AVI BioPharma has announced biopsy data from Study 28, the ongoing phase 1b/2 clinical trial of AVI-4658 ( Eteplirsen ), a drug candidate being developed as a systemically administered treatment for a substantial subgroup of patients with Duchenne muscular dystrophy ( DMD ), a genetic muscle wasting disease caused by failure to produce dystrophin.
Biopsy data from the study demonstrated the first ever reported generation of new dystrophin-positive muscle fibers of more than 50% of normal in a patient with DMD following systemic administration of a drug. 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. Generation of functional dystrophin is considered critical for successful treatment of Duchenne muscular dystrophy.

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 analysis of the post treatment biopsy findings include:

a) Data reported for the 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;

b) 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;

c) All 8 patients in the 10 and 20 mg/kg cohorts demonstrated generation of new dystrophin-positive muscle fibers;

d) 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 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 the patients completing dosing, two serious adverse events ( one instance each of post operative nausea and vomiting, and an ankle fracture ), both deemed unrelated to AVI-4658, were reported in different patients after they completed their 12-week treatment period and during the 14-week follow-up period of the trial.

Treatment with AVI-4658 in all patients in the 10 and 20 mg/kg cohorts showed consistent skipping of exon 51, which is believed necessary to restore the mRNA reading frame and dystrophin expression in a substantial subgroup of patients with specific mutations. Analysis of post-treatment biopsies by reverse transcription-polymerase chain reaction ( RT-PCR ) confirmed the new mRNA resulting from the intended skipping, or exclusion, of exon 51.

All 8 patients in the 10 and 20 mg/kg cohorts treated with AVI-4658 demonstrated generation of new dystrophin-positive muscle fibers as measured by immunofluorescent analysis of their muscle biopsies.

Of note, three patients, one patient in each of the 2.0, 10 and 20 mg/kg cohorts, demonstrated substantial generation of new dystrophin-positive muscle fibers, which increased from 1% to 21%, 1% to 15%, and 3% to 55% of normal, respectively, when comparing pre treatment to post treatment samples. These three patients demonstrated a noted increase in dystrophin per fiber as determined by immunofluorescent analysis as well as multiple fold increases in dystrophin protein expression measured by Western blot over baseline. Patients in the 20 mg/kg cohort demonstrated the greatest fold increases when compared to the other cohorts measured by Western blot.

Overall, patients in the 10 and 20 mg/kg cohorts, both quantitatively and qualitatively, had more uniform and widespread dystrophin-positive fiber distribution than patients receiving lower doses. Additionally, responses of patients in the 20 mg/kg cohort appeared better than the patients in the 10 mg/kg cohort.

AVI-4658 is an RNA-based therapeutic employing phosphorodiamidate morpholino oligomer ( PMO ) based chemistry which can work by exon skipping. It is being developed as a systemic treatment for patients with Duchenne muscular dystrophy.
Study 28 is a Phase 1b/2 open label, dose-ranging, clinical trial assessing the safety, tolerability, pharmacokinetics and exploratory efficacy of AVI-4658 in ambulatory patients with Duchenne muscular dystrophy between the ages of 5 and 15 years of age who have an error in the gene coding for dystrophin that can be treated by skipping exon 51.
Patients were dosed once per week for 12 weeks by intravenous infusion. Nineteen patients were enrolled in total and assigned to one of six dose cohorts: 0.5, 1.0, 2.0, 4.0, 10.0 or 20.0 mg/kg. 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 at these doses over the 26-week duration of the trial. All patients completed dosing. Some patients in the highest dose cohort remain in the 14 week follow-up period.

Duchenne Muscular Dystrophy 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.
Duchenne muscular dystrophy 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.

Source: AVI BioPharma, 2010

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