CK-2127107 (also called CK-107) is an investigative fast skeletal muscle troponin activator that may improve muscle function and physical performance in people with spinal muscular atrophy (SMA). The experimental therapy is being developed by Cytokinetics in collaboration with Astellas.
How CK-2127107 works
CK-107 works by slowing the rate of calcium release from regulatory troponin complex — a protein that plays an important role in muscle contraction — in fast skeletal muscle fibers, sensitizing the sarcomere (long fibrous proteins that slide past each other when muscles contract or relax) to calcium, which leads to an increase in the capacity of skeletal muscles to contract.
Preclinical studies of CK-2127107 evaluated the drug’s effect on skeletal muscle function using two mouse models, one called the 2B/2B-NEO intermediate SMA mice (similar to Type 2 SMA), and the other with Hung Li SMA mice (similar to types 3 and 4 SMA).
Both mouse models had different levels of disease activity, such as nerve dysfunction and/or muscle atrophy as well as a decrease in maximum muscle force production. The studies used single doses of the drug and a range of electrical stimulation frequencies from 10 to 200 Hz applied to the sciatic nerve to measure muscle force production.
In both mouse models, results showed that treatment with CK-2127107 resulted in an increase in skeletal muscle force in response to nerve stimulation. Results also showed a descending curve on the force-frequency response curve, indicating a calcium-sensitizing effect of CK-2127107.
Five Phase 1 clinical trials in healthy volunteers have been completed, testing CK-2127107’s safety, tolerability, bioavailability, pharmacokinetics (how the drug is processed in the body), and pharmacodynamics (how the body reacts to the drug).
Results showed that CK-2127107 was well-tolerated at single doses up to 4,000 mg, and its pharmacokinetics profile was dose-proportional across the range of doses studied. Other data also showed significant dose-concentration and frequency-dependent increases in the force of muscle contraction elicited by nerve stimulation in the participants.
The positive results from both preclinical and Phase 1 studies led to the ongoing Phase 2 trial for people with types 2, 3, or 4 SMA. The primary objective of this trial (NCT02644668) is to demonstrate the potential pharmacodynamics effects of a suspension formulation of the treatment, and secondary objectives are to evaluate the safety, tolerability and pharmacokinetics of CK-2127107.
The trial is expected to enroll 72 patients in the U.S. in two sequential, ascending dose groups (150 mg and 450 mg). Each cohort will be separated according to their ability to walk, and will receive CK-2127107 twice a day for eight weeks.
The second cohort of the study started enrolling participants at the end of March. It is estimated the study will be completed in July 2017.
In May 2017, Cytokinetics announced that the U.S. Food and Drug Administration (FDA) granted CK-2127107 orphan drug status for the treatment of SMA. This designation is given to experimental drugs for rare diseases or disorders that affect fewer than 200,000 people in the U.S. It also grants the company special benefits and incentives, such as tax credits for clinical research and seven years of market exclusivity in the U.S. after the drug’s approval by the FDA.
Besides SMA, Cytokinetics and Astellas are enrolling chronic obstructive pulmonary disease (COPD) patients in a Phase 2a study (NCT02662582) to evaluate CK-2127107 for this disease. About 40 participants will be randomly assigned to one of two treatment sequences to receive both the drug and a matching placebo over two treatment periods. Initial results from this trial are expected by mid-2018.
In addition, two other clinical trials are expected to start in 2017, one with patients with amyotrophic lateral sclerosis (ALS) (NCT03160898) and another in elderly participants with limited mobility (NCT03065959).
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