reldesemtiv (CK-2127107) / Astellas, Cytokinetics - LARVOL DELTA

Analysis of metabolites and metabolic pathways of troponin activator in rats using UHPLC-MS. (PubMed, Anal Bioanal Chem) - "Troponin activators, including Reldesemtiv and Tirasemtiv, represent a class of drugs that enhance the contractility of cardiac muscle and delay the onset of muscle fatigue. This analytical method can characterize the metabolic profiles of the drugs and their metabolites, as well as identify unknown and long-lived metabolites in drug testing. These capabilities are critical for the quantitative analysis of troponin activators within complex biological matrices, supporting their study in physiological and doping-control contexts."

Journal • Preclinical • Fatigue

Participant, site personnel and sponsor perspectives on decentralized trial features in COURAGE-ALS: a randomized clinical trial. (PubMed, Amyotroph Lateral Scler Frontotemporal Degener) - P3 | "COURAGE-ALS was a 48-week, double-blind, randomized, phase III, hybrid DCT of reldesemtiv versus placebo for ALS...COURAGE-ALS demonstrated that an interventional hybrid DCT is feasible in ALS but limitations remain that will need to be considered when designing future DCTs. ClinicalTrials.gov (NCT04944784)."

Clinical • Journal • Amyotrophic Lateral Sclerosis • CNS Disorders

Hospitalizations as an outcome measure in COURAGE-ALS. (PubMed, Amyotroph Lateral Scler Frontotemporal Degener) - "Objective: To describe the development of a methodology to characterize hospitalizations and their relationship to amyotrophic lateral sclerosis (ALS) and provide results using this process in a phase 3 trial of reldesemtiv in ALS... While most hospitalizations in COURAGE-ALS were HR-ALS, HU-ALS and HI-ALS also occurred. When using hospitalization as an endpoint in an ALS clinical trial, recording its relationship to ALS provides additional details to characterize disease burden and clinical meaningfulness of the endpoint."

Journal • Amyotrophic Lateral Sclerosis • CNS Disorders • Infectious Disease • Novel Coronavirus Disease

Application of the ENCALS predictive survival model in assessing the effect of the 24/44 inclusion criteria in FORTITUDE-ALS. (PubMed, J Neuromuscul Dis) - "FORTITUDE-ALS was a study evaluating reldesemtiv in people living with ALS...Of the 272 participants meeting the 24/44 criteria, 73% had very short to intermediate RS compared to 18% not meeting the criteria. Though the 24/44 criteria enriched the FORTITUDE-ALS population with rapidly progressing patients, they did not completely exclude all patients with a very long predicted survival."

Journal

Reldesemtiv in Amyotrophic Lateral Sclerosis: Results From the COURAGE-ALS Randomized Clinical Trial. (PubMed, JAMA Neurol) - P3 | "This randomized clinical trial failed to demonstrate efficacy for reldesemtiv in slowing functional decline in ALS. ClinicalTrials.gov Identifier: NCT04944784."

Clinical • Journal • Amyotrophic Lateral Sclerosis • CNS Disorders

A Study to Assess the Effect of CK-2127107 on Physical Function in Subjects With Chronic Obstructive Pulmonary Disease (clinicaltrials.gov) - P2 | N=46 | Completed | Sponsor: Astellas Pharma Global Development, Inc. | Phase classification: P2a ➔ P2

Phase classification • Chronic Obstructive Pulmonary Disease • Immunology • Pulmonary Disease • Respiratory Diseases

A Study to Assess the Anti-fatigability Effect of CK-2127107 in Elderly Male and Female Subjects With Limitations in Mobility (clinicaltrials.gov) - P1 | N=42 | Terminated | Sponsor: Astellas Pharma Global Development, Inc. | Phase classification: P1b ➔ P1

Phase classification

Identification of human metabolites of fast skeletal troponin activators Tirasemtiv and Reldesemtiv for doping control purposes. (PubMed, Drug Test Anal) - "In addition, a human elimination study was conducted to investigate the metabolism and elimination profile of Tirasemtiv and Reldesemtiv in vivo, suggesting the N-glucuronide of Tirasemtiv and hydroxylated 3-fluoro-2-(3-fluoro-1-methylcyclobutyl)pyridine as well as its glucuronide as suitable target analytes for routine doping controls. Applying a validating HPLC-MS/MS method, optimized to detect Reldesemtiv and Tirasemtiv in human urine, microdosing (50 μg) of each substance was traceable for 24-72 h."

Journal • Amyotrophic Lateral Sclerosis • CNS Disorders

COURAGE-ALS: A Study to Evaluate the Efficacy and Safety of Reldesemtiv in Patients With Amyotrophic Lateral Sclerosis (ALS) (clinicaltrials.gov) - P3 | N=486 | Terminated | Sponsor: Cytokinetics | Trial completion date: Mar 2023 ➔ Jul 2023 | Trial primary completion date: Mar 2023 ➔ Jul 2023

Trial completion date • Trial primary completion date • Amyotrophic Lateral Sclerosis • CNS Disorders

Cytokinetics Presents Results From COURAGE-ALS at the 34th International Symposium on ALS/MND (GlobeNewswire) - P3 | N=486 | COURAGE-ALS (NCT04944784) | Sponsor: Cytokinetics | "Cytokinetics, Incorporated...announced that the full results of COURAGE-ALS (Clinical Outcomes Using Reldesemtiv on ALSFRS-R in a Global Evaluation in ALS), were presented at the 34th International Symposium on ALS/MND by Jeremy Shefner, M.D., Ph.D., Lead Investigator of COURAGE-ALS....Treatment with reldesemtiv for 24 weeks had no effect on the primary efficacy endpoint measure of change from baseline up to Week 24 in the ALS Functional Rating Scale Revised (ALSFRS-R) (joint rank test p=0.11). Patients treated with reldesemtiv declined 5.3 points per month (SD=5.3) while patients treated with placebo declined 4.8 points per month (SD=4.4). No pre-defined patient subgroup favored treatment with reldesemtiv....The main cause of death for patients in COURAGE-ALS was respiratory failure/arrest, assisted suicide/euthanasia, ALS and infections."

P3 data • Amyotrophic Lateral Sclerosis • CNS Disorders

Cytokinetics Announces Five Presentations at the 34th International Symposium on ALS/MND (Yahoo Finance) - "Cytokinetics...today announced five presentations at the 34th International Symposium on ALS/MND taking place in Basel, Switzerland and online from December 6, 2023 - December 8, 2023."

P3 data • Amyotrophic Lateral Sclerosis • CNS Disorders

COURAGE-ALS: results of thephase 3 clinical trial of reldesemtivin ALS (ALS-MND 2023) - P2, P3 | "Inclusion criteria were broad,and subgroup analyses suggested a greater signal in morerapidly progressive participants, as had been reported foredaravone and AMX0035 development programs. COURAGE-ALS was performed after FORTITUDE-ALS showed promising results. Topline data will be presentedand implications for future ALS trials discussed. Given theabsence of clinical efficacy in this clinical trial, further explor-ation of FSTAs in ALS is not warranted."

Clinical • P3 data • Respiratory Diseases

Site and participantperspectives on participating in anALS trial designed to reduceburden: COURAGE-ALS (ALS-MND 2023) - P3 | "COURAGE-ALS (NCT04944784), a phase 3 trial of reldesemtiv,was designed to be patient-centric... Overall, sites and p ALS both endorsed includ-ing remote visits in ALS clinical trials, but for sites, this didnot necessarily mean less work. Performing assessments andobtaining labs remotely had limitations."

Infectious Disease • Novel Coronavirus Disease

Hospitalizations in COURAGE-ALS and Their Relationship to ALS (ALS-MND 2023) - P3 | "Background: Time to hospitalization has been investigated in ALS trials and was a planned endpoint in COURAGE-ALS (NCT04944784), a phase 3 trial of reldesemtiv in people living with ALS (pALS)... While most hospitalizations in COURAGE-ALS were HR-ALS, HU-ALS and HI-ALS also occurred. When using hospitalization as an endpoint in an ALS clinical trial, recording its relationship to ALS provides additional details to more fully characterize disease burden and clinical meaningfulness of the endpoint. srudnicki@cytokinetics.com"

Clinical • Cardiovascular • Infectious Disease • Nephrology • Novel Coronavirus Disease • Pneumonia • Pulmonary Embolism • Respiratory Diseases

Relationship between quantitative strength and functional outcomes in the phase 2 FORTITUDE-ALS trial. (PubMed, Amyotroph Lateral Scler Frontotemporal Degener) - P2 | "In the FORTITUDE-ALS clinical trial (NCT03160898), 456 participants in the full-analysis set were treated with either reldesemtiv or placebo for 12 weeks; this post hoc analysis included all participants regardless of treatment assignments...In this analysis of data from an ALS clinical trial, muscle strength quantified by dynamometry was strongly correlated with functional capacity. These results suggest that muscle strength directly relates to specific functions of importance to people with ALS."

Journal • P2 data • Amyotrophic Lateral Sclerosis • CNS Disorders

COURAGE-ALS: a randomized, double-blind phase 3 study designed to improve participant experience and increase the probability of success. (PubMed, Amyotroph Lateral Scler Frontotemporal Degener) - P2, P3 | "To reduce participant burden, study visits are often remote, and strength evaluation is simplified to reduce time and effort. In COURAGE-ALS, the phase 3 clinical trial to evaluate reldesemtiv, the sensitivity of detecting a potential treatment effect may be increased by defining eligibility criteria that limit the proportion of participants who have slower disease progression. Implementing remote visits and simplifying strength measurements will reduce both site and participant burden.ClinicalTrials.gov identifiers: NCT03160898 (FORTITUDE-ALS) and NCT04944784 (COURAGE-ALS)."

Clinical • Journal • P3 data • Amyotrophic Lateral Sclerosis • CNS Disorders

COURAGE-ALS: A Study to Evaluate the Efficacy and Safety of Reldesemtiv in Patients With Amyotrophic Lateral Sclerosis (ALS) (clinicaltrials.gov) - P3 | N=486 | Terminated | Sponsor: Cytokinetics | Trial completion date: Mar 2024 ➔ Mar 2023 | Recruiting ➔ Terminated | Trial primary completion date: Dec 2023 ➔ Mar 2023; The DMC recommended the trial be discontinued due to futility following a planned second interim analysis.

Trial completion date • Trial primary completion date • Trial termination • Amyotrophic Lateral Sclerosis • CNS Disorders

COURAGE OLE: A Phase 3, Open-Label Extension of COURAGE-ALS (CY 5031) (clinicaltrials.gov) - P3 | N=72 | Terminated | Sponsor: Cytokinetics | N=400 ➔ 72 | Trial completion date: Dec 2024 ➔ Mar 2023 | Recruiting ➔ Terminated | Trial primary completion date: Dec 2024 ➔ Mar 2023; The DMC recommended the trial be discontinued due to futility following a planned second interim analysis.

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Amyotrophic Lateral Sclerosis • CNS Disorders

Cytokinetics Announces COURAGE-ALS Met Criteria for Futility at Second Interim Analysis (GlobeNewswire) - “Cytokinetics, Incorporated…announced that the Data Monitoring Committee (DMC) for COURAGE-ALS (Clinical Outcomes Using Reldesemtiv on ALSFRS-R in a Global Evaluation in ALS), recently convened to conduct the second planned interim analysis of this Phase 3 clinical trial. The DMC reviewed unblinded data from COURAGE-ALS and recommended the discontinuation of the clinical trial due to futility, as it found no evidence of effect in patients treated with reldesemtiv relative to placebo on the primary endpoint of change from baseline to 24 weeks in ALSFRS-R or in key secondary endpoints. Given these results, study conduct in COURAGE-ALS will be concluding. In addition, Cytokinetics plans to discontinue treatment with reldesemtiv in all patients including those in the open-label extension study, COURAGE-ALS OLE.”

Discontinued • DSMB • Amyotrophic Lateral Sclerosis • CNS Disorders

Intermolecular And Dynamic Investigation of The Mechanism of Action of Reldesemtiv on Fast Skeletal Muscle Troponin Complex Toward the Treatment of Impaired Muscle Function. (PubMed, Protein J) - "Arg113 (-3.96 kcal/mol), Met116 (-2.23 kcal/mol), Val114 (-1.28 kcal/mol) and Met121 (-0.63 kcal/mol) of the switch region of the inhibitory subunit were among the residues that contributed the most to the total free binding energy of Reldesemtiv highlighting their importance. These findings present useful insights which could lay the foundation for the development of fast skeletal muscle small molecule activators with high specificity and potency."

Journal • Amyotrophic Lateral Sclerosis • CNS Disorders • Genetic Disorders • Movement Disorders • Myasthenia Gravis • Rare Diseases

Health utilities and quality-adjusted life years for patients with amyotrophic lateral sclerosis receiving reldesemtiv or placebo in FORTITUDE-ALS. (PubMed, J Med Econ) - P2 | "This post hoc analysis of FORTITUDE-ALS suggests that reldesemtiv showed a modest but significant benefit in health utilities and QALYs compared with placebo. Future long-term studies that include direct collection of EQ-5D-5L data will be needed to confirm our findings.ClinicalTrials.gov identifier: NCT03160898."

HEOR • Journal • Amyotrophic Lateral Sclerosis • CNS Disorders

New developments and opportunities in drugs being trialed for amyotrophic lateral sclerosis from 2020 to 2022. (PubMed, Front Pharmacol) - "Six were tested in phase 1 studies, 31 were in phase 2 studies, three failed in phase 3 studies and stopped further development, and the remaining 13 drugs were being tested in phase 3 studies, including methylcobalamin, masitinib, MN-166, verdiperstat, memantine, AMX0035, trazodone, CNM-Au8, pridopidine, SLS-005, IONN363, tofersen, and reldesemtiv. Among them, five drugs, including methylcobalamin, masitinib, AMX0035, CNM-Au8, and tofersen, have shown potent therapeutic effects in clinical trials. Recently, AMX0035 has been the third medicine approved by the FDA for the treatment of ALS after riluzole and edaravone."

Journal • Review • Amyotrophic Lateral Sclerosis • CNS Disorders • Gene Therapies

MiToS and King's staging as clinical outcome measures in ALS: a retrospective analysis of the FORTITUDE-ALS trial. (PubMed, Amyotroph Lateral Scler Frontotemporal Degener) - P2 | "Objective: To evaluate the Milano-Torino staging (MiToS) and King's staging systems as potential outcome measures for clinical trials in amyotrophic lateral sclerosis (ALS) by assessing these outcomes in FORTITUDE-ALS. This was a post hoc analysis of the phase 2b FORTITUDE-ALS trial (NCT03160898), a double-blind, randomized, dose-ranging, placebo-controlled, parallel-group study of reldesemtiv in patients with ALS...The two staging systems exhibited considerably disparate results for risk of progression from baseline to a later stage: hazard ratio (HR) = 0.62 (95% confidence interval [CI] 0.38, 0.99) for MiToS and HR = 0.96 (95% CI 0.63, 1.44) for King's. This exploratory analysis showed the feasibility of MiToS and King's staging as potential outcome measures in ALS. Additional studies of these staging systems are needed to further explore their utility in ALS clinical trials."

Clinical data • Journal • Retrospective data • Amyotrophic Lateral Sclerosis • CNS Disorders

Cytokinetics Presents Data at the Virtual 33rd International Symposium on ALS/MND (GlobeNewswire) - P2 | N=458 | FORTITUDE-ALS (NCT03160898) | Sponsor: Cytokinetics | “Cytokinetics, Incorporated…announced that data were presented at the Virtual 33rd International Symposium on ALS/MND related to survival predictions from FORTITUDE-ALS…the Phase 2 clinical trial of reldesemtiv in ALS….‘We look forward to continuing the conduct of COURAGE-ALS and completing patient enrollment in the first half of 2023’….Among participants in FORTITUDE-ALS, the mean ENCALS risk score at baseline was similar for patients receiving reldesemtiv and for those receiving placebo, and there was no statistically significant difference in the distribution of risk groups for those randomized to reldesemtiv compared to those randomized to placebo. When participants who met the 24/44 criteria (n=272) and those who did not (n=184) were categorized according to their ENCALS risk score..."

Enrollment status • P2 data • Amyotrophic Lateral Sclerosis • CNS Disorders

Cytokinetics Announces Presentation at the Virtual 33rd International Symposium on ALS/MND (GlobeNewswire) - "Cytokinetics, Incorporated...announced one poster presentation at the Virtual 33rd International Symposium on ALS/MND taking place online from December 6, 2022 - December 9, 2022 relating to survival predictions from FORTITUDE-ALS (Functional Outcomes in a Randomized Trial of Investigational Treatment with CK-2127107 to Understand Decline in Endpoints – in ALS), the Phase 2 clinical trial of reldesemtiv in ALS."

P2 data • Amyotrophic Lateral Sclerosis • CNS Disorders