Cytokinetics, Incorporated, today announced that data from two preclinical studies of reldesemtiv were presented at the 2019 Annual Cure SMA Conference in Anaheim, CA, showing that the addition of reldesemtiv to treatment with SMN upregulators (nusinersen and SMN-C1, an analogue to risdiplam) significantly increased muscle force in a mouse model of spinal muscular atrophy (SMA). In collaboration with Astellas, Cytokinetics is developing reldesemtiv, a fast skeletal muscle troponin activator (FSTA), as a potential treatment for people with SMA and certain other debilitating diseases and conditions associated with skeletal muscle weakness and/or fatigue.
“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.”
Preclinical Research
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
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 reldesemtivfurther 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
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.
Cure SMA Funding for Combination Therapies
The clinical trials for CK-2127107 (reldesemtiv) came about because of early seed funding from Cure SMA, supporting research focused on the potential application of these types of skeletal muscle activators to SMA. In 2014, Cytokinetics released encouraging data from preclinical studies conducted with our funding. The data showed this approach had positive effects in preserving muscle strength and reducing muscle fatigue, setting the groundwork for the ongoing clinical trials.
The progress of this program also highlights the importance of developing combination therapies to treat SMA. The goal is that CK-2127107 will show positive results in preserving muscle strength in human clinical trials and may lend itself to combination with other SMA therapies, particularly those that address the SMN protein deficiency caused by the SMN1 mutation. Furthermore, Reldesemtiv has the potential to be a valuable therapeutic option for different ages and stages of disease from pediatric and adult patients with Type II, Type III, or Type IV disease.