ck-2017357 and Amyotrophic-Lateral-Sclerosis

Amyotrophic lateral sclerosis (ALS) is an unrelenting progressive neurodegenerative disease causing progressive weakness, ultimately leading to death. Despite aggressive research, the pathways leading to neuronal death are incompletely understood. Riluzole is the only drug clinically proven to enhance survival of ALS patients, but its mechanism of action is not clearly understood. In this article, the proposed pathophysiology of ALS is reviewed including glutamate excitotoxicity, oxidative stress, mitochondrial dysfunction, autoimmune mechanisms, protein aggregation, SOD1 accumulation, and neuronal death. Based on these mechanisms, past major ALS drug studies will be reviewed as well as promising current ALS drug studies, focusing on the advancement of these studies from the bench to the patient's bedside.

Topics: Amyotrophic Lateral Sclerosis; Antioxidants; Excitatory Amino Acid Antagonists; Genetic Therapy; Humans; Imidazoles; Immunosuppressive Agents; Pyrazines; Stem Cell Transplantation; Superoxide Dismutase; Superoxide Dismutase-1

To assess the efficacy of tirasemtiv, a fast skeletal muscle troponin activator, vs. placebo in patients with amyotrophic lateral sclerosis. Methods: VITALITY-ALS (NCT02496767) was a multinational, double-blind, randomized, placebo-controlled clinical trial. Participants tolerating 2 weeks of open-label tirasemtiv (125 mg twice daily) were randomized 3:2:2:2 to placebo or one of three target tirasemtiv dose levels, using an escalating dosage protocol lasting 28 days. The primary outcome measure was changed in slow vital capacity (SVC) at 24 weeks. Secondary endpoints included a change in muscle strength and time to respiratory milestones of disease progression.. Of 744 participants, 565 tolerated open-label tirasemtiv and received randomized treatment. By 24 weeks, 23 (12.2%) placebo-treated participants discontinued study treatment vs. 129 (34.2%) randomized to tirasemtiv. SVC declined by 14.4% (95% CI: −16.8, −11.9) in the placebo group and 13.4% (95% CI: −15.3, −11.6) in the tirasemtiv group (p = 0.56). Secondary endpoints did not show significant differences. However, participants who tolerated tirasemtiv at their randomized dose showed a numeric trend toward a dose-related slowing of decline in SVC (p = 0.11). Dizziness, fatigue, nausea, weight loss, and insomnia occurred more frequently on tirasemtiv. Serious adverse events were similar across groups.. Tirasemtiv did not alter the decline of SVC or significantly impact secondary outcome measures. Poor tolerability of tirasemtiv may have contributed to this result. However, participants tolerating their intended dose exhibited a trend toward treatment benefit on SVC, suggesting the underlying mechanism of action may still hold promise, as is being tested with a different fast skeletal muscle troponin activator (NCT03160898).

Topics: Adult; Amyotrophic Lateral Sclerosis; Disease Progression; Double-Blind Method; Female; Humans; Imidazoles; Male; Middle Aged; Muscle Strength; Muscle, Skeletal; Pyrazines; Treatment Outcome

To assess the efficacy of tirasemtiv, a fast skeletal muscle troponin activator, vs. placebo on respiratory function and other functional measures in patients with amyotrophic lateral sclerosis (ALS). This study was designed to confirm and extend results from a large phase IIb trial and maximize tolerability with a slower dose escalation.. VITALITY-ALS (NCT02496767) was a multinational, double-blind, randomized, placebo-controlled, parallel-group study in ALS patients. Participants who tolerated two weeks of open-label tirasemtiv (125 mg twice a day) were randomized 3:2:2:2 to placebo or one of three target total daily dose levels of tirasemtiv (250, 375, or 500 mg). Participants randomized to tirasemtiv escalated their dose every two weeks to their target dose level or maximum tolerated dose. The primary outcome measure was change in slow vital capacity from baseline to 24 weeks. Secondary endpoints assessed the effect of tirasemtiv on muscle strength and certain respiratory milestones of disease progression. A four-week randomized withdrawal phase followed 48 weeks of treatment to evaluate the possibility of sustained benefit or rebound decline.. Data collection will be complete in the fourth quarter of 2017.. VITALITY-ALS was a phase III trial designed to evaluate the efficacy, safety, and tolerability of tirasemtiv in ALS.

Topics: Amyotrophic Lateral Sclerosis; Double-Blind Method; Female; Follow-Up Studies; Humans; Imidazoles; Male; Pyrazines; Severity of Illness Index; Troponin

Tirasemtiv is a fast skeletal muscle activator that increases efficiency of muscle contraction. Both single and repeated dose studies suggested beneficial effects on measures of function, muscle strength and endurance. As the outcomes measured were identical in previous studies and the duration of all studies was 21 days or less, we pooled data from all studies and assessed the relationship between outcomes and plasma tirasemtiv concentration to assess consistency of observations as well as to increase sensitivity. We pooled data for ALSFRS-R, three pulmonary function measures, quantitative muscle strength, and submaximal handgrip endurance. Up to 855 values from 143 patients were plotted against tirasemtiv concentrations. Linear associations between tirasemtiv concentrations and changes from baseline of clinical measures were estimated using a repeated-measures mixed model. Trends toward improvement were noted in all measures except for vital capacity, despite the fact that time was not included as a factor so that any time-related decline acted to reduce the magnitude of any noted trend. In conclusion, tirasemtiv appears to have concentration-dependent beneficial effects on both function and measures of strength and endurance when administered for up to 21 days, even when time is eliminated as a cofactor. These findings further support the development of this agent in ALS.

Topics: Aged; Amyotrophic Lateral Sclerosis; Drug Administration Schedule; Female; Humans; Imidazoles; Male; Middle Aged; Muscle Strength; Pyrazines; Recovery of Function; Treatment Outcome

Abstract Tirasemtiv is a fast skeletal muscle activator that increases the sensitivity of the sarcomere to calcium, increasing the efficiency of muscle contraction when the muscle is stimulated at submaximal contraction frequencies. A previous study showed single doses of tirasemtiv to be well tolerated and associated with potentially important improvements in a variety of functional outcomes. This study determined safety of tirasemtiv when given at doses up to 500 mg daily for three weeks. Tirasemtiv was given as a single daily dose up to 375 mg for two weeks, with and without concomitant riluzole. In a separate cohort, an ascending dose protocol evaluated a total dose of 500 mg daily given in two divided doses. Safety and tolerability were assessed, as well as measures of function, muscle strength and endurance. Results showed that tirasemtiv was well tolerated, with dizziness the most common adverse event. Tirasemtiv approximately doubled the serum concentration of riluzole. Trends were noted for improvement in ALSFRS-R, Maximum Minute Ventilation, and Nasal Inspiratory Pressure. In conclusion, tirasemtiv is well tolerated and can be given safely with a reduced dose of riluzole. Positive trends in multiple exploratory outcome measures support the further study of this agent in ALS.

Topics: Adult; Aged; Amyotrophic Lateral Sclerosis; Cohort Studies; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Imidazoles; Male; Middle Aged; Muscle Strength; Pyrazines; Treatment Outcome

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.

Topics: Adult; Aged; Amyotrophic Lateral Sclerosis; Female; Hand Strength; Humans; Imidazoles; Male; Middle Aged; Muscle, Skeletal; Neuroprotective Agents; Pyrazines; Riluzole; Treatment Outcome

Topics: Amyotrophic Lateral Sclerosis; Antipyrine; Benzamides; C9orf72 Protein; Clinical Trials as Topic; Disease Progression; Drug Therapy, Combination; Edaravone; Genetic Therapy; Humans; Imidazoles; Mesenchymal Stem Cells; Motor Neurons; Neuroglia; Off-Label Use; Oligoribonucleotides, Antisense; Piperidines; Precision Medicine; Pyrazines; Pyridines; Riluzole; RNAi Therapeutics; Stem Cell Transplantation; Superoxide Dismutase; Thiazoles; United States; United States Food and Drug Administration

Amyotrophic Lateral Sclerosis (ALS) is a motor neuron disease characterized by progressive motor neuron loss resulting in muscle atrophy, declining muscle function, and eventual paralysis. Patients typically die from respiratory failure 3 to 5 years from the onset of symptoms. Tirasemtiv is a fast skeletal troponin activator that sensitizes the sarcomere to calcium; this mechanism of action amplifies the response of muscle to neuromuscular input producing greater force when nerve input is reduced. Here, we demonstrate that a single dose of tirasemtiv significantly increases submaximal isometric force, forelimb grip strength, grid hang time, and rotarod performance in a female transgenic mouse model (B6SJL-SOD1 G93A) of ALS with functional deficits. Additionally, diaphragm force and tidal volume are significantly higher in tirasemtiv-treated female B6SJL-SOD1 G93A mice. These results support the potential of fast skeletal troponin activators to improve muscle function in neuromuscular diseases.

Topics: Amyotrophic Lateral Sclerosis; Animals; Disease Models, Animal; Female; Humans; Imidazoles; Mice; Mice, Transgenic; Motor Neurons; Muscle Strength; Muscle, Skeletal; Pyrazines; Troponin