tirasemtiv (CK-2017357) / 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

Plasma neurofilament analysis in VITALITY-ALS. (PubMed, Amyotroph Lateral Scler Frontotemporal Degener) - P3 | "Objective: To evaluate correlations between neurofilament (Nf) concentrations and clinical characteristics and disease progression using a large longitudinal dataset from VITALITY-ALS (ClinicalTrials.gov identifier: NCT02496767), a 48-week, randomized, double-blind, placebo-controlled clinical trial of tirasemtiv in people with ALS (pALS)... In this large longitudinal study, baseline NfL concentration correlated with multiple markers of disease progression. The findings suggest Nfs show promise primarily as prognostic markers for pALS, particularly for those with rapid disease progression."

Clinical • Journal • Amyotrophic Lateral Sclerosis • CNS Disorders • Plasma NfL

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

Tirasemtiv enhances submaximal muscle tension in an Acta1:p.Asp286Gly mouse model of nemaline myopathy. (PubMed, J Gen Physiol) - "Additionally, long-term tirasemtiv treatment in NEM3 mice resulted in a decreased respiratory rate with preserved minute volume, suggesting more efficient respiration. Altogether, our data support the therapeutic potential of fast skeletal muscle troponin activators in alleviating skeletal muscle weakness in a mouse model of NEM3 caused by the Acta1:p.Asp286Gly variant."

Journal • Preclinical • Myositis • Respiratory Diseases • ACTA1

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

Plasma neurofilament analysis in VITALITY-ALS: analysis at baseline longitudinal and by rate of disease progression (ALS-MND 2023) - P3 | "Nf measurements were available from 101 placeboand 161 tirasemtiv-treated pALS. There were no significant differences in Nf between placebo vs tirasemtiv groups at any timepoint; therefore, further analysis grouped all samples. At baseline, Nf did not differ by El Escorial category, disease duration, or site of onset."

Molecular Mechanisms of Deregulation of Muscle Contractility Caused by the R168H Mutation in TPM3 and Its Attenuation by Therapeutic Agents. (PubMed, Int J Mol Sci) - "Modulators of troponin (tirasemtiv and epigallocatechin-3-gallate) and myosin (omecamtiv mecarbil and 2,3-butanedione monoxime) have been shown to more or less attenuate the negative effects of the tropomyosin R168H mutant. Tirasemtiv and epigallocatechin-3-gallate may be used to prevent muscle dysfunction."

Journal • Myositis • TPM3

Matrigel 3D bioprinting of contractile human skeletal muscle models recapitulating exercise and pharmacological responses. (PubMed, Commun Biol) - "Furthermore, the known muscle stimulators caffeine and Tirasemtiv acutely increase EPS-induced contractile force of the models. This validated new human muscle MPS will benefit development of drugs against muscle wasting diseases. Moreover, our Matrigel 3D bioprinting platform will allow engineering of non-self-organizing complex human 3D MPS."

Journal • AKT1 • IL6

Discovery of Reldesemtiv, a Fast Skeletal Muscle Troponin Activator for the Treatment of Impaired Muscle Function. (PubMed, J Med Chem) - "Property-based optimization of high throughput screening hit 1 led to compounds with improved free exposure and in vivo muscle activation potency compared to the first-generation FSTA, tirasemtiv. Reldesemtiv demonstrated increased muscle force generation in a phase 1 clinical trial and is currently being evaluated in clinical trials for the treatment of amyotrophic lateral sclerosis."

Journal • Amyotrophic Lateral Sclerosis • CNS Disorders

Acute and chronic tirasemtiv treatment improves in vivo and in vitro muscle performance in actin-based nemaline myopathy mice. (PubMed, Hum Mol Genet) - "Finally, translational studies on permeabilized muscle fibers isolated from a biopsy of a patient with the ACTA1H40Y mutation revealed that at physiological Ca2+ concentrations, tirasemtiv increased force generation to values that were close to those generated in muscle fibers of healthy subjects. These findings indicate the therapeutic potential of fast skeletal muscle troponin activators to improve muscle function in nemaline myopathy due to the ACTA1H40Y mutation, and future studies should assess their merit for other forms of nemaline myopathy and for other congenital myopathies."

Journal • Preclinical • Fatigue • Myositis • Respiratory Diseases

Noninvasive ventilation use by patients enrolled in VITALITY-ALS. (PubMed, Amyotroph Lateral Scler Frontotemporal Degener) - " 565 patients were randomized and dosed with placebo or tirasemtiv in VITALITY-ALS; 195 (34.5%) were prescribed NIV: of these, 78.5% used it for ≥2 h/24 h, 71.3% for ≥4 h/24 h, and 11.8% for ≥22 h/24 h... Despite allowing for NIV initiation at any point following randomization in VITALITY-ALS, only slightly more than two out of three patients whose SVC fell below 50% were prescribed NIV; this was similar in Europe and in North America. Underutilization of NIV could influence survival outcomes in patients with ALS including those involved in clinical trials."

Clinical • Journal • Amyotrophic Lateral Sclerosis • CNS Disorders • Complement-mediated Rare Disorders • Respiratory Diseases

Pathogenic variants in TNNC2 cause congenital myopathy due to an impaired force response to calcium. (PubMed, J Clin Invest) - "Finally, we tested the therapeutic potential of the fast skeletal muscle troponin activator tirasemtiv in patients' myofibers and showed that the contractile dysfunction was repaired. Thus, our data reveal that pathogenic variants in TNNC2 cause congenital muscle disease, and they provide therapeutic angles to repair muscle contractility."

Journal • CNS Disorders • Myositis

Structural Basis of Tirasemtiv Activation of Fast Skeletal Muscle. (PubMed, J Med Chem) - "The structure reveals that tirasemtiv binds in a hydrophobic pocket between the regulatory domain of troponin C and the switch region of troponin I, which overlaps with that of Anapoe in the X-ray structure of skeletal troponin. Multiple interactions stabilize the troponin C-troponin I interface, increase the affinity of troponin C for the switch region of fast skeletal troponin I, and drive the equilibrium toward the active state."

Journal • Amyotrophic Lateral Sclerosis • CNS Disorders • Complement-mediated Rare Disorders • Genetic Disorders • Movement Disorders • Rare Diseases

A phase III trial of tirasemtiv as a potential treatment for amyotrophic lateral sclerosis. (PubMed, Amyotroph Lateral Scler Frontotemporal Degener) - P2, P3 | "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)."

Journal • P3 data • Amyotrophic Lateral Sclerosis • CNS Disorders • Complement-mediated Rare Disorders • Fatigue

Autism-associated SHANK3 mutations impair maturation of neuromuscular junctions and striated muscles. (PubMed, Sci Transl Med) - "Functional motor defects in Shank3Δ11(-/-) mice could be rescued with the troponin activator Tirasemtiv that sensitizes muscle fibers to calcium. Our observations give insight into the function of SHANK3 besides the central nervous system and imply potential treatment strategies for SHANK3-associated ASD."

Journal • Autism Spectrum Disorder • Genetic Disorders

Tirasemtiv: Anticipated expiry of patent in US in 2027 (Cytokinetics) - Annual Report 2016

Anticipated patent expiry • Myasthenia Gravis

CK-2127107 amplifies skeletal muscle response to nerve activation in humans. (PubMed, Muscle Nerve) - "CK-107 appears more potent and produced larger increases in force than did tirasemtiv - a first-generation FSTA - in a similar pharmacodynamic study, thereby supporting its development for improvement of muscle function of patients."

Journal • Biosimilar

Functional Characterization of the Intact Diaphragm in a Nebulin-Based Nemaline Myopathy (NM) Model-Effects of the Fast Skeletal Muscle Troponin Activator tirasemtiv. (PubMed, Int J Mol Sci) - "Load-clamp experiments on diaphragm muscle showed that tirasemtiv increased the shortening velocity, and reduced the deficit in mechanical power by 33%. Thus, tirasemtiv significantly improves muscle function in a mouse model of nebulin-based nemaline myopathy."

Journal

Measurement of Skeletal Muscle Fiber Contractility with High-Speed Traction Microscopy. (PubMed, Biophys J) - "Contractile forces of FDB fibers increase in response to caffeine and the troponin-calcium stabilizer tirasemtiv, similar to responses measured in whole muscle...In summary, we present a technically simple high-speed method for measuring contractile forces and cytosolic calcium dynamics of single muscle fibers. We expect that our method will help to reduce preparation time, costs, and the number of sacrificed animals needed for experiments such as drug testing."

Journal

A Study of CK-2017357 in Patients With Peripheral Artery Disease and Symptomatic Claudication (clinicaltrials.gov) - P2; N=61; Completed; Sponsor: Cytokinetics; N=36 ➔ 61

Clinical • Enrollment change

Update of FORTITUDE-ALS: A Phase 2, Double-blind, Randomized, Placebo-Controlled, Study to Evaluate Efficacy, Safety and Tolerability of Reldesemtiv in Patients with Amyotrophic Lateral Sclerosis (AAN 2019) - "Derived from a different chemical scaffold and designed to limit crossing of the blood-brain barrier, it is expected to have fewer central nervous system adverse effects than tirasemtiv, a molecule with similar though less potent effects on fast skeletal muscle. Efficacy and tolerability data from FORTITUDE-ALS will be presented at the 71st Annual Meeting of the AAN. The results of this study will determine whether phase 3 studies of this compound should be conducted in ALS."

Clinical • P2 data