Safety and Efficacy Study of Antisense Oligonucleotides in Duchenne Muscular Dystrophy

• Status: Completed
• Trial end date: 2009-03-31
• Target enrollment: 0
• Participant gender: Male

Summary

Duchenne muscular dystrophy (DMD), a fatal muscle degenerative disorder, arises from mutations in the dystrophin gene. Antisense therapy with the use of antisense oligonucleotides (AON) has the potential to restore effectively the production of dystrophin, the defective protein, in >70% of DMD. This could result in increased life expectancy through improved muscle survival and function. Recent scientific research has demonstrated the potential of this technique to skip mutated dystrophin exons, restore the reading frame and generate functional dystrophin protein. Having demonstrated proof-of-principle in human cell culture and animal model studies, we now intend to determine efficacy and safety of this approach to induce dystrophin exon skipping in children with DMD.

The specific aim of this phase I/II study is to assess efficacy (dystrophin production) and safety of intramuscular administered morpholino oligomer directed against exon 51 (AVI-4658 PMO). We are performing parallel preclinical studies to develop methods of systemic delivery that will be necessary for future phase II/III clinical studies.

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Imperial College London
• Collaborators: Department of Health, United Kingdom; Sarepta Therapeutics, Inc.

Criteria

Inclusion Criteria:

1. Subject is male ≥ 10 years and ≤ 17 years of age at the time of study drug administration.

2. Subject has clinical diagnosis compatible with Duchenne's Muscular Dystrophy (DMD) and evidence of mutational and dystrophin defects from muscle biopsy consistent with DMD (out-of frame deletions, absent dystrophin).Eligible deletions are those that can be rescued by the skipping of exon 51 [45-50; 47-50; 48-50; 49-50; 50; 52; 52-63].

3. Subject has had a muscle biopsy analysed, showing <5% revertant fibres present. Biopsy may be collected at the time of DMD diagnosis or as part of protocol screening procedures.

4. Subject is unable to ambulate or stand independently.

5. Subject has Stage 1 to 3 EDB muscle preservation determined by MRI.

6. Subject has a forced vital capacity ≥ 25% confirmed within 3 months from Day One.

7. Subject has mean oxygen saturation monitoring > 94% in overnight domiciliary overnight sleep study within 3 months of Day One.

8. Subject has the ability to comply with all study evaluations and return for all study.

9. Subject and parent have psychiatric adjustments, adequately supportive psychosocial circumstances and a full understanding of study aims process and likely outcomes.

Exclusion Criteria:

1. Subject has had external digitorum brevis (EDB) muscle removed.

2. Subject has Stage 4 EDB muscle preservation determined by MRI.

3. Subject has a left ventricular shortening fraction of < 25% and/or an ejection fraction of < 35% by echocardiography at visit one or within three months of visit one.

4. Subject has evidence of nocturnal hypoventilation (mean oxygen saturation at night of ≤ 94%) confirmed via overnight sleep study at Visit One (as screening procedure) or within 3 months of Visit One by overnight sleep study.

5. Subject has severe respiratory insufficiency defined by the need for invasive or non-invasive mechanical ventilation (does not include nocturnal ventilatory support).

6. Subject has severe cognitive dysfunction rendering them unable to understand and collaborate with study protocol.

7. Subject has immune deficiency or autoimmune disease.

8. Subject has a known bleeding disorder or has received chronic anticoagulant treatment within three months of study entry.

9. Subject has received pharmacologic treatment, apart from corticosteroids, that might affect muscle strength or function within 8 weeks of study entry (viz.,anabolic steroids, creatine protein supplementation, albuterol or other beta agonists).

10. Subject has had surgery within 3 months of study entry or planned for anytime during study.

11. Subject has active significant illness at time of study entry.

12. Subject has is unable to undergo MRI testing (viz., has metal implants).

13. Subject or parent has active psychiatric disorder, has adverse psychosocial circumstances, recent significant emotional loss, history of depressive or anxiety disorders that might interfere with protocol completion or compliance.

14. Subject has any known allergies to products likely to be used in the study (viz.,antiseptics, anaesthetics).

15. Subject has used any experimental treatments or has participated in any clinical trial within 4 weeks of study entry.

16. Subject has used intranasal, inhaled or topical steroids for a condition other than muscular dystrophy within 1 weeks of study entry.