PMID- 33624184 OWN - NLM STAT- MEDLINE DCOM- 20220202 LR - 20240204 IS - 1878-7479 (Electronic) IS - 1933-7213 (Print) IS - 1878-7479 (Linking) VI - 18 IP - 2 DP - 2021 Apr TI - Reldesemtiv in Patients with Spinal Muscular Atrophy: a Phase 2 Hypothesis-Generating Study. PG - 1127-1136 LID - 10.1007/s13311-020-01004-3 [doi] AB - 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 H(2)O [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 mug/mL; LS mean differences, 43.3 m [p = 0.010] and 28.8 cm H(2)O [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. CI - (c) 2021. The Author(s). FAU - Rudnicki, Stacy A AU - Rudnicki SA AD - Cytokinetics, Incorporated, South San Francisco, CA, USA. FAU - Andrews, Jinsy A AU - Andrews JA AD - Cytokinetics, Incorporated, South San Francisco, CA, USA. AD - Columbia University, New York, NY, USA. FAU - Duong, Tina AU - Duong T AD - Stanford University, Stanford, CA, USA. FAU - Cockroft, Bettina M AU - Cockroft BM AD - Cytokinetics, Incorporated, South San Francisco, CA, USA. AD - Sangamo Therapeutics, Brisbane, CA, USA. FAU - Malik, Fady I AU - Malik FI AD - Cytokinetics, Incorporated, South San Francisco, CA, USA. FAU - Meng, Lisa AU - Meng L AD - Cytokinetics, Incorporated, South San Francisco, CA, USA. FAU - Wei, Jenny AU - Wei J AD - Cytokinetics, Incorporated, South San Francisco, CA, USA. FAU - Wolff, Andrew A AU - Wolff AA AD - Cytokinetics, Incorporated, South San Francisco, CA, USA. FAU - Genge, Angela AU - Genge A AD - Montreal Neurological Institute, Montreal, QC, Canada. FAU - Johnson, Nicholas E AU - Johnson NE AD - Virginia Commonwealth University, Richmond, VA, USA. AD - University of Utah, Salt Lake City, UT, USA. FAU - Tesi-Rocha, Carolina AU - Tesi-Rocha C AD - Stanford University, Stanford, CA, USA. FAU - Connolly, Anne M AU - Connolly AM AD - Nationwide Children's Hospital, Columbus, OH, USA. AD - Washington University, St Louis, MO, USA. FAU - Darras, Basil T AU - Darras BT AD - Boston Children's Hospital and Harvard Medical School, Boston, MA, USA. FAU - Felice, Kevin AU - Felice K AD - Hospital for Special Care, New Britain, CT, USA. FAU - Finkel, Richard S AU - Finkel RS AD - Nemours Children's Hospital, Orlando, FL, USA. AD - St. Jude Children's Research Hospital, Memphis, TN, USA. FAU - Shieh, Perry B AU - Shieh PB AD - University of California, Los Angeles, Los Angeles, CA, USA. FAU - Mah, Jean K AU - Mah JK AD - University of Calgary, Alberta Children's Hospital, Calgary, AB, Canada. FAU - Statland, Jeffrey AU - Statland J AD - University of Kansas, Lawrence, KS, USA. FAU - Campbell, Craig AU - Campbell C AD - Department of Pediatrics, Epidemiology and Clinical Neurological Sciences, University of Western Ontario, London Health Sciences Centre, London, ON, Canada. FAU - Habib, Ali A AU - Habib AA AD - University of California, Irvine, Orange, CA, USA. FAU - Kuntz, Nancy L AU - Kuntz NL AD - Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA. FAU - Oskoui, Maryam AU - Oskoui M AD - McGill University Health Centre Research Institute, Montreal, QC, Canada. FAU - Day, John W AU - Day JW AUID- ORCID: 0000-0002-0086-9529 AD - Stanford University, Stanford, CA, USA. jwday@stanford.edu. LA - eng PT - Clinical Trial, Phase II PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20210223 PL - United States TA - Neurotherapeutics JT - Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics JID - 101290381 RN - 0 (Drugs, Investigational) RN - 0 (Pyridines) RN - 0 (Pyrimidines) RN - 0 (Pyrroles) RN - 0 (TNNI2 protein, human) RN - 0 (Troponin I) RN - 4S0HBYW6QE (reldesemtiv) SB - IM EIN - Neurotherapeutics. 2021 Jul;18(3):2130. PMID: 34731415 MH - Adolescent MH - Adult MH - Aged MH - Child MH - Cohort Studies MH - Double-Blind Method MH - Drugs, Investigational/chemistry/pharmacology/*therapeutic use MH - Female MH - Humans MH - Male MH - Middle Aged MH - Muscle, Skeletal/*drug effects/metabolism MH - Muscular Atrophy, Spinal/*drug therapy MH - Pyridines/chemistry/pharmacology/*therapeutic use MH - Pyrimidines/chemistry/pharmacology/*therapeutic use MH - Pyrroles/chemistry/pharmacology/*therapeutic use MH - Troponin I/agonists/*metabolism MH - Walk Test/methods MH - Young Adult PMC - PMC8423982 OTO - NOTNLM OT - Reldesemtiv OT - pharmacodynamics OT - pharmacokinetics OT - six-minute walk test OT - spinal muscular atrophy clinical trial EDAT- 2021/02/25 06:00 MHDA- 2022/02/03 06:00 PMCR- 2021/02/23 CRDT- 2021/02/24 05:46 PHST- 2020/12/30 00:00 [accepted] PHST- 2021/02/25 06:00 [pubmed] PHST- 2022/02/03 06:00 [medline] PHST- 2021/02/24 05:46 [entrez] PHST- 2021/02/23 00:00 [pmc-release] AID - S1878-7479(23)01152-2 [pii] AID - 1004 [pii] AID - 10.1007/s13311-020-01004-3 [doi] PST - ppublish SO - Neurotherapeutics. 2021 Apr;18(2):1127-1136. doi: 10.1007/s13311-020-01004-3. Epub 2021 Feb 23.