Tirasemtiv Demonstrates Improvements in Muscle Force, Grip Strength and Resistance to Fatigue in Preclinical Mouse Models of Spinal Muscular Atrophy
Originally published on June 26, 2014
Cytokinetics announced that data from preclinical research relating to tirasemtiv in mouse models of spinal muscular atrophy (SMA) were presented at the 2014 Annual Spinal Muscular Atrophy Conference in National Harbor, Maryland. In these models, tirasemtiv increased muscle force and improved grip strength, grid hang time, and resistance to fatigue. These studies were supported in part by a grant from the Cure SMA.
In both an oral presentation entitled “Small Molecule Tirasemtiv Improves Muscle Function in Two Mouse Models of SMA” and a poster entitled “Tirasemtiv Increases Skeletal Muscle Performance in SMA Mice” Cytokinetics’ scientists shared data from research performed in collaboration with Christine DiDonato, Ph.D., Associate Professor at the Feinberg School of Medicine at Northwestern University and colleagues at the Manne Children’s Research Institute, affiliated with Ann & Robert H. Lurie Children’s Hospital of Chicago and W. David Arnold, MD, Assistant Professor at The Ohio State University.
The objective of the research was to examine the effect of tirasemtiv on measures of muscle function in two mouse models of SMA that were generated in the DiDonato laboratory and exhibit mild to moderate neuromuscular dysfunction. In these models, isometric ankle plantarflexor force was measured following sciatic nerve stimulation and muscle fatigability was assessed by repeated sciatic nerve stimulation. Grip strength was assessed with a pull bar assembly connected to a force measurement gauge and grid hang time was measured by placing the mice on a grid and inverting it. The first model evaluated mild-severity “adult-onset” SMA mice and the second model evaluated “intermediate-severity” SMA mice.
In the “adult-onset” SMA mice, the authors noted that, in response to subtetanic nerve stimulation, mice treated with tirasemtiv produced increases in submaximal isometric force compared to vehicle-treated mice. In addition, treatment with tirasemtiv significantly improved resistance to muscle fatigue. In particular, grid hang time (mean ± sem) increased (138 ± 18 vs. 192 ± 34 seconds for vehicle and tirasemtiv treated mice respectively, p = 0.048) to levels similar to that of wild-type mice (197 ± 23 seconds). In the “intermediate-severity” SMA mice in which the authors noted that muscle weakness was more pronounced than in the “adult-onset” SMA mice, treatment with tirasemtiv also produced more force than vehicle-treated controls in response to subtetanic nerve stimulation. In addition, treatment with tirasemtiv improved forelimb grip strength in these mice (43 ± 4 vs. 52 ± 4 grams for vehicle and tirasemtiv treated mice respectively, p = 0.01) although it was not feasible to normalize grip strength to that of wild-type mice (95 ± 4 grams) in this more severely affected model. The authors concluded that in these animal models of SMA, tirasemtiv increased submaximal muscle force in situ, improved fatigue resistance in situ, improved grip strength in vivo in the “intermediate-severity” mouse model and improved grid hang time in vivo in the “adult-onset” mouse model.
“We are pleased to share results from our research performed with tirasemtiv in preclinical models of Spinal Muscular Atrophy,” stated Fady I. Malik, M.D., Ph.D., Cytokinetics' Senior Vice President, Research and Early Development. “We believe these data lend support to the translation of tirasemtiv as a potential treatment for neuromuscular diseases such as SMA and we continue to evaluate opportunities to expand the development for this novel mechanism drug candidate. We would like to thank Cure SMA for their support of our research.”
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Tirasemtiv, a novel skeletal muscle activator, is the lead drug candidate from Cytokinetics’ skeletal muscle contractility program. Tirasemtiv selectively activates the fast skeletal muscle troponin complex by increasing its sensitivity to calcium and, in preclinical studies, demonstrated increases in skeletal muscle force in response to neuronal input and delays in the onset and reductions in the degree of muscle fatigue. Tirasemtiv was the subject of BENEFIT-ALS (Blinded Evaluation of Neuromuscular Effects and Functional Improvement with Tirasemtiv in ALS), a recently completed Phase IIb clinical trial. BENEFIT-ALS was a multi-national, double-blind, randomized, placebo-controlled, clinical trial designed to evaluate the safety, tolerability and efficacy of tirasemtiv in patients with amyotrophic lateral sclerosis (ALS). BENEFIT-ALS did not achieve its primary efficacy endpoint, the mean change from baseline in the ALS Functional Rating Scale in its revised form (ALSFRS-R). Treatment with tirasemtiv resulted in a statistically significant and potentially clinically meaningful reduction in the decline of Slow Vital Capacity (SVC), a pre-specified secondary efficacy endpoint and a measure of the strength of the skeletal muscles responsible for breathing that has been shown to be an important predictor of disease progression and survival in prior trials of patients with ALS. The analyses of other pre-specified secondary efficacy endpoints produced mixed results. Results from BENEFIT-ALS were presented at the 66th Annual Meeting of the American Academy of Neurology on April 29, 2014 and at the Joint Congress of European Neurology on June 1, 2014. Cytokinetics expects to continue to analyze the data from BENEFIT-ALS to inform the potential further development of tirasemtiv in patients living with ALS.