The investigational drug candidate, formerly known as CK-2127107, is the subject of the phase 2b FORTITUDE-ALS trial, which is assessing the effect of reldesemtiv compared with placebo on respiratory function and additional measures of skeletal muscle function.
Although only 2 drugs, riluzole (Rilutek; Sanofi) and edaravone (Radicava, Mitsubishi Tanabe Pharma America), are currently FDA approved for the treatment of amyotrophic lateral sclerosis (ALS), the number of promising therapies being explored for the condition has grown exponentially. One therapy under investigation is reldesemtiv (Cytokinetics, Astellas), a fast-skeletal muscle troponin activator that aims to slow the decline of muscle function.
The investigational drug candidate, formerly known as CK-2127107, is the subject of the phase 2b FORTITUDE-ALS trial (NCT03160898), which is assessing the effect of reldesemtiv compared with placebo on respiratory function and additional measures of skeletal muscle function.
Reldesemtiv is designed to bind and slow the rate of calcium release from the troponin complex, which boosts the sensitivity of the sarcomere to calcium, thus increasing the ability of the muscles to contract despite reduced nerve signaling.
“[FORTITUDE-ALS] is completely enrolled, so we’re just finishing treating patients, and we do believe that nothing should preclude presenting the data within the first half of the year at this point,” Andrew Wolff, MD, the chief medical officer of Cytokinetics, told NeurologyLive.
Wolff explained that unlike what has been observed with reldesemtiv, in the 2 studies of Cytokinetics’ earlier fast skeletal muscle troponin activator, tirasemtiv, participants who discontinued from treatment tended to do so soon after randomization—often within the first week but ultimately within the first 2 or 3 weeks—because of adverse events (AEs) such as dizziness, nausea, and fatigue.
Wolff said that Cytokinetics has gleaned from previous data with reldesemtiv, including those with healthy volunteers, that it was likely to be better tolerated than its predecessor.
“Now we have evidence that, when looking at the blinded data again…overall there are fewer patients dropping off treatment. Furthermore, the pattern of the early terminations that we are seeing and the nature of them are different from what we saw with tirasemtiv,” Wolff said. In FORTITUDE-ALS, he added, the pattern of early terminations was related more to events that might be associated with disease progression in ALS.
FORTITUDE-ALS is a randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study of approximately 450 participants with ALS from centers in the United States, Canada, Europe, and Australia. Participants are being randomized 1:1:1 to receive either placebo or a 150-mg, 300-mg, or 450-mg dose of reldesemtiv twice daily for 12 weeks.
To be enrolled in the study, participants were required to have a diagnosis of familial or sporadic ALS for ≤24 months prior to screening; an upright slow vital capacity of ≥60% predicted for age, height, and sex at screening; the ability to swallow tablets; the capability to perform reproducible pulmonary function tests; and preclinical laboratory findings within the normal range or, if outside the normal range, regarded as not clinically significant by the investigator; in addition, participants were required to be 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 be planning to start the therapy during the trial.
Enrollment criteria included that men who have not undergone a vasectomy and a confirmed sperm count of 0 must either use acceptable methods of contraception or remain abstinent after receiving the first dose of reldesemtiv until 10 weeks after the last dose. Participating women must be postmenopausal or sterile or not be breastfeeding, have a negative pregnancy test, have no intention to become pregnant during the trial, and use acceptable methods of contraception or remain abstinent from heterosexual intercourse from screening until 10 weeks after the last dose of reldesemtiv.
The study’s primary end point is the change in vital capacity from baseline to the end of 12 weeks. Secondary end points include the slope of change from baseline in the megascore of muscle strength as measured by handheld dynamometry and handgrip dynamometry, the change in the ALS Functional Rating Scale-Revised score, the incidence and severity of treatment-emergent AEs, and the mean plasma concentrations of reldesemtiv at the sampled time points in the study.
The investigators are also measuring exploratory end points such as the effect of reldesemtiv versus placebo on self-assessments of respiratory function at home by the participant with aid from a caregiver, disease progression through quantitative measurement of speech production characteristics over time, disease progression through quantitative measurement of handwriting abilities over time, and the change in quality of life as measured by the ALS Assessment Questionnaire 5.
Reldesemtiv has been the subject of 5 completed phase 1 clinical trials that evaluated its safety, tolerability, bioavailability, pharmacokinetics, and pharmacodynamics in healthy volunteers. Its antifatigability was also assessed in a phase 1 trial including patients with limitations in mobility (NCT03065959); however, that trial was terminated early because of a lack of efficacy at the interim analysis. Additionally, the treatment was assessed in a phase 2 trial in spinal muscular atrophy (SMA), with the results announced in June 2018 at the Annual Cure SMA Conference in Dallas, Texas (NCT02644668).
The treatment showed a statistically significant concentration-dependent increase from baseline in the 6-minute walk test and maximal expiratory pressure in 70 patients, with improvements sustained for 4 weeks post-treatment. AEs were similar between patients receiving reldesemtiv and those on the placebo.1
FORTITUDE-ALS is ongoing, and results are expected to be reported in the first half of 2019.
1. Day J. Update of CY 5021: a phase 2 clinical trial of
, a fast-skeletal muscle troponin activator (FSTA), for the potential treatment of spinal muscular atrophy. Presented at: 2018 Annual Cure SMA Conference; June 16, 2018; Dallas, TX.