trial, while some earlier trials had been encouraging.

Also, he said, the phase 3 trial was only 48 weeks, which is shorter than some of the extension studies, and this too may have accounted for the lack of demonstrated benefit.

  • Compared with participants in other drisapersen trials, participants in the phase 3 trial were older, with an average age of 8 years in the placebo group and 8.3 years in the drisapersen group.
  • Compared with participants in other drisapersen trials, participants had been experiencing DMD symptoms longer and were farther away from their initial diagnosis of DMD.
  • Compared with participants in other drisapersen trials, participants in the phase 3 trial walked a shorter distance in six minutes when baseline testing was conducted.
  • Boys in the phase 3 trial who were in the placebo group had an average six-minute walking distance of 348 meters (1,142 feet), and boys in the drisapersen group walked an average at baseline of 337 meters (1,106 feet); by contrast, boys in other drisapersen trials had an average baseline walking distance of 396 to 428 meters (1,299 to 1,404 feet).
  • Compared with participants in other drisapersen trials, participants in the phase 3 trial took longer at baseline to walk or run 10 meters (33 feet), climb or descend four stairs, or rise from the floor.
  • Participants in the phase 3 trial had less muscle strength at baseline than did participants in two other drisapersen trials.
  • Participants in the phase 3 trial had poorer average respiratory function measurements at baseline than did participants in other drisapersen trials.
  • Participants in the phase 3 trial were not treated with drisapersen for as long a time period as some of the participants in long-term extension trials.

Safety results

In three trials, including the phase 3, the most common adverse events were injection site reactions, kidney abnormalities and moderate to severe reduction of platelets (cells involved in blood clotting).

Next steps for drisapersen

At the Jan. 16 presentation, Hans Schikan said that Prosensa will:

  • complete the analyses of all drisapersen studies;
  • engage with patient groups, clinical experts and regulators;
  • continue evaluating patients in extension trials at scheduled visits regarding safety monitoring and other relevant assessments; and
  • consider restarting dosing with drisapersen in trials, depending on additional data.

Next steps for other Prosensa drugs for DMD

Prosensa is developing several additional exon-skipping drugs for DMD. These include:

  • PRO044, targeting dystrophin exon 44, in a phase 2 trial;
  • PRO045, targeting exon 45, in a phase 1 trial;
  • PRO052, targeting exon 52, in preclinical development; and
  • PRO055, targeting exon 55, in preclinical development.

In addition, the company is developing a strategy to skip multiple exons and a new method to assess dystrophin levels.

It is also conducting a study to better understand the natural history of DMD.

In his Jan. 16 presentation, Schikan said that ongoing studies of additional drugs will continue and may be adapted based on the complete analysis of the drisapersen trials.

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