Duchenne Muscular Dystrophy
Duchenne muscular dystrophy (DMD) is a rare neuromuscular disorder that causes progressive muscle loss, leading to severe disability and premature death. DMD is an X-linked genetic disorder that primarily affects boys and young men. It occurs in about one in every 3,500 boys worldwide.
DMD is associated with specific errors in the gene that encodes instructions for dystrophin, a protein that plays a key structural role in muscle fiber function.
Symptoms of DMD usually appear by age three. Affected children may experience developmental delays that can include difficulty in walking, climbing stairs or standing from a sitting position. Progressive muscle weakness in the lower limbs spreads to the arms, neck and other areas. Most patients require full-time use of a wheelchair by age 12. Eventually, increasing difficulty in breathing due to respiratory muscle dysfunction requires ventilation support, and cardiac dysfunction can lead to heart failure. The condition is universally fatal, and patients usually succumb to the disease in their twenties.
Currently, there are no approved disease-modifying therapies for DMD, and the outpatient cost of care is very high for boys who are non-ambulatory.
Sarepta’s Exon-Skipping Technology Platform for DMD
Sarepta is developing multiple drug candidates for DMD based on its proprietary RNA-based technology and expertise with phosphorodiamidate morpholino oligomer – or PMO – chemistries. These potential treatments are designed to skip an exon of the dystrophin gene to correct for specific genetic mutations and restore the gene’s ability to make a functional, though shorter, form of dystrophin.
Sarepta’s lead drug candidate in clinical trials is eteplirsen, and it is designed to skip exon 51. About 13 percent of patients with DMD have genotypes amenable to treatment with eteplirsen.
The company has additional earlier-stage drug candidates targeting exons 45, 50 and 53 that are currently in preclinical testing. In the long term, Sarepta is committed to exploring the potential of its exon-skipping technology to address all boys and young men with DMD who could potentially benefit from an exon-skipping therapy.
Following is a summary of common out-of-frame deletion mutations that may be addressed by a targeted exon-skipping therapy.
|Exon skipped||Potentially Repairable Deletions|
|51||45-50, 47-50, 48-50, 49-50, 50, 52|
|50||51, 51-53, 51-55|
|45||12-44, 18-44, 44, 46-47, 46-48, 46-49, 46-51, 46-53, 46-55|
|53||10-52, 45-52, 47-52, 48-52, 49-52, 50-52, 52|
|44||10-43, 19-43, 30-43, 35-43, 36-43, 40-43, 42-43, 45, 45-54|
|8||3-7, 4-7, 5-7, 6-7|
|55||47-54, 48-54, 49-54, 50-54, 52-54, 54, 56, 56-62|
|7||2-6, 8-11, 8-17, 8-43, 8-45|
|52||53, 53-55, 53-57, 53-59, 53-60|
|17||12-16, 18, 18-20, 18-22, 18-25, 18-27, 18-29, 18-33, 18-36, 18-38, 18-41, 18-44|
Note: Additional less common genetic mutations that may be amenable to treatment with an exon-skipping therapy are not listed in the above table. Sarepta encourages families to speak with their physician to understand the relationship between a patient’s genotype and a potential exon-skipping treatment approach.
Eteplirsen Development Program
Sarepta has completed three clinical trials of eteplirsen in boys with DMD. Across all studies, eteplirsen was well tolerated with no clinically significant treatment-related adverse events. Patients treated with eteplirsen demonstrated evidence of dystrophin production and a statistically significant difference versus a placebo/delayed-treatment cohort on the 6-minute walk test (6MWT), a standard and well-accepted measure of walking ability and clinical function in DMD.
In 2012, Sarepta completed a 24-week randomized, double-blind, placebo-controlled Phase IIb clinical study of eteplirsen (Study 201). Upon completing Study 201, all patients enrolled in an open-label extension study (Study 202) designed to assess the long-term safety and efficacy of eteplirsen. The Phase IIb clinical study program was initiated at Nationwide Children’s Hospital in Columbus, Ohio, and currently includes several satellite clinical centers across the U.S.
Study 201 enrolled 12 boys between the ages of 7 and 10 years with deletion mutations correctable by skipping exon 51. Patients were randomized to one of three treatment arms including placebo (n=4), eteplirsen 30 mg/kg (n=4) and eteplirsen 50 mg/kg (n=4), and received eteplirsen or placebo by intravenous injection once a week. After 24 weeks, all placebo-treated patients initiated weekly eteplirsen treatment at 30 mg/kg (n=2) or 50 mg/kg (n=2). After Week 28, all patients were rolled over into the extension Study 202.
The primary efficacy endpoint in Study 201 and Study 202 was the change from baseline in the percent of dystrophin-positive fibers present in muscle biopsies. A key secondary endpoint in the studies, and the principal clinical outcome measure, was the 6MWT.
Studies 201 and 202 met their primary efficacy endpoints. After 48 weeks of treatment, eteplirsen administered at either 30 mg/kg or 50 mg/kg for 48 weeks (n=8) resulted in a statistically significant increase (p≤0.001) in dystrophin-positive fibers to 47.0 percent of normal. The placebo/delayed-treatment cohort, which had received 24 weeks of eteplirsen at either 30 mg/kg or 50 mg/kg following 24 weeks of placebo (n=4), also showed a statistically significant increase in dystrophin-positive fibers to 38.3 percent of normal (p≤0.009).
In June 2013, Sarepta reported clinical results through 84 weeks from Study 202, which showed a continued stabilization of walking ability in eteplirsen-treated patients evaluable on the 6MWT. After 84 weeks, patients in the 30 mg/kg and 50 mg/kg dose cohorts who were able to perform the 6MWT (modified Intent-to-Treat* or mITT population; n=6) showed a statistically significant treatment benefit of 46.4 meters (p≤0.045) when compared to the placebo/delayed-treatment cohort (n=4). The eteplirsen-treated patients in the mITT population demonstrated less than a 6 percent decline (20.5 meters) from baseline in walking ability. After experiencing a substantial decline earlier in the study, the placebo/delayed-treatment cohort also demonstrated stabilization in walking ability from Week 36 through 84, the period in which meaningful levels of dystrophin were likely produced, with an increase of 3.3 meters over this timeframe. These analyses were based on the maximum 6MWT scores when the test was performed on two consecutive days.
Through 84 weeks, eteplirsen was well tolerated and there were no clinically significant treatment-related adverse events, serious adverse events, hospitalizations or discontinuations.
*The mITT population used in the 6MWT analyses consisted of 10 of the 12 enrolled patients, including four patients in the 50 mg/kg cohort, two patients in the 30 mg/kg cohort and four patients in the placebo/delayed-treatment cohort. Two patients in the 30 mg/kg cohort showed rapid disease progression upon enrollment and lost ambulation by week 24, and thus were excluded.
Advocacy Group Resources
- Action Duchenne (United Kingdom)
- Charley’s Fund
- Cure Duchenne
- DMD Hero
- Duchenne Alliance
- Duchenne Connect
- Muscular Dystrophy Association
- Parent Project Muscular Dystrophy
- The Jett Foundation
- National Institutes of Health (NIH) Clinical Trials Web Site
- National Institute of Neurological Disorders & Stroke (NINDS) Muscular Dystrophy Info Page
- U.S. Food and Drug Administration (FDA) Rare Diseases Program
Page updated January 24, 2014
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