title: Safety, tolerability and pharmacodynamics of a skeletal muscle activator in amyotrophic lateral sclerosis.
abstract: This study was designed to evaluate the safety and tolerability of single doses of CK-2017357, an orally bioavailable fast skeletal muscle troponin activator, in patients with amyotrophic lateral sclerosis (ALS), and to explore pharmacodynamic markers related to strength, endurance, and function. Sixty-seven patients with ALS received single doses of placebo, CK-2017357 at 250 mg and 500 mg in random order, separated by one week. Safety measures assessments were performed, as well as tests of pulmonary function, limb muscle strength and endurance, and global impression of change. Pharmacokinetics of both CK-2017357 and riluzole were studied. Sixty-three patients completed all three dosing periods. CK-2017357 was well tolerated, with dizziness and general fatigue being the most frequent adverse events. Both patients and investigators perceived a dose-dependent benefit of CK-2017357 as measured by global impression of change. Maximum voluntary ventilation and submaximal handgrip endurance also improved. Only small changes were seen in maximal strength. In conclusion, single doses of 250 mg and 500 mg of CK-2017357 were safe and well tolerated by patients with ALS. Measures of endurance appear to be improved in a dose-related fashion, and both patients and investigators perceived a global benefit. Further study of this agent is warranted.
authors.affiliation: Department of Neurology, Upstate Medical University, Syracuse, NY 13210-2306, USA. shefnerj@upstate.edu
authors.forename: Jeremy
authors.initials: J
authors.lastname: Shefner
authors.forename: Jesse M
authors.initials: JM
authors.lastname: Cedarbaum
authors.forename: Merit E
authors.initials: ME
authors.lastname: Cudkowicz
authors.forename: Nicholas
authors.initials: N
authors.lastname: Maragakis
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Lee
authors.forename: Drew
authors.initials: D
authors.lastname: Jones
authors.forename: Mary Lou
authors.initials: ML
authors.lastname: Watson
authors.forename: Katy
authors.initials: K
authors.lastname: Mahoney
authors.forename: Michael
authors.initials: M
authors.lastname: Chen
authors.forename: Khalil
authors.initials: K
authors.lastname: Saikali
authors.forename: John
authors.initials: J
authors.lastname: Mao
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Russell
authors.forename: Richard L
authors.initials: RL
authors.lastname: Hansen
authors.forename: Fady
authors.initials: F
authors.lastname: Malik
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Wolff
mesh_terms: D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy*; D005260:Female; D018737:Hand Strength / Q000502:physiology; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D011719:Pyrazines / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D019782:Riluzole / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: C572767:CK-2017357; D007093:Imidazoles; D018696:Neuroprotective Agents; D011719:Pyrazines; D019782:Riluzole