Safety, Tolerability, and Efficacy of Viltolarsen in Boys With Duchenne Muscular Dystrophy Amenable to Exon 53 Skipping: A Phase 2 Randomized Clinical Trial

Abstract

Importance: An unmet need remains for safe and efficacious treatments for Duchenne muscular dystrophy (DMD). To date, there are limited agents available that address the underlying cause of the disease.

Objective: To evaluate the safety, tolerability, and efficacy of viltolarsen, a novel antisense oligonucleotide, in participants with DMD amenable to exon 53 skipping.

Design, setting, and participants: This phase 2 study was a 4-week randomized clinical trial for safety followed by a 20-week open-label treatment period of patients aged 4 to 9 years with DMD amenable to exon 53 skipping. To enroll 16 participants, with 8 participants in each of the 2 dose cohorts, 17 participants were screened. Study enrollment occurred between December 16, 2016, and August 17, 2017, at sites in the US and Canada. Data were collected from December 2016 to February 2018, and data were analyzed from April 2018 to May 2019.

Interventions: Participants received 40 mg/kg (low dose) or 80 mg/kg (high dose) of viltolarsen administered by weekly intravenous infusion.

Main outcomes and measures: Primary outcomes of the trial included safety, tolerability, and de novo dystrophin protein production measured by Western blot in participants' biceps muscles. Secondary outcomes included additional assessments of dystrophin mRNA and protein production as well as clinical muscle strength and function.

Results: Of the 16 included boys with DMD, 15 (94%) were white, and the mean (SD) age was 7.4 (1.8) years. After 20 to 24 weeks of treatment, significant drug-induced dystrophin production was seen in both viltolarsen dose cohorts (40 mg/kg per week: mean [range] 5.7% [3.2-10.3] of normal; 80 mg/kg per week: mean [range] 5.9% [1.1-14.4] of normal). Viltolarsen was well tolerated; no treatment-emergent adverse events required dose reduction, interruption, or discontinuation of the study drug. No serious adverse events or deaths occurred during the study. Compared with 65 age-matched and treatment-matched natural history controls, all 16 participants treated with viltolarsen showed significant improvements in timed function tests from baseline, including time to stand from supine (viltolarsen: -0.19 s; control: 0.66 s), time to run/walk 10 m (viltolarsen: 0.23 m/s; control: -0.04 m/s), and 6-minute walk test (viltolarsen: 28.9 m; control: -65.3 m) at the week 25 visit.

Conclusions and relevance: Systemic treatment of participants with DMD with viltolarsen induced de novo dystrophin production, and clinical improvement of timed function tests was observed.

Trial registration: ClinicalTrials.gov Identifier: NCT02740972.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Clemens has received grants from NS Pharma during the conduct of the study as well as grants from Spark Therapeutics, Amicus Therapeutics, Sanofi Genzyme, ReveraGen BioPharma, and TRiNDS and personal fees from Spark Therapeutics, UCB, Pfizer, and Roche outside the submitted work. Dr Rao has received nonfinancial support from Ann and Robert H. Lurie Children’s Hospital of Chicago during the conduct of the study as well as personal fees from PTC Therapeutics and Sarepta Therapeutics outside the submitted work. Dr Connelly has received grants from the Washington University School of Medicine and TRiNDS during the conduct of the study as well as grants from Sarepta Therapeutics and AveXis and personal fees from Sarepta Therapeutics, AveXis, Genentech-Roche, Acceleron Pharma, and Catabasis Pharmaceuticals outside the submitted work. Dr Harper has received grants from NS Pharma, Italfarmaco, ReveraGen BioPharma, Catabasis Pharmaceuticals, AveXis, CSL Behring, Teva Pharmaceutical Industries, National Institutes of Health, and US Centers for Disease Control and Prevention. Dr Mah has received grants from NS Pharma during the conduct of the study as well as grants from PTC Therapeutics, Pfizer, Roche, Sarepta Therapeutics, Italfarmaco, Novartis, Biogen, ReveraGen BioPharma, Catabasis Pharmaceuticals, Sanofi-Genzyme, and Bristol-Myers Squibb outside the submitted work. Dr Smith has received salary support from NS Pharma during the conduct of the study as well as personal fees from Pfizer and Sarepta Therapeutics and salary support from Pfizer and ReveraGen BioPharma outside the submitted work. Dr McDonald has received grants from NS Pharma during the conduct of the study as well as personal fees from Bristol-Myers Squibb, Astellas/Mitobridge, Cardero Therapeutics, Capricor Therapeutics, Catabasis Pharmaceuticals, Eli Lilly and Company, Epirium Bio, FibroGen, Halo Therapeutics, Italfarmaco, BioMarin Pharmaceutical, Novartis, Pfizer, Prosensa, PTC Therapeutics, Santhera Pharmaceuticals, and Sarepta Therapeutics outside the submitted work. Dr Zaidman has received nonfinancial support from Biogen outside the submitted work. Ms Morgenroth has received salary support from TRiNDS during the conduct of the study. Mr Osaki and Dr Yamashita are employed by NS Pharma. Mr Satou is employed by NS Pharma and has patent PCT/JP2011/070318 issued and licensed to Nippon Shinyaku and the National Center of Neurology and Psychiatry and has patent PCT/JP2019/026393 pending. Dr Hoffman has received grants from AGADA Biosciences and TRiNDS during the conduct of the study and grants from ReveraGen BioPharma outside the submitted work.

Figures

Figure 1.. CONSORT Diagram

Participant flow throughout the trial.

Figure 2.. Evaluation of Dystrophin Induction

Muscle biopsies randomized and tested by blinded analysts. A, Dystrophin Western blot. Examples of participants with Duchenne muscular dystrophy treated with 40 mg/kg per week (low-dose cohort) and 80 mg/kg per week (high-dose cohort) of viltolarsen are shown, together with standard curve for dystrophin (D) quantitation. The lanes indicate individual participants; samples were pretreatment (baseline) and posttreatment (week 25 visit) biopsies. Normalization was to both myosin heavy chains (M) and α-actinin (A). All biopsies were analyzed with triplicate gels. B, Percentage of normal dystrophin levels was graphed for each participant at baseline and posttreatment at the week 25 visit. Dystrophin was measured using Western blot and normalized to myosin heavy chains. The blue line denotes 3% of normal dystrophin levels. Each line indicates a different patient. C, Dystrophin mRNA reverse transcription–polymerase chain reaction (RT-PCR). Examples of pretreatment and posttreatment biopsies from the high-dose group are shown, each tested in duplicate assays. D, Immunofluorescence staining of muscle biopsies for dystrophin and colocalization controls. Serial cryosections were double stained with dystrophin and laminin α2 or dystrophin and α-sarcoglycan from a participant who received 80 mg/kg per week of viltolarsen.

Figure 3.. Change in Timed Function Tests in Viltolarsen-Treated Participants and Cooperative International Neuromuscular Research Group (CINRG) Duchenne Natural History Study (DNHS)

The change in timed function tests of viltolarsen-treated participants from both dose groups (blue) and CINRG DNHS steroid-treated, age-matched comparators (orange) are shown. Assessments were performed at baseline and the 13-week and 25-week visits.