Exon skipping, a treatment strategy currently being developed for Duchenne muscular dystrophy (DMD), causes cells to "skip" (splice out, or leave out) certain sections of genetic code called exons during the protein production process. Leaving out these sections allows for the creation of shorter-than-normal, but partially functional, dystrophin — the muscle protein missing in DMD.
Furthest along in development are the two exon-skipping drugs drisapersen and eteplirsen, both of which target exon 51 using a molecule called an antisense oligonucleotide (AON). (It's been estimated that 13 percent of boys with DMD may benefit from skipping exon 51.)
Although drisapersen and eteplirsen both have been developed along a similar timeline and are designed to work by the same mechanism, subtle differences in their chemical composition may cause them to have dissimilar safety and efficacy characteristics. Clinical testing currently is under way to determine safety and assess each drug's effect in people with DMD.
Updated September 20, 2013
|Snapshot View of Two Exon-Skipping Compounds in Development
|Designed to:||skip exon 51||skip exon 51|
|May help people with DMD
caused by deletions in:
|Early development:||From 2003 to 2006, MDA supported molecular biologist Judith van Deutekom at Leiden (Netherlands) University Medical Center to develop exon skipping related to the dystrophin gene.
She later moved to Prosensa, where she is now vice president of drug discovery, and continued this work.
|In 1997 MDA began funding Stephen Wilton at the University of Western Australia in Perth to develop a technique for blocking specific exons of genes. Wilton, who continues to receive MDA support, has since worked with Sarepta Therapeutics to continue development of the therapeutic strategy.|
|Currently being developed by:||GlaxoSmithKline in collaboration with Prosensa||Sarepta Therapeutics (formerly AVI BioPharma)|
|Chemical makeup:||Synthetic molecule composed of a short segment of RNA bound to a "2-O-methyl" (2'-O-methyl phosphorothioate oligonucleotide, or 2'OMe) backbone||Synthetic molecule composed of a short segment of RNA bound to a "morpholino" (phosphorodiamidate morpholino oligomer, or PMO) backbone|
|How the drug is given in humans:||Systemic; subcutaneous injection||Systemic; intravenous infusion|
|In early studies, was tested in:||Boys ages 5 years and older, able to walk||Boys ages 10-17 years, unable to walk
Boys ages 5-15 years, able to walk
|In later studies, has been tested in:||Boys ages 5 years and older, able to walk
Note: Trial participants had an average age of 7, at which walking ability is fairly stable in DMD.
|Boys ages 7 to 13 years, able to walk
Note: Participants were selected so as to comprise a population in which more rapid decline in walking ability would be expected.
|Completed clinical trials:||
Phase 2 (trial sites in seven countries not including the United States) — Phase 2 Doubleblind Exploratory Study of GSK2402968 in Ambulant Subjects with Duchenne Muscular Dystrophy
Phase 3 (trial sites in 19 countries not including the United States) — A Clinical Study to Assess the Efficacy and Safety of GSK2402968 in Subjects with Duchenne Muscular Dystrophy (DMD114044)
|Phase 1-2 (United Kingdom) — Safety and Efficacy Study of Antisense Oligonucleotides in Duchenne Muscular Dystrophy|
|Ongoing clinical trials:||Phase 2 (United States) — A Clinical Study to Assess Two Doses of GSK2402968 in Subjects with Duchenne Muscular Dystrophy (DMD) (DMD114876)
Phase 3 (trial sites in 22 countries not including the United States) — Open Label Study of GSK2402968 in Subjects with Duchenne Muscular Dystrophy
|Phase 2 (United States) — Efficacy, Safety and Tolerability Rollover Study of Eteplirsen in Subjects with Duchenne Muscular Dystrophy|
|Trial results (safety):||Generally well-tolerated in testing through 48 weeks. The majority of adverse events were related to injection site reactions and proteinuria. Some indications of adverse effects on kidney function were noted in testing, but kidney biomarkers returned to normal during off-treatment periods.||Generally well-tolerated in testing through 74 weeks. No serious adverse events, hospitalizations or discontinuations were reported. In 62-week results it was reported that one participant had proteinuria, which resolved with no clinical symptoms. The participant continued treatment without interruption and remained free of proteinuria through week 74.|
|Trial results (efficacy):||
A large-scale, phase 3 trial 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.
|In a U.S.-based phase 2 trial, boys with DMD who were treated with eteplirsen walked farther in six minutes than boys who received a placebo for the first 24 weeks, followed by eteplirsen for the remainder of the study.|
|Dystrophin protein produced?||Yes||Yes|
|Current status:||May 2013 — GSK has indicated that the earliest the company would file an application for approvalof drisapersen in the United States or Europe would be the first quarter of 2014.
June 2013 — GSK announced that drisapersen has received breakthrough therapy designation from the U.S. Food and Drug Administration (FDA).
September 2013 — GSK and Prosensa announced that a large-scale, phase 3 trial 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.
|April 2013 — The U.S. Food and Drug Administration (FDA) has said it will consider accepting an application for accelerated approval for eteplirsen after it reviews additional data from clinical trials of the drug.
A phase 3 confirmatory trial is slated for early 2014.
July 2013 — Sarepta Therapeutics announced in a press release that the company will submit a new drug application (NDA) to the U.S. Food and Drug Administration in the first half of 2014, based on a July 23 meeting the company had with the agency. Sarepta does not yet know whether eteplirsen will be eligible for the FDA’s accelerated approval program.