Duchenne Muscular Dystrophy
About DMD/Exon Skipping
Resources
Drug Candidates/Clinical Trials
Duchenne Muscular Dystrophy (DMD) is one of the most common fatal genetic disorders to affect children around the world. Approximately one in every 3,500 boys worldwide is affected with DMD. Girls are rarely affected by the disorder. DMD is a devastating and incurable muscle-wasting disease associated with specific inborn errors in the gene that codes for dystrophin, a protein that plays a key structural role in muscle fiber function. Symptoms usually appear in children by age three. Progressive muscle weakness of the legs and pelvis eventually spreads to the arms, neck and other areas. By age 10, braces may be required for walking, and most patients require full-time use of a wheelchair by age 12. Eventually, this progresses to complete paralysis and increasing difficulty in breathing due to respiratory muscle dysfunction requiring ventilatory support, and cardiac muscle dysfunction leading to heart failure. The condition is terminal, and death usually occurs before the age of 30. The outpatient cost of care for a non-ambulatory DMD patient is very high. There is currently no cure for DMD, but for the first time ever there are promising therapies in, or moving into, development.
Sarepta Therapeutics is currently evaluating drug candidates for DMD.
Eteplirsen, formerly known as AVI-4658, is our lead therapeutic candidate for DMD and uses our core PMO chemistry applied as a splice switching oligomer (SSO). The drug is intended to skip exon 51 of the dystrophin gene. By skipping exon 51, eteplirsen may restore the gene’s ability to make a shorter – but still functional – form of dystrophin. Data from a Phase 1b/2 clinical trial of eteplirsen presented in October 2010 demonstrated a broadly favorable therapeutic profile with promising safety, biological and exploratory clinical performance assessments (read Press Release). In 2011 Sarepta initiated a plan to accelerate development by conducting key NDA-enabling activities for the Duchenne muscular dystrophy program, including a long-term in vivo toxicology study necessary for pivotal studies, GMP manufacturing scale-up plan and a six month Phase 2 clinical study of eteplirsen at higher doses.
Sarepta is also developing several other SSO exon skipping drug candidates intended to help patients with DMD, including AVI-5038. This candidate uses our PPMO chemistry platform and is intended to skip exon 50. AVI-5038 is currently in preclinical development.
Drug Candidates/Clinical Trials
Eteplirsen
Eteplirsen, our lead DMD therapeutic candidate based on our proprietary exon-skipping technology, has completed a Phase 1b/2 clinical trial at two sites in the United Kingdom. The investigational drug candidate demonstrated a broadly favorable therapeutic profile with promising safety, biological and exploratory clinical performance assessments.
Eteplirsen employs our core PMO chemistry and is intended to skip exon 51 of the dystrophin gene. By skipping exon 51, we believe eteplirsen may restore the gene’s ability to make a shorter – but still functional – form of dystrophin from mRNA. We further believe that promoting the synthesis of a truncated dystrophin protein might improve, stabilize or significantly slow the disease process and might prolong and improve the quality of life for specific patients with DMD.
AVI-5038
We are also developing several other drug candidates intended to help patients with DMD, including AVI-5038. This candidate uses our PPMO chemistry and is intended to skip exon 50. AVI-5038 is currently in preclinical development.
Mutations that could be potentially corrected by skipping exons 51and 50 include, as follows:
| Exon to be skipped | Drug Candidate | Stage | Potentially Treatable Deletions* |
| 51 | AVI-4658 | Clinical Development Phase 1b/2 (UK) Preclinical Development stage (US) |
45-50, 47-50, 48-50, 49-50, 50, 52 |
| 50 | AVI-5038 | Preclinical Development (US) | 51, 51-53, 51-55 |
*This is not necessarily an exhaustive list of repairable deletions
Approximately 85% of all DMD patients could potentially be treated with exon–skipping drugs. Because of the specificity of each drug, different errors in the dystrophin gene may require different oligomer drugs to repair the error.
Status of Clinical Trials
Eteplirsen
We have completed a Phase 1b/2 clinical trial of eteplirsen in the U.K. In the completed open label Phase 1b/2 dose-ranging clinical trial, eteplirsen demonstrated a favorable therapeutic profile with promising safety, biological and exploratory clinical performance assessments. The study enrolled 19 ambulatory patients with DMD between the ages of 5 and 15 years of age who have an error in the gene coding for dystrophin that could be treated by skipping exon 51. Patients received one of six doses of eteplirsen ranging from 0.5 to 20 mg/kg once weekly for 12 weeks by intravenous infusion. After completion of dosing, patients were followed for a further 14 weeks. The primary objective of the trial was to assess the safety of eteplirsen over the 26-week duration of the trial.
Topline biopsy data from the Phase 1b/2 clinical trial of eteplirsen were announced in December 2009 (read Press Release) and June 2010 (read Press Release), and results from the completed trial were announced in October 2010 (read Press Release).
A review of the data from all patients who completed the trial establishes support for the following conclusions:
- Eteplirsen was well tolerated in all patients. Adverse events were mostly mild or moderate in intensity, not dose-related, and none were considered probably or definitely related to eteplirsen. There were also no drug-related serious adverse events or severe adverse events, except for one patient that exhibited deteriorating cardiac function, which was considered probably disease related.
- Substantial and novel dystrophin expression and dystrophin-positive fiber generation reaching up to 55%, although variable among patients, tended to be greatest in the highest two cohorts.
- Dystrophin expression was correctly localized and was accompanied by restoration of the Dystrophin-associated Glycoprotein Complex (DGC), a protein complex necessary for the proper function of muscle cells.
- Reductions in key inflammatory markers, including CD3, CD4 and CD8 counts, potentially suggest an alteration in the underlying degenerative disease process. There was no immune response to newly made dystrophin.
- There was general stability in exploratory markers of patient clinical performance, including cardiac, pulmonary and muscle functional assessments.
AVI-4658 Phase 1b/2: Percent Positive Dystrophin Muscle Fibers
In January 2009, we announced results from a Phase 1 trial of eteplirsen conducted in the United Kingdom. (Read press release) Biopsy data showed that injection of the drug into a foot muscle in a series of DMD patients also significantly increased the amount of dystrophin in the muscle compared to the placebo-treated muscle in the patient’s other foot. The amount of dystrophin expressed was related to the amount of drug injected, the drug was well tolerated and there were no significant drug–related serious adverse events.
AVI-4658 Phase 1: Dystrophin-Positive Fiber Count
| Patient | Positive Fibers | Negative Fibers | Total | % Above Background |
| 3 | 182 | 196 | 378 | 48 |
| 4 | 623 | 169 | 792 | 79 |
| 5 | 116 | 147 | 263 | 44 |
| 6 | 164 | 98 | 262 | 63 |
| 7 | 264 | 140 | 404 | 65 |
*AVI-4658 injected at 0.9 mg total dose; dystrophin detection with Mandys 106 antibody
In preparation for a U.S. based clinical trial, we completed a series of 12-week preclinical studies of eteplirsen under Good Laboratory Practice (GLP) conditions required to open an Investigational New Drug (IND) application. The results from these studies were submitted to the FDA and are subject to its review for approval to initiate a U.S. based clinical trial.
We were granted orphan drug designation for eteplirsen by the U.S. Food and Drug Administration (FDA) in November 2007 and by the European Medicines Agency (EMEA) in December 2008. We also received fast track status for eteplirsen from the FDA in December 2007.
AVI-5038
Sarepta has initiated preclinical studies with AVI-5038, a drug candidate employing our PPMO chemistry and intended to skip exon 50 of the dystrophin gene. In a preclinical study evaluating AVI-5038 administered once weekly by bolus intravenous injection for 4 weeks, it was generally well tolerated at doses up to 9 mg/kg. Preliminary results from an ongoing preclinical study at doses up to 15 mg/kg for 12 weeks demonstrated significant toxicological findings in some groups following bolus intravenous administration. The in-life portion of this study is complete, but the collection and analysis of data from the study is still ongoing. We believe the data set is not yet sufficient for the company to make a decision on the future development of this drug candidate.
In February 2010, we received an orphan drug designation from the Committee for Orphan Medical Products of the European Medicines Agency (EMEA) for AVI-5038.
We are examining other target deletions with the hope of developing the best candidates for treating these target deletions.
DMD & Exon Skipping
About Duchenne Muscular Dystrophy
The dystrophin protein is essential for the function of muscles. Muscle fibers stretch and contract with great force when a muscle is used. Dystrophin acts as a spring and a shock absorber between the muscle fiber surface and its internal motor made up of a protein called actin. In DMD, due to a mutation in the dystrophin gene, dystrophin is missing and as the actin motor causes the muscle to contract it damages the muscle fiber’s surface membrane because the force-absorbing protection of dystrophin is missing. In small children with DMD, the force of muscle contraction is weak, so there is not much damage and repair can stay ahead of muscle damage. As children with DMD grow, their muscle strength increases and, eventually, muscle damage cannot be adequately repaired. Permanent muscle damage becomes more and more widespread and eventually becomes life threatening as the vital muscles for breathing (diaphragm) and the blood circulation (heart) are affected.
The gene that encodes the information for the production of the dystrophin protein is the largest gene in the human body, containing 2.4 million base pairs of genetic information. DMD is caused by mutation of the dystrophin gene that prevents the production of dystrophin protein. The most common defects in the dystrophin gene leading to DMD are deletions, or missing pieces of DNA needed to properly direct the production of dystrophin. More specifically, the genetic mutations leading to DMD arise when a fragment of DNA is lost at a point in the gene that severely disrupts correct translation of the genetic information needed to direct dystrophin production.
Sometimes there is a less severe mutation that causes the loss of a small fragment of DNA at a point in the gene where the remaining information is not ruined and the cell has sufficient information to make a truncated, but still functional, form of dystrophin. In this case, although the dystrophin protein is smaller than dystrophin produced from the instructions of a whole gene, it can still perform some of the shock-absorbing tasks of dystrophin. Mutations leading to a shorter but functional dystrophin protein are seen in the milder, Becker form, of muscular dystrophy (BMD).
Exon Skipping
Several years ago scientists identified a way to potentially restore the functionality of a gene containing a mutation resulting in DMD by a process called exon skipping. Through exon skipping it may be possible to realign the translation of genetic information in the dystrophin gene and promote synthesis of a shortened, but functional, version of the protein. We are developing exon skipping drug candidates with this potential. If these drugs are successful the course of DMD could be slowed down and the severity of the muscle disease could be reduced.
The relationship between exon skipping and the DMD deletions is shown below for some of the more frequent deletions in DMD. The deletions shown in the table are such that skipping of a single exon could be expected to repair the RNA and benefit the patients. There are also deletions (not shown) that require skipping of more than one exon and therefore need more than one drug to be beneficial. This is not an exhaustive list of repairable deletions.
| 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 |
The information set forth above is current only as of the dates noted. While we will make reasonable attempts to keep the information current, there is no guarantee that we will be successful and, except as required under applicable federal and state laws, we disclaim any obligation to do so. Readers are invited to visit the press release and SEC documents sections of this website for more up to date information about the Company and its research, development and clinical programs as well as other aspects of its business.
Additional information and resources concerning Duchenne muscular dystrophy can be found at the following websites:
Action Duchenne – Funding DMD research and advocating for improved medical care
Charley’s Fund – Non-profit organization funding research for DMD
ClinicalTrials.gov – Service of the U.S. National Institutes of Health offering up-to-date information on federally and privately supported clinical trials for a range of diseases and conditions
CureDuchenne – Non-profit organization focused on raising funds to support research for DMD treatments
Duchenne Muscular Dystrophy Information Page – National Institute of Neurological Disorders & Stroke
The Foundation to Eradicate Duchenne – Parent foundation dedicated to funding research for Duchenne muscular dystrophy
Muscular Dystrophy Association – A non-profit health agency dedicated to curing muscular dystrophies
Parent Project Muscular Dystrophy – A nonprofit organization with a mission to improve the treatment, quality of life and long-term outlook for all individuals affected by DMD.
