Cytokinetics Announces Preclinical Data For Reldesemtiv Presented at the 2019 Annual Cure SMA Conference
Two Studies Show Addition of Reldesemtiv to SMN-Directed Treatment Increases Muscle Force in Mouse Model of Spinal Muscular Atrophy
“Advancements in the treatment landscape for SMA have demonstrated positive effects to improve nerve and muscle function and to extend lifespan for people with SMA; however, substantial residual muscle weakness persists,” said Fady I. Malik, M.D., Ph.D., Cytokinetics’ Executive Vice President, Research and Development. “Data from these preclinical studies suggest that reldesemtiv may complement SMN-directed therapies to further improve muscle function, especially for routine activities that may be fatiguing and don’t require maximum exertion.”
In one preclinical study, a cohort of Hung Li SMA mice were treated with nusinersen alone or with nusinersen plus reldesemtiv. In another preclinical study, a cohort of Hung Li SMA mice were treated with either SMN-C1 alone or SMN-C1 plus reldesemtiv. In both studies, the mice were evaluated using an invivo plantar flexor assay measuring isometric muscle force production in response to sciatic nerve stimulation of 10 Hz-200 Hz.
Hung Li SMA mice treated with nusinersen (40, 80 and 160 µg/g) showed increased body weight, tail length and muscle mass, confirming efficacy of treatment. In addition, nusinersen produced dose-dependent increases in muscle force in response to nerve stimulation. The administration of single doses of reldesemtiv further increased muscle force in response to sub-tetanic nerve stimulation in all groups of Hung Li SMA mice treated with nusinersen. At a submaximal stimulation frequency of 50 Hz, treatment of Hung Li SMA mice with nusinersen (160 µg/g) and reldesemtiv (30 mg/kg) significantly increased muscle force by 290% (p<0.0001) relative to control Hung Li SMA mice in comparison to 100% (p<0.05) relative to control in Hung Li SMA mice treated with nusinersen alone.
Hung Li SMA mice treated with SMN-C1 (10 mg/kg) showed increased survival, body weight and muscle mass also confirming the efficacy of treatment. In addition, treatment with SMN-C1 increased muscle force in response to nerve stimulation. The administration of single doses of reldesemtiv further increased muscle force in response to sub-tetanic nerve stimulation in Hung Li SMA mice treated with SMN-C1. At a submaximal stimulation frequency of 50 Hz, treatment of Hung Li SMA mice with SMN-C1 (10 mg/kg) and reldesemtiv (30 mg/kg) significantly increased muscle force by 320% (p<0.0001) relative to control Hung Li SMA mice in comparison to 32% (p<0.05) relative to control in Hung Li SMA mice treated with SMN-C1 alone.
In these studies, the addition of reldesemtiv to either nusinersen or SMN-C1 resulted in a leftward shift of the force-frequency curve, indicating an increase in calcium sensitivity of the muscle at submaximal stimulation frequencies and confirming the efficacy of fast skeletal muscle activation in muscle in conjunction with SMN upregulators. Augmentation of muscle force at submaximal stimulation frequencies may be relevant to activities such as breathing and walking. These data suggest that treatment with reldesemtiv in combination with an SMN upregulating therapy such as nusinersen or SMN-C1, may complement and further improve muscle function in SMA.
Nusinersen is an approved anti-sense oligonucleotide therapy for SMA that increases production of Survival Motor Neuron (SMN) protein. SMN-C1 is a small molecule therapy that increases SMN protein expression, similar to risdiplam, an investigational treatment in development for SMA.
Skeletal muscle contractility is driven by the sarcomere, the fundamental unit of skeletal muscle contraction and a highly ordered cytoskeletal structure composed of several key proteins. Skeletal muscle myosin is the motor protein that converts chemical energy into mechanical force through its interaction with actin. A set of regulatory proteins, which includes tropomyosin and several types of troponin, make the actin-myosin interaction dependent on changes in intracellular calcium levels. Reldesemtiv, a next-generation FSTA arising from Cytokinetics’ skeletal muscle contractility program, slows the rate of calcium release from the regulatory troponin complex of fast skeletal muscle fibers, which sensitizes the sarcomere to calcium, leading to an increase in skeletal muscle contractility. Reldesemtiv has demonstrated pharmacological activity that may lead to new therapeutic options for diseases associated with skeletal muscle weakness and fatigue. In non-clinical models of spinal muscular atrophy, a skeletal muscle activator increased submaximal skeletal muscle force and power in response to neuronal input and delayed the onset and reduced the degree of skeletal muscle fatigue. Reldesemtiv has been the subject of five completed Phase 1 clinical trials in healthy volunteers, which evaluated the safety, tolerability, bioavailability, pharmacokinetics and pharmacodynamics of the drug candidate. Mid-stage clinical trials in patients with SMA, ALS, COPD and elderly adults with limited mobility have been completed. In the Phase 2 hypothesis-generating clinical study in patients with SMA, patients treated with reldesemtiv demonstrated increases in measures of endurance and stamina consistent with the mechanism of action.
SMA is a severe, genetic neuromuscular disease that leads to debilitating muscle function and progressive, often fatal, muscle weakness. It occurs in 1 in 6,000 to 10,000 live births each year and is one of the most common potentially fatal genetic disorders. Spinal muscular atrophy manifests in various degrees of severity as progressive muscle weakness resulting in respiratory and mobility impairment. There are four types of SMA, named for age of initial onset of muscle weakness and related symptoms: Type 1 (Infantile), Type 2 (Intermediate), Type 3 (Juvenile) and Type 4 (Adult onset). Of the prevalent population, approximately 80% of the patients are characterized as Type 2 and Type 3. Life expectancy and disease severity vary by type of SMA. Type 1 patients have the worst prognosis, with a life expectancy of no more than two years unless treated with SMN-directed therapies; Type 2 patients have delayed motor milestones with the most advanced milestone normally achieved being sitting unsupported; Type 3 patients can usually stand and walk but have increasingly limited mobility as their abilities regress as they age; Type 4 patients may have a normal life span but eventually suffer gradual weakness in the proximal muscles of the extremities, eventually resulting in mobility issues. With the recent introduction of SMN-directed therapies, it is expected that patients may live longer, but will still have a significant need to address ongoing disabilities related to respiration and mobility. Approximately 50% of Type 3 patients with SMA are believed to maintain ambulatory function today and an increasing number of Type 2 patients with SMA are expected to remain ambulatory with the advent of complementary new therapies that can enable motor milestones.1 Over the next 5 years, the prevalence of ambulatory adolescents and adults with SMA may exceed 5-10,000 patients in the
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1 Zeres er al.
2 Proprietary market research and company estimates
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