SOUTH SAN FRANCISCO, Calif.—Roughly one in 6,000 to 10,000 children born each year present with spinal muscular atrophy (SMA), a genetic neuromuscular disease characterized by debilitating muscle function and progressive muscle weakness that is often fatal. There are four types of SMA, and the disease severity and projected lifespan for patients ranges from gradual weakness in extremities and a normal lifespan, to a life expectancy of no more than two years without treatment.
While treatments exist that can successfully extend patients’ lifespans, most still face some muscular weakness, and that is a need that Cytokinetics Inc. is aiming to address. The company recently shared data from two preclinical studies of reldesemtiv in SMA, which demonstrated that administering reldesemtiv along with SMN upregulators (nusinersen and SMN-C1, an analogue of risdiplam) resulted in significantly increased muscle force in a mouse model of SMA. Cytokinetics is developing reldesemtiv in collaboration with Astellas, per an agreement inked in 2013.
“Reldesemtiv is a fast skeletal muscle troponin activator that sensitizes the sarcomere to calcium. So for a certain amount of nerve input, reldesemtiv can actually amplify the amount of muscle force that’s being produced,” Dr. Darren Hwee, senior group leader at Cytokinetics, tells DDNews.
Skeletal muscle contractility relies on the sarcomere, a cytoskeletal structure comprised of several proteins. Skeletal muscle myosin, a motor protein, converts chemical energy into mechanical force via interaction with actin, and certain regulatory proteins make actin-myosin interaction dependent on changes in intracellular calcium levels. A slower rate of calcium release sensitizes the sarcomere to calcium, which in turn leads to increased skeletal muscle contractility.
Hwee and Dr. Brad Morgan, senior vice president of research and nonclinical development at Cytokinetics, report that at present there are two approved treatments for SMA: nusinersen, an antisense oligonucleotide, and Zolgensma, a gene therapy, which increase SMN2 and SMN1 levels, respectively. A third compound with the same mechanism is currently in clinical trials—risdiplam, which is a small molecule being developed by Roche and PTC Therapeutics.
“What I think is especially important for the SMA patients that have limited survival—the average survival in Type 1 patients is often less than two to three years—what current treatments will do is improve their nerve and motor function to improve quality of life and extend lifespan; however, they will still have limited muscle function,” Morgan explains. “All these modalities that increase SMN levels and allow patients to live longer with a better quality of life, they still have limited function. What we’ve been able to show preclinically is that reldesemtiv can actually improve the muscle function on top of this.”
The aforementioned preclinical studies featured Hung Li SMA mice that were treated with either nusinersen alone or nusinersen plus reldesemtiv, while the other featured Hung Li SMA mice treated with either SMN-C1 alone or SMN-C1 plus reldesemtiv. Both studies measured the mice’s isometric muscle force production in response to sciatic nerve stimulation of 10 Hz-200 Hz with an in-vivo plantar flexor assay.
The mice treated solely with nusinersen presented with increased body weight, tail length and muscle mass, as well as dose-dependent increases in muscle force response to nerve stimulation. The cohort that received nusinersen and reldesemtiv saw further increased muscle force—in fact, while nusinersen-only mice saw 100 percent increased muscle force relative to control, the mice receiving the combined regimen saw an increase of 290 percent relative to control.
In the other study, mice treated solely with SMN-C1 saw increased survival, body weight and muscle mass, as well as increased muscle force in response to nerve stimulation. When combined with reldesemtiv, mice saw increased muscle force; those receiving SMN-C1 alone saw increased muscle force of 32 percent relative to control, while those receiving both therapies saw increased muscle force of 320 percent relative to control.
In both studies, adding reldesemtiv led to a leftward shift of the force-frequency curve, which indicates an increase in calcium sensitivity of the muscle at submaximal stimulation frequencies and confirms the efficacy of fast skeletal muscle activation in conjunction with SMN upregulators.
“Initially we had shown that reldesemtiv can improve muscle function in healthy wild type mice. These results show that in a disease setting, with moieties that have been shown to improve lifespan and help patients, we can further improve the muscle function,” says Morgan. “We can augment the treatments that are out there. They’re actually pretty stellar treatments, and I think it’ll be pretty revolutionary for this patient population, but we can help them even more. Reldesemtiv may complement all of these therapies, to help these patients hopefully live a richer and fuller life.”
Diane Weiser, vice president of corporate communications and investor relations for Cytokinetics, notes that the company reported SMA results for reldesemtiv last year, as well as Phase 2 results in amyotrophic lateral sclerosis patients, which were presented earlier this year. Cytokinetics is working to advance the compound in both indications, Weiser says, with the expectation that Phase 3 trials will likely take place some time in 2020.