A Study to Evaluate Efficacy, Safety and Tolerability of CK-2127107 in Patients With Amyotrophic Lateral Sclerosis (ALS)

This was a double-blind, randomized, placebo-controlled, dose ranging study of reldesemtiv in patients with ALS. Eligible patients were randomized (1:1:1:1) to receive placebo or one of three doses of reldesemtiv (150, 300, or 450 mg twice daily) for 12 weeks. Randomization was stratified by riluzole concomitant use/non-use and edaravone concomitant use/non-use. Concomitant riluzole and edaravone were allowed as long as the riluzole dose had been stable for at least 30 days prior to screening and edaravone had been taken for 2 cycles prior to screening; these drugs could not be initiated during the study.

A total of 7 study visits were planned: screening, Day 1 (first dosing day), Weeks 2, 4, 8, and 12, and follow-up (4 weeks after the last dose of study drug). Study drug (placebo or reldesemtiv) was to be taken twice daily, approximately 12 hours (± 2 hours) apart and within 2 hours following a meal.

• Reldesemtiv (Drug), also known as CK-2127107: Oral tablet
• Placebo (Drug): Oral tablet

Primary outcomes

• Change From Baseline to Week 12 in the Percent Predicted Slow Vital Capacity (SVC) [Baseline to Week 12]: Slow vital capacity was measured using a spirometer (in units of liters). Following 3 to 5 breaths at rest, patients were instructed to take as deep an inspiration as possible followed by a maximum exhalation (blowing out all the air in their lungs). Values obtained were converted to percent predicted values using the Global Lung Initiative equation (ie, the test result as a percent of predicted values for patients of similar demographic and baseline characteristics \[eg, height, age, sex\]).

Secondary outcomes

• Change From Baseline to Week 12 in the ALS Functional Rating Scale - Revised (ALSFRS-R) Total Score [Baseline to Week 12]: The ALSFRS-R is used to measure the progression and severity of disability in patients with ALS. The ALSFRS-R consists of 12 questions, assessing a patient's capability and independence in functional activities relevant to ALS, categorized in the following 4 domains: gross motor tasks, fine motor tasks, bulbar functions, and respiratory function. Each question is scored from 0 (indicating incapable or dependent) to 4 (normal). The total score ranges from 0 to 48. Higher scores reflect more normal function and lower scores reflect more impaired function.
• Slope of Muscle Strength Mega-score From Baseline to Week 12 [Baseline to Week 12]: A hand-held dynamometer, with a scale of 0 to 300 pounds, was used to measure muscle strength and handgrip strength (bilateral). The muscle groups tested were: elbow flexion, wrist extension, first dorsal interosseous, hip flexion, knee extension, and ankle dorsiflexion; all muscle groups were evaluated bilaterally. For each postbaseline assessment of muscle strength, the percent change from baseline was calculated for each muscle group and handgrip strength, using the following equation: (\[postbaseline value - baseline value\] / baseline value) × 100. The muscle-strength mega-score was calculated as the average of the changes (ie, percent change from baseline) observed for each of the muscle groups as well as handgrip strength. For this endpoint, negative values indicate a decline in muscle strength.

Sex: All, ages: 18 Years to 80 Years

Inclusion Criteria:

* Diagnosis of familial or sporadic ALS ≤ 24 months prior to screening
* Upright Slow Vital Capacity (SVC) ≥ 60% of predicted for age, height and sex at screening
* Able to swallow tablets
* A caregiver (if one is needed)
* Able to perform reproducible pulmonary function tests
* Pre-study clinical laboratory findings within the normal range or, if outside the normal range, deemed not clinically significant by the Investigator
* Male patients who have not had a vasectomy and confirmed zero sperm count must agree after receiving the first dose of study drug until 10 weeks after the last dose to either use acceptable methods of contraception or abstain from sex
* Female patients must be post-menopausal or sterilized or must not be breastfeeding, have a negative pregnancy test, have no intention to become pregnant during the study and use acceptable methods of contraception or abstain from heterosexual intercourse from Screening until 10 weeks after last dose of study drug
* Patients must be either on riluzole for at least 30 days prior to screening or have not taken riluzole for at least 30 days prior to screening and not planning to start riluzole during the course of the study.
* Patients on edaravone must have completed at least 2 cycles of dosing with edaravone at the time of screening or have not taken edaravone for at least 30 days prior to screening and not planning to start edaravone during the course of the study.

Exclusion Criteria:

* At the time of screening, any use of non-invasive ventilation (NIV), e.g. continuous positive airway pressure \[CPAP\], noninvasive bi-level positive airway pressure \[NPPV\] or noninvasive volume ventilation \[NVV\] for any portion of the day, or mechanical ventilation via tracheostomy, or on any form of oxygen supplementation
* Neurological impairment due to a condition other than ALS
* Presence at screening of any medically significant cardiac, pulmonary, GI, musculoskeletal, or psychiatric illness that might interfere with the patient's ability to comply with study procedures or that might confound the interpretation of clinical safety or efficacy data
* Has taken any investigational study drug within 30 days or five half-lives of the prior agent, whichever is longer, prior to dosing
* Known to have received CK-2127107 or tirasemtiv in any previous clinical trial
* Has received or is considering receiving during the course of the study any form of stem cell therapy for the treatment of ALS
* Has received or is considering receiving during the course of the study any form of gene therapy for the treatment of ALS
* Has received or is considering obtaining during the course of the study a diaphragmatic pacing system
* History of substance abuse within the past 2 years
* Use of certain medications

Participant flow

Outcome results

• Change From Baseline to Week 12 in the Percent Predicted Slow Vital Capacity (SVC) (Primary), Least squares mean, percent predicted: Placebo -6.46 +/- 0.964; Reldesemtiv 150 mg Twice Daily -4.97 +/- 0.952; Reldesemtiv 300 mg Twice Daily -4.62 +/- 0.963; Reldesemtiv 450 mg Twice Daily -4.58 +/- 0.927; Reldesemtiv 300 mg & 450 mg -4.60 +/- 0.701 (p 0.1095)
• Change From Baseline to Week 12 in the ALS Functional Rating Scale - Revised (ALSFRS-R) Total Score (Secondary), Least squares mean, change in score: Placebo -3.53 +/- 0.313; Reldesemtiv 150 mg Twice Daily -2.40 +/- 0.311; Reldesemtiv 300 mg Twice Daily -2.62 +/- 0.317; Reldesemtiv 450 mg Twice Daily -2.94 +/- 0.307; Reldesemtiv 300 mg & 450 mg -2.78 +/- 0.228 (p 0.0930)
• Slope of Muscle Strength Mega-score From Baseline to Week 12 (Secondary), Least squares mean, change in mega-score per day: Placebo -0.1444 +/- 0.02492; Reldesemtiv 150 mg Twice Daily -0.1198 +/- 0.02463; Reldesemtiv 300 mg Twice Daily -0.1299 +/- 0.02474; Reldesemtiv 450 mg Twice Daily -0.0956 +/- 0.02421; Reldesemtiv 300 mg & 450 mg -0.1127 +/- 0.01731 (p 0.3134)

Adverse events

Time frame: Adverse events (AEs) were collected from administration of the first dose of study drug through 4 weeks after the last dose of study drug.

Serious adverse events by term

Other adverse events by term

• Results publication: Shefner JM, Jacobsen B, Kupfer S, Malik FI, Meng L, Wei J, Wolff AA, Rudnicki SA. Relationship between quantitative strength and functional outcomes in the phase 2 FORTITUDE-ALS trial. Amyotroph Lateral Scler Frontotemporal Degener. 2024 Feb;25(1-2):162-169. doi: 10.1080/21678421.2023.2252468. Epub 2023 Aug 29. PMID 37641579
• Results publication: Shefner JM, Al-Chalabi A, Andrews JA, Chio A, De Carvalho M, Cockroft BM, Corcia P, Couratier P, Cudkowicz ME, Genge A, Hardiman O, Heiman-Patterson T, Henderson RD, Ingre C, Jackson CE, Johnston W, Lechtzin N, Ludolph A, Maragakis NJ, Miller TM, Mora Pardina JS, Petri S, Simmons Z, Van Den Berg LH, Zinman L, Kupfer S, Malik FI, Meng L, Simkins TJ, Wei J, Wolff AA, Rudnicki SA. COURAGE-ALS: a randomized, double-blind phase 3 study designed to improve participant experience and increase the probability of success. Amyotroph Lateral Scler Frontotemporal Degener. 2023 Aug;24(5-6):523-534. doi: 10.1080/21678421.2023.2216223. Epub 2023 May 30. PMID 37254449
• Results publication: Gebrehiwet P, Meng L, Rudnicki SA, Sarocco P, Wei J, Wolff AA, Chio A, Andrews JA, Genge A, Jackson CE, Lechtzin N, Miller TM, Shefner JM. MiToS and King's staging as clinical outcome measures in ALS: a retrospective analysis of the FORTITUDE-ALS trial. Amyotroph Lateral Scler Frontotemporal Degener. 2023 May;24(3-4):304-310. doi: 10.1080/21678421.2022.2154678. Epub 2022 Dec 12. PMID 36503310
• Results publication: Rudnicki SA, Andrews JA, Genge A, Jackson C, Lechtzin N, Miller TM, Cockroft BM, Malik FI, Meng L, Wei J, Wolff AA, Shefner JM; FORTITUDE-ALS STUDY GROUP. Prescription and acceptance of durable medical equipment in FORTITUDE-ALS, a study of reldesemtiv in ALS: post hoc analyses of a randomized, double-blind, placebo-controlled clinical trial. Amyotroph Lateral Scler Frontotemporal Degener. 2022 May;23(3-4):263-270. doi: 10.1080/21678421.2021.1946083. Epub 2021 Jul 5. PMID 34218726
• Results publication: Shefner JM, Andrews JA, Genge A, Jackson C, Lechtzin N, Miller TM, Cockroft BM, Meng L, Wei J, Wolff AA, Malik FI, Bodkin C, Brooks BR, Caress J, Dionne A, Fee D, Goutman SA, Goyal NA, Hardiman O, Hayat G, Heiman-Patterson T, Heitzman D, Henderson RD, Johnston W, Karam C, Kiernan MC, Kolb SJ, Korngut L, Ladha S, Matte G, Mora JS, Needham M, Oskarsson B, Pattee GL, Pioro EP, Pulley M, Quan D, Rezania K, Schellenberg KL, Schultz D, Shoesmith C, Simmons Z, Statland J, Sultan S, Swenson A, Berg LHVD, Vu T, Vucic S, Weiss M, Whyte-Rayson A, Wymer J, Zinman L, Rudnicki SA. A Phase 2, Double-Blind, Randomized, Dose-Ranging Trial Of Reldesemtiv In Patients With ALS. Amyotroph Lateral Scler Frontotemporal Degener. 2021 May;22(3-4):287-299. doi: 10.1080/21678421.2020.1822410. Epub 2020 Sep 24. PMID 32969758
• Results publication: Shefner JM, Cudkowicz ME, Hardiman O, Cockcroft BM, Lee JH, Malik FI, Meng L, Rudnicki SA, Wolff AA, Andrews JA; VITALITY-ALS Study Group. A phase III trial of tirasemtiv as a potential treatment for amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener. 2019;0(0):1-11. doi: 10.1080/21678421.2019.1612922. PMID 31081694

• Study Protocol (PDF, 2018-04-18)
• Statistical Analysis Plan (PDF, 2018-12-14)

• MD Cytokinetics, Study director, Cytokinetics