Thursday June 2, 2011, 4:00 pm EDT
Cytokinetics Announces Successful Completion of Phase IIA "Evidence of Effect" Clinical Trial of CK-2017357, in Patients With Claudication Associated With Peripheral Artery Disease
Clinical Trial Demonstrates Translation of Mechanism of Action of Novel Drug Candidate in 2nd Disease Population
SOUTH SAN FRANCISCO, CA--(Marketwire - 06/02/11) - Cytokinetics, Incorporated (NASDAQ:CYTK - News) announced the successful completion of its Phase IIa "Evidence of Effect" clinical trial of CK-2017357, a fast skeletal muscle activator, in patients with claudication associated with peripheral artery disease in connection with a poster presentation today at the 22nd Annual Sessions of the Society for Vascular Medicine being held June 2-4 in Boston, MA. In addition, a second poster presentation today highlighted the potential role of a novel functional endpoint, bilateral heel raise testing, in clinical trials in patients with claudication associated with peripheral artery disease. CK-2017357 is the lead drug candidate from the company's skeletal muscle contractility program.
Phase IIa Evidence of Effect Clinical Trial Presentation
A poster titled "A Phase II, Double-Blind, Randomized, Placebo-Controlled, Three-Way Crossover Pharmacokinetic and Pharmacodynamic Study of CK-2017357, a Fast Skeletal Muscle Troponin Activator, in Patients with Claudication" was presented by Alan Hirsch, MD, Cardiovascular Division and Lillehei Heart Institute, University of Minnesota, on June 2, 2011.
This poster summarized the results of a recently completed Phase IIa Evidence of Effect clinical trial in patients with calf muscle claudication associated with peripheral artery disease. The authors concluded that CK-2017357 increased calf muscle performance in these patients as evidenced by an increase in work achieved during bilateral heel raise testing, a performance measure in this patient population developed for this trial and presented by Dr. Hirsch in a second poster described below. The authors also concluded that increases in calf muscle performance and adverse events appear related to both increasing dose and to the plasma concentration of CK-2017357.
"This clinical trial successfully translated the mechanism of fast skeletal muscle activation with CK-2017357 to an improvement in human skeletal muscle function, as evidenced by the ability of these patients with claudication due to peripheral artery disease to do more calf muscle work before intolerable claudication or limiting fatigue," stated William R. Hiatt, MD, Principal Investigator of this clinical trial, President, CPC Clinical Research and Professor of Cardiovascular Research, University of Colorado School of Medicine. "The increases in calf muscle performance, evidenced during bilateral heel raise testing, were observed after only a single dose of CK-2017357. Further studies are warranted to refine the choice of dose and duration of treatment to minimize systemic adverse effects while still retaining the potential clinical benefit."
"We designed this clinical trial to develop hypotheses that could inform the further development of our fast skeletal muscle troponin activators and therefore we are pleased that it produced pharmacodynamic results that are encouraging and consistent with data generated in our preclinical and Phase I studies," stated Andrew A. Wolff, MD, FACC, Cytokinetics' Senior Vice President of Clinical Research and Development and Chief Medical Officer. "We now have clinically relevant hypotheses regarding CK-2017357 for the possible treatment of claudication associated with peripheral artery disease that we believe warrant further exploration, much as was the case with our previously announced clinical trial of this same drug candidate in patients with amyotrophic lateral sclerosis."
Phase IIa Clinical Trial Design
This Phase IIa Evidence of Effect clinical trial was a double-blind, randomized, placebo-controlled, three-way crossover, pharmacokinetic and pharmacodynamic study of CK-2017357 in male and female patients with symptoms of claudication associated with peripheral artery disease. The primary objective of this trial was to demonstrate an effect of single doses of CK-2017357 on measures of skeletal muscle function and fatigability in patients with peripheral artery disease and claudication. The secondary objectives of this clinical trial were to evaluate and characterize the relationship, if any, between the doses and plasma concentrations of CK-2017357 and its pharmacodynamic effects, and to evaluate the safety and tolerability of CK-2017357 administered as single doses to these patients. Accordingly, in this hypothesis-generating trial, multiple pharmacodynamic assessments were made without specifying a single primary pharmacodynamic endpoint.
A total of 61 patients were enrolled in this three-period crossover trial; in random order and with a 6 to 10 day wash-out period between each of the three treatments, 56 patients received a single dose of CK-2017357 at 375 mg, 33 received a single dose of CK-2017357 at 750 mg, and 57 received a single dose of matching placebo. As was previously announced, the protocol was amended after 33 patients were dosed so that the patients enrolled subsequently received a maximum dose of 500 mg (n = 27). Maximum plasma concentrations of CK-2017357 were generally achieved between 3 and 6 hours after dosing, which is when most assessments were made.
Bilateral heel raise testing was performed before each dose of study drug, and 3 hours and 6 hours after each dose. Six measurements were made during bilateral heel raise testing: time, number of repetitions, and work performed to claudication onset, as well as time, number of repetitions, and total work performed to intolerable claudication or calf muscle fatigue, when the test was ended. Work performed during each repetition was calculated by multiplying the maximal heel elevation achieved during that repetition (measured by an instrument attached to the patient's ankle called an electrogoniometer) by the patient's weight; work to the end of testing was the sum of work performed during all repetitions performed during the test. In addition, a six-minute walk test was conducted at 4 hours after dosing, in which the distance walked by the patient during a six minute period was measured.
Phase IIa Clinical Trial Results
The authors concluded that there was an overall trend for CK-2017357 to increase the parameters of calf muscle function as assessed by bilateral heel raise testing. In general, these increases were most evident after the 750 mg dose and at the highest plasma concentrations achieved during the trial. In addition, they were more prominent at 6 hours than at 3 hours, on measurements taken at the end of testing than at the onset of claudication, and on work performed than on time or number of repetitions. For example, at 6 hours after dosing, the change from baseline in work performed to the end of testing increased by a median value of 5.7 kg-m on placebo, 14.2 kg-m on 375 mg of CK-2017357, 20.2 kg-m on 500 mg of CK-2017357, and 34.1 kg-m on 750 mg of CK-2017357 (p = 0.097, 0.181, and 0.002 for 375, 500, and 750 mg of CK-2017357 versus placebo, respectively). In addition, the overall relationship between CK-2017357 dose and work performed to the end of testing achieved conventional statistical significance (p = 0.007).
Increases in work performed to the end of testing were related not only to dose but also to the plasma concentration of CK-2017357 measured at the time of the test. At the highest concentrations observed in the trial ( > 14 mg/mL, n = 37 observations), the change from baseline in work performed to the end of testing increased by an average of 24.4 kg-m versus placebo (p = 0.007). In the concentration ranges from 0 to 7 ng/mL (n = 50 observations), > 7 to 10 ng/mL (n = 72 observations), and > 10 to 14 ng/mL (n = 45 observations), the average increases versus placebo were 9.5 kg-m (p = 0.247), 5.4 kg-m (p = 0.440), and 16.6 kg-m (p = 0.047), respectively. In addition, the relationship between total work performed to the end of testing and the plasma concentration of CK-2017357 also achieved conventional statistical significance (p = 0.005).
In contrast to the increases in calf muscle performance observed during bilateral heel raise testing, there were dose- and plasma concentration-related decreases in the six-minute walking distances. From a mean baseline six-minute walk distance of 1079 feet, after CK-2017357 doses of 375 mg , 500 mg, and 750 mg, the average six-minute walk distances declined versus placebo by 23.8 feet (p = 0.147), 34.1 feet (p = 0.120), and 106.6 feet (p < 0.001), respectively, and the relationship of these declines in six-minute walk distance to dose was also statistically significant (p < 0.001). Similar decreases in the six-minute walk distance were also observed in relation to increasing plasma concentrations of CK-2017357 (p < 0.001).
The authors also concluded that the single doses of CK-2017357 administered in this study appeared safe and generally well-tolerated by the patients in this trial. A substantial majority of the adverse events reported in the study were deemed mild or moderate and were consistent with those observed in prior studies with CK-2017357; however, the percentage of patients reporting severe adverse events during the trial increased with the dose of CK-2017357. The most commonly reported adverse event was dizziness, which was observed in 80% of the patients in the trial and was dose-related. Severe dizziness was reported by more patients than was any other severe adverse event; all four patients who reported severe dizziness did so after receiving the 750 mg dose. The authors speculated that dizziness and other dose-related adverse events may have negatively impacted walking distance but not heel raise testing because walking is a more complex functional task, requiring integration of numerous abilities in addition to calf muscle performance (vision, balance, and coordination, for example). As previously reported, two patients experienced serious adverse events after treatment with CK-2017357 at 750 mg, which were judged to have been related to treatment with the study drug. Both patients required hospitalization but recovered fully without specific therapy. A third patient was hospitalized for severe worsening of cholecystitis following his second dose of study drug at the 500 mg level but investigators deemed that this was unrelated to study drug. The authors concluded that CK-2017357 merits further study and the potential next steps may include studies to explore whether the adverse events observed, such as dizziness, could abate with repeated dosing, alternate dosing regimens, and/or gradual dose titration.
Bilateral Heel Raise Poster Presentation
A second poster titled "Bilateral Heel Raise Test: A Novel Functional Endpoint for Early Stage Clinical Trials in Peripheral Artery Disease (PAD)," was also displayed and presented by Dr. Hirsch on Thursday, June 2, 2011. This poster described in more detail the bilateral heel raise test that was used in the Evidence of Effect trial reported above and evaluated its utility as a functional assessment in patients with calf muscle claudication. The parameters assessed from a single bilateral concentric heel raise test demonstrated modest reliability across baseline measurements during a 3-week period in patients with peripheral artery disease and claudication. Intra-class correlations by patient for time, number of repetitions, and work to the end of testing were 79%, 76%, and 75%, respectively. The authors concluded that bilateral heel raises performed according to a specified-protocol consistently elicited claudication in patients with a history of claudication associated with peripheral artery disease and thus may be a functionally relevant, easy-to-deploy, and cost-effective measure of calf muscle endurance and fatigue in patients with claudication due to peripheral artery disease. Consequently, the use of the heel raise test in early phase "proof of concept" clinical trials may facilitate demonstration of clinical efficacy in patients with claudication without requiring treadmill procedures. Comparison of bilateral heel raise tests with standardized treadmill testing will be needed to establish this test as a surrogate endpoint that parallels the current gold standard for functional exercise testing in the peripheral artery disease population.
