AVI BioPharma, Inc. announced data from a Phase 1b/2 study of eteplirsen, demonstrating that the treatment was well tolerated and was shown to induce statistically significant and dose-dependent improvements in dystrophin expression in patients.
“Our observations of significant and dose dependent improvements in novel dystrophin expression and other associated biochemical markers suggest that eteplirsen has the potential to reduce muscle damage in DMD patients and positively modify the severe progressive nature of the disease,” says Francesco Muntoni, professor of pediatric neurology and head of the Dubowitz Neuromuscular Center at the UCL Institute of Child Health. “Restoration of dystrophin with a safe therapeutic candidate could have a considerable positive impact on the quality of life for patients, their mobility and the way their condition is managed as they age, and we are eager to continue the investigation of eteplirsen in placebo-controlled trials to evaluate biochemical markers and clinical endpoints over a longer treatment duration.”
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. While results were variable among patients, the substantial, statistically significant, 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, 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 research was published in The Lancet.
Filed Under: Drug Discovery