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 (Cmax > 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.
Highlights
Spinal muscular atrophy (SMA) is a genetic neuromuscular disease in which reduced amounts of functional survival motor neuron (SMN) protein result in progressive muscle weakness and atrophy, leading to various degrees of functional motor impairment [1]
No deaths were reported during the study. In this hypothesis-generating study, 6-minute walk distance (6MWD) and maximum expiratory pressure (MEP) improved versus placebo in patients with SMA receiving reldesemtiv, consistent with increased skeletal muscle force production by reldesemtiv
The least squares (LS) mean change from baseline in the 6MWD at week 4 was significantly greater for reldesemtiv 450 mg bid compared with placebo, and difference at week 8 trended to conventional statistical significance
Summary
Spinal muscular atrophy (SMA) is a genetic neuromuscular disease in which reduced amounts of functional survival motor neuron (SMN) protein result in progressive muscle weakness and atrophy, leading to various degrees of functional motor impairment [1]. All three recently approved SMA course-modifying treatments increase motor neuron SMN protein content. Nusinersen, an antisense oligonucleotide drug that increases SMN production by altering SMN2 splicing [5, 6], was the first approved medication for the specific treatment of SMA. Risdiplam, a small molecule SMN2 splicing modifier, is approved to treat patients 2 months and older with SMA, and has been studied in a randomized, double-blind, placebo-controlled study in patients up to the age of 25 [13, 14]. Even after treatment with these new therapies, many very young SMA patients fail to meet age-specific motor milestones, and treatment later in the course of disease results in even less dramatic benefits
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