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.
AVI BioPharma is currently evaluating drug candidates for DMD.
AVI-4658, our lead therapeutic candidate for DMD, 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, AVI-4658 may restore the gene’s ability to make a shorter – but still functional – form of dystrophin. AVI-4658 is in a Phase 1b/2 clinical trial at two sites in the United Kingdom.
We are 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
AVI-4658
We are currently evaluating AVI-4658, our lead DMD therapeutic candidate based on our proprietary exon-skipping technology. It is in a Phase 1b/2 clinical trial at two sites in the United Kingdom.
AVI-4658 employs our core PMO chemistry and is intended to skip exon 51 of the dystrophin gene. By skipping exon 51, we believe AVI-4658 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
AVI-4658
We are planning to initiate a Phase 1b/2 clinical trial of AVI-4658 in patients with DMD in the U.S. in the second half of 2010. It is anticipated that our future clinical evaluation will include exploration of increasing doses of AVI-4658 in light of the generally well tolerated nature of the drug candidate exhibited in the clinical and preclinical studies to date, and the substantial, but variable, increases in dystrophin measurements demonstrated in patients with DMD in the U.K. based Phase 1b/2 clinical trial.
AVI-4658 is in an ongoing, open label Phase 1b/2 dose-ranging clinical trial in the U.K. evaluating safety, tolerability, pharmacokinetics and exploratory efficacy. 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 AVI-4658 ranging from 0.5 to 20 mg/kg once weekly for 12 weeks by intravenous infusion. After completion of dosing, patients are followed for a further 14 weeks. The primary objective of the trial is to assess the safety of AVI-4658 over the 26-week duration of the trial.
Topline biopsy data from the Phase 1b/2 clinical trial of AVI-4658 were announced in December 2009 (read Press Release) and June 2010 (read Press Release). All patients in the two highest dose cohorts of the study demonstrated generation of new dystrophin-positive muscle fibers, although treatment responses varied across and within treatment groups.
Patients completing 12 weeks of treatment with six different doses of AVI-4658 (0.5, 1.0, 2.0, 4.0, 10 or 20 mg/kg) had their muscles biopsied before and after treatment, and findings from the post treatment biopsy analysis include:
- Patients in the 10 and 20 mg/kg drug-treatment cohorts completing the 12 weekly doses (8 of 8 patients) showed consistent skipping of exon 51 in the dystrophin mRNA, providing evidence of systemic biologic activity of AVI-4658.
- Three patients, one each in the 2.0, 10 and 20 mg/kg cohorts, demonstrated substantial generation of new dystrophin-positive muscle fibers, including the first ever reported generation of dystrophin-positive muscle fibers of more than 50% of normal in a patient following systemic administration of a drug.
- All 8 patients in the 10 and 20 mg/kg cohorts demonstrated generation of new dystrophin-positive muscle fibers.
- The three patients, one each in the 2.0, 10 and 20 mg/kg cohorts, demonstrating substantial generation of new dystrophin-positive muscle fibers had multiple fold increases in dystrophin protein expression measured by Western blot over baseline, with patients in the 20 mg/kg cohort demonstrating the highest increases. These three patients also had noted increases in dystrophin per fiber.
AVI-4658 Phase 1b/2: Percent Positive Dystrophin Muscle Fibers
AVI-4658 was generally well tolerated in all Study 28 patients, and there has been no evidence of anti-dystrophin antibodies or T and B cell infiltration.
In January 2009, we announced results from a Phase 1 trial of AVI–4658 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 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 AVI-4658 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 AVI–4658 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 AVI-4658 from the FDA in December 2007.
AVI-5038
AVI 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 dsytrophin. 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. This is not necessarily 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, 46-52, 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 | 4-7, 5-7, 6-7, 3-7 |
| 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 Duchenne Muscular
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 dystrophy
United Parent Project Muscular Dystrophy – International support organization for DMD families and caregivers
This page was last updated on July 31, 2010.
