1. A Phase 2, Double-Blind, randomized, Dose-Ranging trial Of Reldesemtiv in patients with ALS
- Author
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Shefner, J.M., Andrews, J.A., Genge, A., Jackson, C., Lechtzin, N., Miller, T.M., Cockroft, B.M., Meng, L., Wei, J., Wolff, A.A., Malik, F.I., Bodkin, C., Brooks, B.R., Caress, J., Dionne, A., Fee, D., Goutman, S.A., Goyal, N.A., Hardiman, O., Hayat, G., Heiman-Patterson, T., Heitzman, D., Henderson, R.D., Johnston, W., Karam, C., Kiernan, M.C., Kolb, S.J., Korngut, L., Ladha, S., Matte, G., Mora, J.S., Needham, M., Oskarsson, B., Pattee, G.L., Pioro, E.P., Pulley, M., Quan, D., Rezania, K., Schellenberg, K.L., Schultz, D., Shoesmith, C., Simmons, Z., Statland, J., Sultan, S., Swenson, A., Berg, L.H.V.D., Vu, T., Vucic, S., Weiss, M., Whyte-Rayson, A., Wymer, J., Zinman, L., Rudnicki, S.A., Shefner, J.M., Andrews, J.A., Genge, A., Jackson, C., Lechtzin, N., Miller, T.M., Cockroft, B.M., Meng, L., Wei, J., Wolff, A.A., Malik, F.I., Bodkin, C., Brooks, B.R., Caress, J., Dionne, A., Fee, D., Goutman, S.A., Goyal, N.A., Hardiman, O., Hayat, G., Heiman-Patterson, T., Heitzman, D., Henderson, R.D., Johnston, W., Karam, C., Kiernan, M.C., Kolb, S.J., Korngut, L., Ladha, S., Matte, G., Mora, J.S., Needham, M., Oskarsson, B., Pattee, G.L., Pioro, E.P., Pulley, M., Quan, D., Rezania, K., Schellenberg, K.L., Schultz, D., Shoesmith, C., Simmons, Z., Statland, J., Sultan, S., Swenson, A., Berg, L.H.V.D., Vu, T., Vucic, S., Weiss, M., Whyte-Rayson, A., Wymer, J., Zinman, L., and Rudnicki, S.A.
- Abstract
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 = 458) were enrolled; 85% completed 12-week treatment. The primary analysis failed to reach statistical significance (p = 0.11); secondary endpoints showed no statistically significant effects (ALSFRS-R, p = 0.09; muscle strength mega-score, p = 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)
- Published
- 2020