A Phase 2, Double-Blind, Randomized, Dose-Ranging Trial Of Reldesemtiv In Patients With ALS

Abstract

Objective: To evaluate safety, dose response, and preliminary efficacy of reldesemtiv over 12 weeks in patients with amyotrophic lateral sclerosis (ALS). Methods: Patients (2 years since diagnosis) with slow upright vital capacity (SVC) of !60% were randomized 1:1:1:1 to reldesemtiv 150, 300, or 450 mg twice daily (bid) or placebo; active treatment was 12 weeks with 4-week follow-up. Primary endpoint was change in percent predicted SVC at 12 weeks; secondary measures included ALS Functional Rating Scale-Revised (ALSFRS-R) and muscle strength mega-score. Results: Patients (N ¼ 458) were enrolled; 85% completed 12-week treatment. The primary analysis failed to reach statistical significance (p ¼ 0.11); secondary endpoints showed no statistically significant effects (ALSFRS-R, p ¼ 0.09; muscle strength megascore, p ¼ 0.31). Post hoc analyses pooling all active reldesemtiv-treated patients compared against placebo showed trends toward benefit in all endpoints (progression rate for SVC, ALSFRS-R, and muscle strength mega-score (nominal p values of 0.10, 0.01 and 0.20 respectively)). Reldesemtiv was well tolerated, with nausea and fatigue being the most common side effects. A dose-dependent decrease in estimated glomerular filtration rate was noted, and transaminase elevations were seen in approximately 5% of patients. Both hepatic and renal abnormalities trended toward resolution after study drug discontinuation. Conclusions: Although the primary efficacy analysis did not demonstrate statistical significance, there were trends favoring reldesemtiv for all three endpoints, with effect sizes generally regarded as clinically important. Tolerability was good; modest hepatic and renal abnormalities were reversible. The impact of reldesemtiv on patients with ALS should be assessed in a pivotal Phase 3 trial. (ClinicalTrials.gov Identifier: NCT03160898)

An old friend who has overstayed their welcome: the ALSFRS-R total score as primary endpoint for ALS clinical trials

“…Unfortunately, subscale-specific treatment effects are rarely reported in ALS clinical trials and it is not known how treatments have affected the ALSFRS-R subscales in the past. The clinical trials with sodium phenylbutyrate-taurursodiol (25), Nuedexta and Reldesemtiv (19,30), however, provide important evidence that these non-uniform treatments do exist and may dilute the treatment effect estimate when quantified by the ALSFRS-R total score.…”

Pathogenic variants in TNNC2 cause congenital myopathy due to an impaired force response to calcium

“…Although tirasemtiv did not meet its primary endpoint in a recent phase III clinical trial in patients with amyotrophic lateral sclerosis, due in part to tolerability (including dizziness, fatigue, nausea, weight loss, and insomnia) (37), our findings illustrate the great therapeutic promise of fast skeletal muscle Tn activation. Reldesemtiv, a second-generation fast skeletal muscle Tn activator that is structurally distinct from tirasemtiv, has a lower side-effect profile and is currently under clinical trial investigation (38,39). In summary, we characterized 2 families with a distinct congenital myopathy caused by dominantly acting variants in TNNC2.…”

Skeletal Muscle in ALS: An Unappreciated Therapeutic Opportunity?

“…Its functions are similar to tirasemtiv, but it has different chemical characteristics. A double-blind, randomized, placebo-controlled, variable dosage trial (NCT03160898) tested the safety of reldesemtiv and demonstrated that the drug was well tolerated by patients and that there was a trend towards improvement in primary and secondary outcomes, though it was not statistically significant [ 161 ]. The therapeutic potential of reldesemtiv is currently studied for the treatment of other diseases associated with muscle dysfunction and weakness, such as SMA, chronic obstructive pulmonary disease (COPD), and in elderly subjects with reduced mobility (NCT02644668sma- NCT03065959-copd).…”