DIA Oligonucleotide Conference, Neuromuscular Session Summary

At a Washington meeting last week on oligonucleotide-based therapeutics  co-sponsored by the Drug Information Association (DIA) and the Food and Drug Administration, several speakers addressed recent developments in the use of antisense oligonucleotides for Duchenne muscular dystrophy.  Allison Durham of FaegreBD captured the highlights of those talks for PPMD.

Update on Sarepta’s AVI-4658 in Exon 51 Skipping Amenable Duchenne Muscular Dystrophy Boys

Jerry R Mendell, MD

Professor of Pediatrics, Neurology, Pathology & Physiology

Nationwide Children's Hospital, United States

  • Went over disease pathogenesis and consequences of absent dystrophin
  • Background on Eteplirsen
    • An RNA modulator that addresses the underlying cause of disease
    • Exon skipping trial is now extending to 84 weeks
    • Overview of Eteplirsen Study 201 and Study 202
      • 24-week randomized, double-blind, placebo-controlled Phase IIb clinical study
      • After completing trial 201, all patients enrolled in an open-label extension study, study 202
      • All patients were on stable dose of steroids
      • Enrolled 12 boys between the ages of 7 and 10 years
      • Treatment groups of 201 included the 30 mg dose, 50 mg dose, and placebo, and consisted of four boys in each
      • By week 24, the four boys in the placebo group began Eteplirsen, two at the 30 mg dose and two at the 50 mg dose
      • After week 28, all boys were moved into extension study 202
      • The primary endpoint for studies 201 and 202 was the increase of dystrophin present in muscle fibers and met in each
      •  An important secondary endpoint and clinical outcome measure was the 6 minute walk test (mwt) which was also met by the stabilization of walking ability in study 202
      • There is movement to move into a Phase III trial



Update on GSK’s Drisapersen in Exon 51 Skipping Amenable DMD

Craig McDonald, MD

UC Davis Children's Hospital

  • Drisapersen is an antisense oligonucleotide that skips exon 51 and creates a Becker-like dystrophin protein.
  • The Phase II clinical trial, GSK 117, was a double blind placebo controlled clinical study to assess two dosing regimens, intermittent and continuous dosing
    • The primary efficacy endpoint was the change from baseline at Week 25 in the 6mwt
    • Natural Histories of 6mwt
      • Depends on the severity and baseline level of function
      • Boys who performed above 55% in the 6mwt (younger boys) at the beginning of the study showed less of a decline throughout
      • Boys who performed at 55% or below in the 6mwt continued to decline
      • At week 25 data showed an increase in performance in the 6mwt
      • At week 49 the data showed that increase was maintained and at a statistically significant and clinically meaningful but only at younger ages
      • North Star data did not show much change
      • The most significant adverse events were injection site reactions and renal abnormalities
      • Pivotal trail, Phase III
        • Contained 186 boys, 125 received drisapersen, 61 received placebo
        • After 48 weeks, no statically significant difference was seen in the 6mwt
          • Dr. McDonald noted to pay attention to the age of the patient and that age effects performance in the 6mwt
          • The question is do patients at an older age have enough dystrophin left to stabilize with treatment
          • There may be a need for a longer trial
      • Glucocorticoids add complexity to DMD trials
        • Deflazacort may be more efficacious than prednisone
        • Need to consider steroid when looking at the data
        • Steroids are working better in younger patients so newborn screening is critical
      • Need to keep in mind that less severe patients respond to a greater degree to both steroids and exon skipping treatments
      • Future plans will be to perform a full benefit-risk profile which will include a pooled analysis of the data, muscle biopsy with dose variations, CPK levels, and the duration of time dystrophin remains after the drug is removed



Update on Prosensa’s other Splice Switching Oligomers (PRO044) in DMD

Giles V. Campion, MD,PhD

Chief Medical Officer and Senior Vice President for Research and Development

Prosensa Therapeutics B.V., Netherlands

  • Prosensa has 7 slice switching oligomer candidates for DMD
  • Drisapersen recently failed to meet its primary endpoint
  • However, data from two smaller placebo studies was promising
  • Discussed the advanced candidate selection process (in vitro pharmacokenetics, in vitro safety, etc.)
  • Because they see trace amounts of dystrophin in pre-treatment samples, Prosensa uses a sensitive test to accurately assess novel dystrophin—Definiens
    • Trace dystrophin levels are higher in patients with deletions flanking exon 44
    • The full results of the PRO44 studdy will be presented next week at the World Muscle Society Conference
    • Overviewed the challenges of clinical development for DMD therapies (only one approved biomarker, the 6mwt)
    • Prosensa is currently recruiting patients from 10 countries to characterize the natural history and progression of DMD. 
      • Their goal is to enroll 250 patients, both ambulatory and non-ambulatory, in three years.


Antisense Therapies for Neurodegenerative Diseases
Richard Stephen Geary, PhD
Senior Vice President, Development
Isis Pharmaceuticals, Inc., United States

  • Dr. Geary’s presentation focused solely on Isis’ SMN treatment for Spinal Muscular Atrophy and contained no pertinent information for PPMD.

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Comment by mehrzad haidari on September 27, 2013 at 3:50pm

why Gsk and Prosensa never published the result of dytrophine production level clearly?

from 2 years ago that i followed them, i didn't see anything about this important endpoint, but sarepta clearly published the result last year in Phase 2.

So, i must ask how FDA gave them Breakthrough therapy? only because of 6mwt endpoint?

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