Complete and extremely encouraging findings from a phase 1b-2 trial of eteplirsen (AVI-4658), an exon skipping drug in development to treat a portion of the Duchenne muscular dystrophy (DMD) population, show the compound is safe and well-tolerated, and that it can significantly increase production of the needed dystrophin protein in recipients without eliciting an unwanted immune response.
The investigators say the results show eteplirsen has the potential to slow the progressive course of DMD and now needs to be investigated in longer clinical trials that can demonstrate functional effectiveness. A new trial is now open at Nationwide Children's Hospital in Columbus, Ohio, that will employ higher doses and a longer treatment duration than the U.K. trial did.
Encouraging preliminary results for this 12-week trial plus an additional 12 weeks of observation were announced in April 2011 at an American Academy of Neurology meeting (see Exon skipping drug AVI-4658 [eteplirsen] results in dystrophin production in Duchenne MD trial, Quest News, April 20, 2011). However, limited information was available at that time.
The experimental compound is being developed by AVI BioPharma, a biotechnology company in Bothell, Wash. The company announced the findings July 25, 2011, in conjunction with publication of the findings in the British medical journal The Lancet. The study was funded by AVI BioPharma and the United Kingdom Medical Research Council. Sebahattin Cirak and colleagues wrote the scientific paper, on which Francesco Muntoni was the corresponding author. Cirak and Muntoni are both located at the University College London Institute of Child Health.
Eteplirsen is an antisense oligonucleotide designed to keep a section of the dystrophin gene called exon 51 from being included in the final genetic instructions that cells use to make the muscle protein dystrophin. The drug is given intravenously.
DMD involves a complete or nearly complete absence of functional dystrophin protein in the skeletal and cardiac muscles, as a result of any of a large number of mutations in the dystrophin gene. The goal of exon skipping is to induce production of a shortened, partially functional dystrophin protein from a patient's existing genetic instructions.
Developers of exon skipping hope that a successful exon skipping drug will convert a DMD disease course to a disease course more like that of Becker muscular dystrophy (BMD) or perhaps even better than the usual BMD course. People with BMD make partially functional, short dystrophin protein molecules, which allow them to walk longer and function better than those with DMD.
Nineteen boys ages 6-13 with DMD and a mutation amenable to treatment by skipping exon 51 received eteplirsen intravenously once a week for 12 weeks. There were six dosage groups, each group receiving a higher dose than the previous one.
The main purpose of this phase 1b-2 trial, conducted in London and Newcastle Upon Tyne, United Kingdom, was to evaluate the safety and tolerability of various dosage levels of eteplirsen.
Secondary purposes were to assess how the body metabolizes and distributes the drug, as well as eteplirsen's ability to induce skipping of exon 51 and to restore dystrophin production. (For a full description of the trial, see Dose-Ranging Study of AVI-4658 or enter NCT00844597 into the search box at www.clinicaltrials.gov.)
Participants underwent a muscle biopsy before starting treatment and after 12 weekly infusions of eteplirsen.
Eteplirsen was safe and well-tolerated, with no drug-related serious adverse events occurring.
The treatment caused skipping of exon 51 in all dosage groups. Production of significant new dystrophin protein was seen in seven participants (in groups 3, 5 and 6). In general (although not true in every case), the amount of dystrophin that trial participants produced was correlated with the dosage of eteplirsen, with higher dosages corresponding to higher dystrophin production.
The three greatest responders to treatment were in groups 3, 5 and 6. One person in group 3 had a pretreatment biopsy sample showing 1 percent dystrophin-producing fibers and a post-treatment biopsy showing 21 percent dystrophin-producing fibers.
In group 5, one person's pretreatment biopsy showed 1 percent dystrophin-positive fibers, while his post-treatment sample showed 15 percent.
The high responder from group 6 had a pretreatment biopsy with 3 percent dystrophin-positive fibers and a post-treatment biopsy with 55 percent dystrophin-positive fibers.
Participants with high levels of dystrophin also had increased levels of proteins normally associated with dystrophin at the muscle-fiber membrane, which the investigators interpreted to mean that the dystrophin protein was functional.
In the two high-dose groups, analysis of biopsy samples showed a reduced number of potentially harmful T-cells from the immune system after treatment compared to before treatment. No antibodies (immune system proteins) to newly produced dystrophin were detected in any of the eteplirsen recipients.
Experts in the field have been concerned that any treatment that increases functional dystrophin protein levels could trigger an adverse immune response in recipients who have not previously produced functional dystrophin. So far, however, eteplirsen at the dosages used in this trial have not resulted in rejection of dystrophin by the immune system.
Muscle function testing did not show any dose-related changes, and most participants remained functionally stable during the study period. Four lost the ability to walk during the follow-up period, which was expected, the investigators say.
The investigators note that a longer treatment period at the dosage level used in group 5 or higher would likely result in "sufficient dystrophin expression to have a positive effect on the prevention of muscle degeneration in Duchenne muscular dystrophy."
They also say eteplirsen "has the potential to ameliorate the progressive natural history of Duchenne muscular dystrophy and now needs to be investigated in clinical efficacy trials."
AVI BioPharma is sponsoring a phase 2 trial of eteplirsen in the United States in approximately 12 boys with DMD who can potentially benefit from skipping exon 51 of the dystrophin gene. This trial, which was temporarily delayed in June 2011, is now under way.
The trial is taking place at Nationwide Children's Hospital in Columbus, Ohio, and is being overseen by neurologist Jerry Mendell, who co-directs the MDA clinic at that institution.
Participants must be 7-13 years old and meet all of several study criteria, including having one of the following mutations in the dystrophin gene: deletions of exons 45-50, 47-50, 48-50, 49-50, 50, 52 or 52-63. Potential participants must know their mutation prior to screening.
For more details, see Efficacy Study of AVI-4658 to Induce Dystrophin Expression in Selected Duchenne Muscular Dystrophy Patients, or search for NCT01396239 at www.clinicaltrials.gov.
Contact Ana Maria Gomez, study coordinator, at AnaMaria.Gomez@nationwidechildrens.org, for more about participating in this trial.
Editor's note 7/29/11: This story was amended 7/29/11 to reflect that all potential participants in the trial of eteplirsen at Nationwide Children's Hospital must know their gene mutation prior to screening.