Systemic administration of PRO051 in Duchenne's muscular dystrophy.

Abstract

BACKGROUND:

Local intramuscular administration of the antisense oligonucleotide PRO051 in patients with Duchenne's muscular dystrophy with relevant mutations was previously reported to induce the skipping of exon 51 during pre-messenger RNA splicing of the dystrophin gene and to facilitate new dystrophin expression in muscle-fiber membranes. The present phase 1-2a study aimed to assess the safety, pharmacokinetics, and molecular and clinical effects of systemically administered PRO051.

METHODS:

We administered weekly abdominal subcutaneous injections of PRO051 for 5 weeks in 12 patients, with each of four possible doses (0.5, 2.0, 4.0, and 6.0 mg per kilogram of body weight) given to 3 patients. Changes in RNA splicing and protein levels in the tibialis anterior muscle were assessed at two time points. All patients subsequently entered a 12-week open-label extension phase, during which they all received PRO051 at a dose of 6.0 mg per kilogram per week. Safety, pharmacokinetics, serum creatine kinase levels, and muscle strength and function were assessed.

RESULTS:

The most common adverse events were irritation at the administration site and, during the extension phase, mild and variable proteinuria and increased urinary α(1)-microglobulin levels; there were no serious adverse events. The mean terminal half-life of PRO051 in the circulation was 29 days. PRO051 induced detectable, specific exon-51 skipping at doses of 2.0 mg or more per kilogram. New dystrophin expression was observed between approximately 60% and 100% of muscle fibers in 10 of the 12 patients, as measured on post-treatment biopsy, which increased in a dose-dependent manner to up to 15.6% of the expression in healthy muscle. After the 12-week extension phase, there was a mean (±SD) improvement of 35.2±28.7 m (from the baseline of 384±121 m) on the 6-minute walk test.

CONCLUSIONS:

Systemically administered PRO051 showed dose-dependent molecular efficacy in patients with Duchenne's muscular dystrophy, with a modest improvement in the 6-minute walk test after 12 weeks of extended treatment. (Funded by Prosensa Therapeutics; Netherlands National Trial Register number, NTR1241.).

• Authors: Nathalie M Goemans, Mar Tulinius, Johanna T van den Akker, Brigitte E Burm, Peter F Ekhart, Niki Heuvelmans, Tjadine Holling, Anneke A Janson, Gerard J Platenburg, Jessica A Sipkens, J M Ad Sitsen, Annemieke Aartsma-Rus, Gert-Jan B van Ommen, Gunnar Buyse, Niklas Darin, Jan J Verschuuren, Giles V Campion, Sjef J de Kimpe, Judith C van Deutekom
• Journal: The New England journal of medicine (N Engl J Med) Vol. 364 Issue 16 Pg. 1513-22 (Apr 21 2011) ISSN: 1533-4406 [Electronic] United States
• PMID: 21428760 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Dystrophin
• Oligonucleotides
• PRO051
• RNA
• Creatine Kinase

Topics

• Adolescent
• Alternative Splicing
• Child
• Child, Preschool
• Creatine Kinase (urine)
• Dose-Response Relationship, Drug
• Dystrophin (genetics, metabolism)
• Exercise Test
• Exons
• Humans
• Injections, Subcutaneous
• Male
• Muscle Strength (drug effects)
• Muscle, Skeletal (chemistry, metabolism)
• Muscular Dystrophy, Duchenne (drug therapy, genetics)
• Mutation
• Oligonucleotides (administration & dosage, adverse effects, blood, therapeutic use)
• RNA (analysis)