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Moving forward on SMA
August 2017
by DDNews Staff  |  Email the author


SOUTH SAN FRANCISCO, Calif.—Cytokinetics Inc. recently announced that data relating to patient baseline characteristics and the reasons for patient screen failure, both from the first cohort of the Phase 2 clinical trial of CK-2127107 in spinal muscular atrophy (SMA), were presented at the Cure SMA 2017 Annual SMA Conference in Orlando, Fla. by Dr. Stacy Rudnicki, director of clinical research at Cytokinetics. In collaboration with Astellas Pharma Inc., Cytokinetics is developing CK-2127107 as a potential treatment for people living with SMA and certain other debilitating diseases and conditions associated with skeletal muscle weakness and/or fatigue.
Patients enrolled in Cohort 1 of this Phase 2, hypothesis-generating, double-blind, randomized, placebo-controlled clinical trial were on average 27.7 years of age and had symptom onset 22.2 years prior to enrollment with a confirmed diagnosis 11.6 years before enrollment. Of the 39 patients enrolled in Cohort 1, 54 percent were male, 19 patients were ambulatory (all with SMA Type III) and 20 patients were non-ambulatory (five with Type II and 15 with SMA Type III). With respect to respiratory measurements, patients had on average a forced vital capacity (FVC) of 84 percent of predicted, a maximal expiratory pressure (MEP) of 88.7 cm H2O and a maximal inspiratory pressure (MIP) of -99.4 cm H2O.
In terms of motor measurements at baseline, ambulatory patients had an average score of 48.8 in the Hammersmith Functional Motor Scale Expanded (HFMSE), 39.2 in the Revised Upper Limb Module (RULM), 17.7 seconds in the timed-up-and-go and 290.7 meters in the six-minute walk. Non-ambulatory patients scored 18.9 in the HFMSE and 28.0 in the RULM. The HFMSE ranges from zero to 66 points, with higher scores indicating a greater degree of function.
Screen failures in cohort 1 were primarily due to a HFMSE score that was either too high in ambulatory patients or too low in non-ambulatory patients. There were no statistically significant differences otherwise in the baseline demographics of enrolled patients compared to screen failures.
“The baseline demographics we observed in cohort 1 are consistent with our expectations for the patient population targeted in this first Phase 2 clinical trial of CK-2127107,” said Dr. Fady I. Malik, Cytokinetics’ executive vice president of research and development. “Adolescent and adult patients with SMA have previously had limited opportunities to participate in clinical trials, and we are pleased to be gaining real-world insights into how to optimize design and inclusion criteria for future trials that may enroll this growing patient population.”
The primary objective of this clinical trial is to determine the potential pharmacodynamic effects of a suspension formulation of CK-2127107 following multiple oral doses in patients with Type II, Type III or Type IV SMA. Secondary objectives are to evaluate the safety, tolerability and pharmacokinetics of CK-2127107. There is no single primary endpoint.
Skeletal muscle contractility is driven by the sarcomere, the fundamental unit of skeletal muscle contraction. It is 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.
CK-2127107, a novel skeletal muscle activator 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. CK-2127107 has demonstrated pharmacological activity that may lead to new therapeutic options for diseases associated with muscle weakness and fatigue. In non-clinical models of SMA, a skeletal muscle activator has demonstrated increases in submaximal skeletal muscle force and power in response to neuronal input and delays in the onset and reductions in the degree of muscle fatigue.
CK-2127107 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. In addition to the Phase 2 clinical trial in patients with SMA, Cytokinetics is collaborating with Astellas on the conduct of a Phase 2 clinical trial in patients with chronic obstructive pulmonary disease (COPD). Astellas also recently began a Phase 1b clinical trial of CK-2127107 in elderly adults with limited mobility.
Code: E081719



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