Clinical-stage biopharmaceutical company Cytokinetics presented their lead drug candidate for the treatment of amyotrophic lateral sclerosis (ALS), a novel skeletal muscle activator called tirasemtiv, in an oral presentation and four poster presentations, at the 25th International Symposium on ALS/MND, which took place between December 5 and 7 at the Square Brussels Meeting Centre in Brussels, Belgium. During the internationally recognized event, the company focused their lectures on the results of their ongoing studies to evaluate tirasemtiv.
The investigational tirasemtiv therapy is part of the company’s skeletal muscle contractility program, and is formulated to selectively activate the fast skeletal muscle troponin complex through the improvement of calcium sensitivity. The company has conducted both preclinical studies and early clinical trials, in which the scientists were able to demonstrate the drug’s ability to improve muscle force in response to neuronal input, and delay and reduce muscle fatigue.
In addition, the company conducted a Phase IIb, multi-national, double-blind, randomized, placebo-controlled, clinical trial, called BENEFIT-ALS, to assess tirasemtiv’s safety, tolerability and efficacy in ALS patients. The results of the study, which included 711 patients in 73 centers at 8 different nations, revealed encouraging results, as patients treated with tirasemtiv registered significant and potentially clinically meaningful slowing of the rate of decline of Slow Vital Capacity (SVC), when compared to the ones treated with placebo.
“We are pleased to present clinical and preclinical data relating to tirasemtiv, as well as other related analyses, at this important annual meeting of the ALS community,” said the senior vice president for Research and Development at Cytokinetics, Fady I. Malik, M.D., Ph.D. “We believe that the effects of tirasemtiv on Slow Vital Capacity in patients treated with tirasemtiv in BENEFIT-ALS are consistent with its novel mechanism of action and therapeutic rationale for use in patients with ALS. Potentially clinically meaningful effects of tirasemtiv on this key measure of respiratory function merit further investigation in a trial of longer duration.”
The company’s director of clinical research and development, Jinsy Andrews, MD, MSc, was responsible for the oral presentation, titled “The Effects of Tirasemtiv on Measures of Respiratory Function in Amyotrophic Lateral Sclerosis,” which tackled the results of BENEFIT-ALS on respiratory function measurements. Andrews explained that tirasemtiv revealed cumulative, longer term pharmacologic effects on SVC. Not only did SVC seem robust, but the effects brought about by the drug were statistically significant and similar to the ones verified in all subgroups evaluated.
“Relationships between Riluzole and Tirasemtiv Levels on Outcomes in the BENEFIT-ALS Trial” was the first poster presentation, held by the lead investigator for BENEFIT-ALS, Jeremy M. Shefner, MD, PhD, who is also a professor and chair of neurology at the Barrow Neurological Institute. His presentation was focused on the trial conclusions that tirasemtiv is able to decrease by half the slope of the decline in SVC, which was verified during all doses of the trial with a flat concentration-response relationship.
In addition, the investigator explained that the muscle strength measured by hand-held dynamometry was decreased by the therapy, even though its effects were only observed in the lower two quartiles of plasma concentrations of tirasemtiv. The drug did not impact ALSFRS-R in any plasma concentration group, while riluzole wasn’t not able to increase the plasma concentration of tirasemtiv, or the drug’s tolerability. Riluzole did not have any effects on the observed reduction of decline in SVC, caused by tirasemtiv. Researchers added that the effects of a lower target dose of tirasemtiv on SVC and muscle strength need further study.
The scientist Darren T. Hwee, PhD, reported on the pathological conditions that can cause weakness of the diaphragm and other serious consequences, including dyspnea, reduction in quality of life, and potential respiratory failure and death, during the poster presentation “Effect of Tirasemtiv on Submaximal Rodent Diaphragm Strength and Respiratory Function.” The medication was found able to improve the mouse diaphragm fiber calcium sensitivity in a concentration-dependent manner, and the mouse diaphragm submaximal force production ex vivo and the tidal volume in vivo, on a mouse model of ALS. This suggests the drug may help increase respiratory muscle function.
The monthly medical expenses of ALS diagnosis are significantly higher than latter months of therapy, and expenses rise exponentially approximately eight months prior to diagnosis of ALS, in both Medicare and commercial insurance holders, according to data presented by the director of biometrics at Cytokinetics, Lisa Meng, PhD, during her “Profile of Medical Care Costs in Patients with Amytrophic Lateral Sclerosis in the Medicare Program and under Commercial Insurance” poster presentation.
Meng also explained that the costs during the month after the ALS diagnosis tend to increase. Patients who benefit from commercial insurance coverage, become eligible for Medicare by more than half, even though there is no tendency of transition. About 30% of the patients studied received supportive services for disabilities when they were diagnosed, and the medical expenses they had enlarged greatly with each disability milestone.
Finally, “Fast Skeletal Muscle Troponin Activator Tirasemtiv Increases Muscle Function and Performance in Mouse Models of Spinal Muscular Atrophy” was presented by scientist Darren T. Hwee who explained “intermediate-severity” and “adult-onset” spinal muscle atrophy (SMA) mice exhibited nerve dysfunction, muscle atrophy, and weakness. However, tirasemtiv has been effective in increasing grip strength in vivo in “intermediate-severity” mice, and in inverting grid hang time in vivo in “adult-onset” mice, suggesting that the drug is also a viable treatment for SMA.