Cytokinetics’ Spinal Muscular Atrophy Drug Shows Promise in Phase II
Published: Jun 18, 2018 By Mark Terry
Cytokinetics, based in South San Francisco, released data from its Phase II clinical trial of reldesemtiv in patients with spinal muscular atrophy (SMA). The results were presented at the 2018 Annual Cure SMA Conference held in Dallas.
SMA is a severe, genetic neuromuscular disease that can be fatal. It shows up in 1 in 6,000 to 10,000 live births annually. There are four types named for age of initial onset of muscle weakness and symptoms. Type 1 (infantile), Type 2 (intermediate), Type 3 (juvenile) and type 4 (adult). About 80 percent of patients are seen as type 2 and Type 3.
Reldesemtiv is a next-generation fast skeletal muscle troponin activator (FSTA). It slows the rate of calcium release from the regulatory troponin complex of fast skeletal muscle fibers. It leads to increased skeletal muscle contractility.
The trial’s primary objective was to determine potential pharmacodynamic effects of the drug after multiple oral doses. A secondary objective was to evaluate safety, tolerability and pharmacokinetics.
Patients received two dose levels of the drug, 150 mg or 450 mg twice a day. They showed dose-dependent increases in 6MWD (Six Minute Walk Distance) in ambulatory patients.
“This hypothesis-generating study provides the first data indicating that a muscle-directed therapy, namely a fast-skeletal muscle troponin activator, may be clinically beneficial in patients with SMA,” said John Day, professor of Neurology and Pediatrics (Genetics) at Stanford University, who gave the oral presentation, in a statement. “These data are especially encouraging given the unmet need among those adolescent and adult individuals with SMA who have persistent muscle weakness, fatigue and functional impairment.”
The trial enrolled 70 patients, 39 in Cohort 1 and 31 in Cohort 2. Type II or Type III patients 12 years of age and older were randomized two-to-one, stratified by ambulatory ability, to receive reldesemtiv or placebo twice a day for eight weeks. The first cohort received 150 mg of reldesemtiv or placebo and the second received 450 mg of one or the other. Multiple evaluations of skeletal muscle function and fatigability were performed, including respiratory assessments, upper limb strength and functionality for non-ambulatory patients, in addition to a Six Minute Walk Distance and Timed-Up-and-Go for ambulatory patients.
The 150 mg dose didn’t show statistically significant results in the Six Minute Walk test. The 450 mg dose did at four weeks, but dropped below a significant response at eight weeks. The concern is that the drug only shows a transient effect. The company suggests it’s related to the small patient population, and that in a bigger study, they will be able to double the dose, as well as extend endpoints out to 12 weeks.
The company had a previous failure for a related drug, tirasemtiv. The company has essentially replaced tirasemtiv with reldesemtiv, which is argues is safer. Tirasemtiv’s side effects were exacerbated by its ability to cross the blood-brain barrier, which caused dizziness and limited dosing.
Cytokinetics is developing the drug in partnership with Astellas. The two companies signed a research, development and commercialization deal in 2013 to develop skeletal muscle activators. They expanded the collaboration in 2014, and amended it further in 2016.
In addition to SMA, they are also evaluating the drugs or are planning studies for ALS, COPD and frailty in the elderly.