Currently, there are two ongoing Phase II clinical trials and one completed Phase IIa clinical trial evaluating CK-2017357 in patients with ALS. The first ongoing Phase II clinical trial is evaluating multiple doses of CK-2017357 in ALS patients with and without the concurrent administration of riluzole. The first cohort, or Part A, of this clinical trial in ALS patients not concurrently taking riluzole was completed recently. The second ongoing Phase II clinical trial is dose titration study to evaluate multiple ascending doses of CK-2017357 in patients with ALS. More information on each trial is available below.

The ongoing Phase II clinical trial is a double-blind, randomized, placebo-controlled trial designed to evaluate the safety and tolerability of multiple doses of CK-2017357 in patients with ALS. The primary objective of this clinical trial is to assess the safety and tolerability of CK-2017357, after multiple oral doses to steady state plasma concentrations, in patients with ALS. A secondary objective of this clinical trial is to evaluate the ALSFRS-R, other measures of pulmonary function, muscle strength and fatigue, and physician and patient global assessments in these patients while receiving two weeks of treatment with CK-2017357 at the indicated doses or placebo.

In December 2011, we announced that Part A of this Phase II clinical trial successfully met its primary objective of defining the tolerability and pharmacokinetic profile of CK-2017357 during two weeks of daily dosing in 24 ALS patients who were not taking riluzole concurrently. CK-2017357 was well-tolerated as a single agent at all dose levels from 125 mg daily to 375 mg daily for two weeks in these patients.

83% of patients in the combined CK-2017357 dose groups reported at least one treatment-emergent adverse event, compared with 67% of the patients receiving placebo. In the combined dose groups receiving CK-2017357, the most common and dose-related side effect reported was dizziness, observed in no patients receiving placebo and 8 of the 18 patients receiving CK-2017357. The dizziness did not persist beyond the second day of dosing in all but one of the patients studied. A total of 14 episodes of dizziness were reported, 12 of which were mild in severity. The incidence of dizziness appeared dose-related and self-limiting in all patients who completed study drug treatment except for one patient in whom it was mild in severity. Two patients withdrew early, both due to treatment-emergent dizziness. No serious adverse events were reported.

Plasma concentrations of CK-2017357 increased with escalating doses; however, there was considerable overlap between the dose groups in the range of observed plasma levels. As expected, due to the small sample size of 24 patients, the large inter-patient variability and the short, two-week duration, Part A of this trial lacked the statistical power to detect significant differences in clinical outcome measures. However, trends to improved clinical outcome measures were observed, especially at the highest CK-2017357 dose of 375 mg daily. Four of five patients who completed treatment in this dose group reported improvement in their Global Assessments and three of these five patients improved at least 1 point on the ALS Functional Rating Scale-Revised (ALSFRS-R). The changes observed in Maximum Voluntary Ventilation (MVV) after two weeks of dosing at 375 mg compare favorably to improvements observed at 24 hours after a single 500 mg dose of CK-2017357 in the prior Phase IIa Evidence of Effect clinical trial in ALS patients. Additional analyses from this ongoing clinical trial, including results from efficacy outcome measures, are expected to be presented at a later date.

Part B of this clinical trial is currently enrolling an estimated 24 patients at eight to ten study centers in the United States. Patients in the trial will be randomized to one of four different treatment groups, to receive daily oral doses of placebo, 125 mg, 250 mg, or 375 mg of CK-2017357, respectively, in addition to 50 mg of riluzole for two weeks; clinical assessments will take place at pre-determined times during the course of treatment. Patients will also participate in follow-up evaluations one week after their final dose.

The primary objective of this clinical trial is to assess the safety and tolerability of CK-2017357, after multiple oral doses to steady state plasma concentrations, in patients with ALS who are also receiving riluzole. A secondary objective of this clinical trial is to evaluate the ALS Functional Rating Scale-revised (ALSFRS-R), other measures of pulmonary function, muscle strength and fatigue, and physician and patient global assessments in these patients while receiving two weeks of treatment with CK-2017357 at the indicated doses or placebo.

This ongoing clinical trial is a double-blind, randomized, placebo-controlled, ascending dose titration study designed to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamic effects of multiple ascending doses of CK-2017357. An estimated 24 patients with ALS who are also receiving riluzole are planned to be enrolled at eight to ten study centers in the United States. Patients will be randomized to one of two dosing groups and receive twice daily oral ascending doses of CK-2017357 or placebo. Clinical assessments will take place at pre-determined times during the course of treatment; patients will also participate in follow-up evaluations one week after their final dose.

The primary objective of this clinical trial is to assess the safety and tolerability of this alternative dosing regimen of CK-2017357 in patients with ALS. The secondary objectives of this clinical trial are to evaluate the ALS Functional Rating Scale-Revised (ALSFRS-R), other measures of pulmonary function, muscle strength and fatigue, relationships between dose, plasma concentrations and functional effects and physician and patient global assessments in these patients while receiving two weeks of treatment with CK-2017357 at the indicated doses or placebo.

CK-2017357 previously demonstrated potentially clinically relevant pharmacodynamic effects in a completed Phase IIa Evidence of Effect clinical trial in ALS patients. In that trial, the single doses of CK-2017357 evaluated appeared generally well-tolerated. In addition, both patients and investigators perceived a positive change in the patients’ overall status, in a dose-dependent fashion, at 6 hours after dosing with CK-2017357, based on a Global Assessment in which the patient and the investigator each independently assessed patients’ status compared to prior to dosing. Furthermore, there was a clear relationship between improvements in Global Assessments and the CK-2017357 plasma concentration. Also at this 6-hour time point, there was a trend towards decreased muscle fatigability, as evidenced by data from a test of sub-maximal hand-grip endurance. Data from that clinical trial also demonstrated a statistically significant increase in the maximum volume of air patients could inhale and exhale in ten seconds (Maximum Voluntary Ventilation) at both 6 and 24 hours after 500 mg of CK-2017357, as well as small but statistically significant increases in maximum strength of certain muscle groups tested.

In June 2011, Cytokinetics 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 at the 22nd Annual Sessions of the Society for Vascular Medicine. In this Phase IIa clinical trial, 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. 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 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.

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 mcg/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 mgc/mL (n = 50 observations), >7 to 10 mcg/mL (n = 72 observations), and >10 to 14 mcg/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.

In January 2011, Cytokinetics opened enrollment in a Phase IIa "Evidence of Effect" (EoE) clinical trial of CK-2017357 in patients with generalized myasthenia gravis (MG). In July 2010, Cytokinetics was awarded a grant in the amount of $2.8 million by the National Institute of Neurological Disorders and Stroke to support research and development of CK-2017357 in MG.

This Phase IIa EoE clinical trial is a double-blind, randomized, three-period crossover, placebo-controlled, pharmacokinetic (PK) and pharmacodynamic (PD) study of CK-2017357 in patients with generalized MG. At least 36 and up to 78 patients may be enrolled at approximately 15 study centers in the United States. Patients enrolled in the trial will receive single oral doses of placebo, 250 mg, and 500 mg of CK-2017357 in random order. A wash-out period of at least 7 days (to a maximum of 10 days) will be employed between the individual doses for each patient.

The primary objective of this hypothesis-generating clinical trial is to assess the effects of CK-2017357 on measures of muscle strength, muscle fatigue and pulmonary function utilizing the standardized Quantitative MG score, Manual Muscle Test, and MG Composite score. The secondary objectives of this clinical trial are to evaluate and characterize the relationship, if any, between the doses and plasma concentrations of CK-2017357 and its PD effects; to evaluate the safety and tolerability of CK-2017357 administered as single doses to patients with MG; and to evaluate the effect of CK-2017357 on investigator and patient determined global functional assessment and the Modified MG Symptom Score.

Cytokinetics has previously announced data from two Phase I clinical trials evaluating CK-2017357. The first trial was a two-part, single-dose, Phase I clinical trial of CK-2017357. Part A of this trial was designed to assess the safety, tolerability and pharmacokinetic profile of increasing single doses of this drug candidate in healthy volunteers and to determine its maximum-tolerated dose and associated plasma concentrations. Single doses up to 2000 mg were administered without intolerable adverse events being observed. Part B of this trial was designed to assess the pharmacodynamic effects of CK-2017357 on skeletal muscle function after single oral doses of 250, 500 and 1000 mg, and to assess the relationship of the effects observed to the associated plasma concentrations of CK-2017357, also in healthy volunteers. In Part B, CK-2017357 produced concentration-dependent, statistically significant increases versus placebo in the force developed by the tibialis anterior, the muscle evaluated in Part B of this trial. CK-2017357 was well-tolerated and no serious adverse events were reported.

The second trial was a multiple-dose, Phase I clinical trial of CK-2017357 designed to investigate the safety, tolerability and pharmacokinetic profile of CK-2017357 after multiple oral doses to steady state in healthy male volunteers. The trial evaluated doses that produced plasma concentrations in the range associated with pharmacodynamic activity in Part B of the single-dose Phase I study. At steady state, both the maximum plasma concentration and the area under the CK-2017357 plasma concentration versus time curve from before dosing until 24 hours after dosing were generally dose-proportional. In general, systemic exposure to CK-2017357 in this trial was high and inter-subject variability was low. In addition, these multiple-dose regimens of CK-2017357 were well-tolerated, and no serious adverse events were reported.