Dr Michael Panzara, MD, MPHMichael Panzara, MD, MPH
Findings from Wave Life Sciences’ phase 1 clinical trial investigating suvodirsen (WVE-210201) in boys with Duchenne muscular dystrophy amenable to exon 51 skipping suggest that suvodirsen was generally safe and well tolerated at doses up to and including 5 mg/kg.

The results, presented at the 2019 Muscular Dystrophy Association Clinical and Scientific Conference in Orlando, Fla., support the initiation of the global phase 2/3 efficacy and safety trial (DYSTANCE 51) of suvodirsen in Duchenne muscular dystrophy amenable to exon 51 skipping.

“We are delighted that suvodirsen’s phase 1 results demonstrate a favorable safety and tolerability profile that allow us to proceed rapidly into phase 2/3 clinical development with doses we expect to be within the therapeutic window,” Michael Panzara, MD, MPH, chief medical officer, Wave Life Sciences, said in a statement.1 “Later this year, we expect to report interim efficacy data from the ongoing open-label extension study of suvodirsen and intend to use those data as an important component of a submission for accelerated approval in the United States.”

The phase 1 trial (NCT03508947), a global, double-blind, placebo-controlled study, was designed to evaluate the safety, tolerability, and plasma concentrations of single ascending doses of suvodirsen administered intravenously.

Participants were enrolled in the trial if they met the following criteria: ambulatory and nonambulatory male patients; 5–18 years of age; confirmed Duchenne muscular dystrophy gene mutation amenable to exon 51 skipping; may have been previously treated with eteplirsen or ataluren, with appropriate washout.

Primary endpoints focused on the safety and tolerability of suvodirsen compared to placebo assessed by the percentage of subjects with adverse effects, severity of adverse effects, percentage of those with serious adverse effects, and the percent of those who withdrew due to adverse effects. The secondary endpoint was the assessment of pharmacokinetic parameters following single-dose administration.

Thirty-six participants received a dose of 0.5 mg/kg, 1 mg/kg, 2 mg/kg, 5 mg/kg, 7 mg/kg, or 10 mg/kg of suvodirsen (n=26) or placebo (n=10) in 5 ascending dose cohorts and were monitored for 85 days.

There were no serious adverse effects, deaths or discontinuations due to adverse effects reported in any subject in the intervention arm. The most common adverse effects were headache, pyrexia, vomiting, and tachycardia, and a majority of these were infusion-related reactions, mild to moderate in severity, associated with transient increases in hsCRP and complement factor Bb, resolved with symptomatic treatment, and increased in severity at doses above 5 mg/kg.2

DYSTANCE 51 (NCT03907072), the phase 2/3 efficacy and safety clinical trial of suvodirsen which has been selected for the FDA Complex Innovative Trial Design Pilot Program, is designed to enroll boys between 5 and 12 years of age with a genetically confirmed diagnosis of Duchenne muscular dystrophy amenable to exon 51 skipping therapy. Participants will be randomized to receive 4.5 mg/kg—which provides the same amount of active ingredient as the 5 mg/kg dose in the phase 1 trial—or 3 mg/kg of suvodirsen or placebo administered intravenously once weekly for 48 weeks. The doses have been selected base on the phase 1 clinical results.

The primary efficacy endpoint will measure change in dystrophin protein level through 46 weeks, while the key secondary endpoint includes the change in the North Star Ambulatory Assessment score at 48 weeks or dystrophin protein levels at 46 weeks.

Suvodirsen has been granted orphan drug designation for treatment of Duchenne muscular dystrophy by the FDA and European Commission, as well as rare pediatric disease designation by the FDA.

The investigational therapy is being studied in an ongoing, multi-dose, open-label extension that was initiated in August 2018 and includes participants from the phase 1 trial. Interim efficacy data are expected in the second half of 2019, which are intended to serve as a component of a submission to the FDA for accelerated approval.
REFERENCE
1. Wave Life Sciences Announces Suvodirsen Phase 1 Safety and Tolerability Data and Phase 2/3 Clinical Trial Design [news release]. Cambridge, Mass.: Wave Life Sciences; April 16, 2019. ir.wavelifesciences.com/news-releases/news-release-details/wave-life-sciences-announces-suvodirsen-phase-1-safety-and. Accessed April 18, 2019.
2. Wave Life Sciences Muscular Dystrophy Association Clinical and Scientific Conference Investor Update. Wave Life Sciences. ir.wavelifesciences.com/static-files/4b471bd1-5fa2-454f-be89-4af1f05f6a8d. Published April 16, 2019. Accessed April 18, 2019.