Reldesemtiv in Patients with Spinal Muscular Atrophy: a Phase 2 Hypothesis-Generating Study

Abstract

This phase 2, double-blind, placebo-controlled, hypothesis-generating study evaluated the effects of oral reldesemtiv, a fast skeletal muscle troponin activator, in patients with spinal muscular atrophy (SMA). Patients ≥ 12 years of age with type II, III, or IV SMA were randomized into 2 sequential, ascending reldesemtiv dosing cohorts (cohort 1: 150 mg bid or placebo [2:1]; cohort 2: 450 mg bid or placebo [2:1]). The primary objective was to determine potential pharmacodynamic effects of reldesemtiv on 8 outcome measures in SMA, including 6-minute walk distance (6MWD) and maximum expiratory pressure (MEP). Changes from baseline to weeks 4 and 8 were determined. Pharmacokinetics and safety were also evaluated. Patients were randomized to reldesemtiv 150 mg, 450 mg, or placebo (24, 20, and 26, respectively). The change from baseline in 6MWD was greater for reldesemtiv 450 mg than for placebo at weeks 4 and 8 (least squares [LS] mean difference, 35.6 m [p = 0.0037] and 24.9 m [p = 0.058], respectively). Changes from baseline in MEP at week 8 on reldesemtiv 150 and 450 mg were significantly greater than those on placebo (LS mean differences, 11.7 [p = 0.038] and 13.2 cm H₂O [p = 0.03], respectively). For 6MWD and MEP, significant changes from placebo were seen in the highest reldesemtiv peak plasma concentration quartile (C_max > 3.29 μg/mL; LS mean differences, 43.3 m [p = 0.010] and 28.8 cm H₂O [p = 0.0002], respectively). Both dose levels of reldesemtiv were well tolerated. Results suggest reldesemtiv may offer clinical benefit and support evaluation in larger SMA patient populations.

Keywords: Reldesemtiv; pharmacodynamics; pharmacokinetics; six-minute walk test; spinal muscular atrophy clinical trial.

Fig. 1

Least squares mean change in outcome measures from baseline to week 8 in participants receiving reldesemtiv at doses of (A) 150 mg bid, and (B) 450 mg bid compared with placebo. *LSM change on reldesemtiv minus LSM change on placebo for all measures except TUG and SMA-HI, which are LSM change on placebo minus LSM change on reldesemtiv. bid = twice daily; FVC = forced vital capacity; HFMS-E = Hammersmith Functional Motor Score-Expanded; LSM = least squares mean; MEP = maximum expiratory pressure; MIP = maximum inspiratory pressure; pbo = placebo; RULM = revised upper limb module; SMA-HI = Spinal Muscular Atrophy-Health Index; TUG = timed up and go

Fig. 2

(A) Changes from baseline in 6MWD over time and (B) waterfall plot of individual changes from baseline to week 8 in 6MWD. 6MWD = 6-minute walking distance; bid = twice daily; LSM = least squares mean; m = meters; SEM = standard error of the mean

Fig. 3

Waterfall plots of individual changes in MEP from baseline to week 8 in (A) ambulatory and (B) non-ambulatory patients. MEP = maximum expiratory pressure; bid = twice daily

Fig. 4

Plasma concentrations of reldesemtiv over time. Error bars represent standard errors. bid = twice daily

Fig. 5

(A) Individual changes from baseline to week 8 in 6MWD by C_max, and (B) changes from baseline to week 8 in MEP and 6MWD by quartiles of C_max. *Difference between placebo and reldesemtiv. 6MWD = 6-minute walking distance; C_max = maximum observed plasma concentration; LSM = least squares mean; MEP = maximum expiratory pressure; pbo = placebo