AVI BioPharma, a developer of RNA-based therapeutics, has announced that data published in The Lancet from a Phase 1b/2 study of Eteplirsen ( AVI-4658 ), a exon-skipping therapy for the treatment of Duchenne muscular dystrophy ( DMD ), have demonstrated that the treatment was well tolerated and was shown to induce statistically significant and dose-dependent improvements in dystrophin expression in patients.
Duchenne muscular dystrophy is a genetic muscle wasting disease caused by the absence of functional dystrophin, an essential muscle protein.

The primary objective of the 19-patient, 12-week, six dose cohort study was to assess Eteplirsen's safety and tolerability. Secondary objectives were assessments of the pharmacokinetic profile and ability to restore dystrophin expression.
Eteplirsen was well tolerated in all patients, with no clear drug-related serious adverse events. Reported adverse events were mostly mild or moderate in intensity and not dose-related. The plasma half-life was short, and there was no plasma accumulation observed between doses. Clearance of Eteplirsen was primarily via the kidney.

Eteplirsen induced exon 51 skipping in all cohorts, and novel dystrophin protein expression was observed in a dose-dependent manner ( p=0.02 ). While results were variable among patients, the substantial, statistically significant ( p=0.04 ), new dystrophin expression was observed in the highest two dose cohorts. Moreover, novel dystrophin expression was accompanied by a significant reduction of inflammatory cell infiltrates in the two highest dose cohorts, including CD3 ( p=0.01 ), CD4 and CD8 inflammation markers, suggesting an alteration in the underlying degenerative disease process. The functional properties of the novel dystrophin expression were confirmed by localization of the protein at the sarcolema, or cell membrane. Clinical muscle function evaluations found that most patients remained stable during the study period.
The study was not designed to evaluate clinical benefit, and longer drug exposure is believed necessary to influence disease progression.

Eteplirsen uses AVI's novel phosphorodiamidate morpholino oligomer ( PMO )-based chemistry and exon-skipping technology to skip exon 51 of the dystrophin gene. By skipping exon 51, Eteplirsen may restore the gene's ability to make a shorter, but still functional, form of dystrophin from mRNA. Promoting the synthesis of a truncated dystrophin protein is intended to improve, stabilize or significantly slow the disease process and prolong and improve the quality of life for patients with Duchenne muscular dystrophy.

Source: AVI BioPharma, 2011

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