Randomized controlled trial of N -acetylcysteine therapy for RYR1 -related myopathies

Abstract

ObjectiveTo investigate the efficacy of N-acetylcysteine (NAC) for decreasing elevated oxidative stress and increasing physical endurance in individuals with ryanodine receptor 1-related myopathies (RYR1-RM).MethodsIn this 6-month natural history assessment (n = 37) followed by a randomized, double-blinded, placebo-controlled trial, 33 eligible participants were block-randomized (1:1) to receive NAC (n = 16) or placebo (n = 17), orally for 6 months (adult dose 2,700 mg/d; pediatric dose 30 mg/kg/d). The primary endpoint was urine 15-F2t isoprostane concentration and the clinically meaningful co-primary endpoint was 6-minute walk test (6MWT) distance.ResultsWhen compared to the general population, participants had elevated baseline 15-F2t isoprostane concentrations and most had a decreased 6MWT distance (mean ± SD 3.2 ± 1.5 vs 1.1 ± 1.7 ng/mg creatinine and 468 ± 134 vs 600 ± 58 m, respectively, both p < 0.001). 15-F2t isoprostane concentration and 6MWT distance did not change over the 6-month natural history assessment (p = 0.98 and p = 0.61, respectively). NAC treatment did not improve 15-F2t isoprostane concentration (least squares means difference 0.1 [95% confidence interval [CI] −1.4 to 1.6] ng/mg creatinine, p = 0.88) or 6MWT distance (least squares means difference 24 [95% CI −5.5 to 53.4] m, p = 0.11). NAC was safe and well-tolerated at the doses administered in this study.ConclusionIn ambulatory RYR1-RM–affected individuals, we observed stable disease course, and corroborated preclinical reports of elevated oxidative stress and decreased physical endurance. NAC treatment did not decrease elevated oxidative stress, as measured by 15-F2t isoprostane.Classification of evidenceThis study provides Class I evidence that, for people with RYR1-RM, treatment with oral NAC does not decrease oxidative stress as measured by 15-F2t isoprostane.Clinicaltrials.gov identifierNCT02362425.

Antioxidants Reduce Muscular Dystrophy in the dy2J/dy2J Mouse Model of Laminin α2 Chain-Deficient Muscular Dystrophy

“…NAC did not decrease the oxidative stress in these patients but showed clinically improved physical endurance. The dose in individuals with RYR1-RM was 2,700 mg/d for adults and the pediatric dose was 30 mg/kg/d [49]. Dy 2J /dy 2J mice received 150 mg/kg/d but it should be pointed out that the optimal dose of NAC is unclear, and studies may show equal efficacy at lower doses or greater efficacy at higher doses [50].…”

N-Acetylcysteine Reduces Skeletal Muscles Oxidative Stress and Improves Grip Strength in Dysferlin-Deficient Bla/J Mice

“…NAC has also been evaluated in individuals with ryanodine receptor 1-related myopathies. However, this antioxidant agent, administered orally for six months, did not reduce OS in these patients [66].…”

Identification of drug modifiers for RYR1-related myopathy using a multi-species discovery pipeline

“…Based on these data, NAC was recently tested via clinical trial in RYR1-RM patients, where a non-significant trend toward improvement was observed (Todd et al, 2020). These observations open the prospective of polytherapy as a potential treatment strategy.…”

“…However, as of yet none of these targets has successfully translated to patients, though Nacetylcysteine was tested in a recently completed clinical trial (ClinicalTrials.gov identifier: NCT02362425), where it failed to achieve its primary endpoint (Todd et al, 2020). There is thus a critical need to identify and develop new treatment strategies.…”