Benzinga | Jul 19, 2021 07:37AM EDT

Cytokinetics Announces Announces Phase 2 Clinical Trial Of CK-274 'Demonstrated Consistent and Clinically Meaningful Reductions in Left Ventricular Outflow Tract Gradients Within Two Weeks in Patients with Obstructive Hypertrophic Cardiomyopathy'

Phase 2 Clinical Trial of CK-274 Demonstrated Consistent and Clinically Meaningful Reductions in Left Ventricular Outflow Tract Gradients Within Two Weeks in Patients with Obstructive Hypertrophic Cardiomyopathy

No Treatment Interruptions or Discontinuations Due to Reduction in Left Ventricular Ejection Fraction

Phase 3 Registrational Trial of CK-274 Expected to Start Before Year End

Company to Host Conference Call and Webcast Today at 8:30 a.m. Eastern Time

SOUTH SAN FRANCISCO, Calif., July 19, 2021 (GLOBE NEWSWIRE) -- Cytokinetics, Incorporated (NASDAQ:CYTK) today announced positive topline results from Cohorts 1 and 2 of REDWOOD-HCM (Randomized Evaluation of Dosing With CK-274 in Obstructive Outflow Disease in HCM), the Phase 2 clinical trial of CK-3773274 (CK-274), an investigational next-generation cardiac myosin inhibitor in development for the potential treatment of hypertrophic cardiomyopathy (HCM). The results of REDWOOD-HCM inform dose selection and support progression of CK-274 to a planned Phase 3 registrational clinical trial which is expected to start before year end.

Results from Cohorts 1 and 2 of REDWOOD-HCM demonstrated that treatment with CK-274 for 10 weeks resulted in statistically significant reductions from baseline compared to placebo in the average resting left ventricular outflow tract pressure gradient (LVOT-G) (p=0.0003, p=0.0004, Cohort 1 and Cohort 2, respectively) and the average post-Valsalva LVOT-G (p=0.001, p<0.0001, Cohort 1 and Cohort 2, respectively). The majority of patients treated with CK-274 (78.6% in Cohort 1 and 92.9% in Cohort 2) achieved the target goal of treatment, defined as resting gradient <30 mmHg and post-Valsalva gradient <50 mmHg at Week 10 compared to placebo (7.7%). Reductions in LVOT-G occurred within two weeks of initiating treatment with CK-274, were maximized within two to six weeks of the start of dose titration, and were sustained until the end of treatment at 10 weeks. The observed reductions in LVOT-G were dose dependent, with patients achieving greater reductions of LVOT-G with increasing doses of CK-274.

Treatment with CK-274 in REDWOOD-HCM was generally well tolerated. The incidence of adverse events was similar between treatment arms. No serious adverse events were attributed to CK-274 and no treatment interruptions occurred on CK-274. No new cases of atrial fibrillation in patients treated with CK-274 were reported. In this dose-range finding trial, one patient experienced a transient decrease in left ventricular ejection fraction (LVEF) that required dose adjustment but not dose interruption. LVEF returned to baseline within two weeks after the end of treatment in both cohorts, which was consistent with the reversibility of LVEF decreases that were similarly observed in healthy participants in the Phase 1 study of CK-274.

"The combined data from Cohorts 1 and 2 in REDWOOD-HCM met our high expectations for this trial of CK-274 in patients with obstructive HCM, given the observed onset of response to initiation of treatment, magnitude and breadth of response, reversibility of LVEF decreases and favorable tolerability profile," said Fady I. Malik, M.D., Ph.D., Cytokinetics' Executive Vice President of Research & Development. "These findings inform the design of our Phase 3 trial, in which we expect to titrate patients with a flexible dosing scheme of 5, 10, 15, and 20 mg to personalize and maximize the potential treatment effect for patients. We would like to thank the investigators and clinical site coordinators for their commitment to REDWOOD-HCM particularly given the challenges they overcame enrolling a trial in the midst of a global pandemic."

"We are pleased to see the impressive results in terms of substantial reduction of outflow tract gradient from REDWOOD-HCM and the clinically relevant combination of efficacy and safety findings and reversibility of effect evident from treatment with CK-274," said Marty Maron, M.D., Director, Hypertrophic Cardiomyopathy Center; Director, Cardiac CT and MRI; Tufts University School of Medicine, and Principal Investigator of REDWOOD-HCM. "We look forward to seeing how these results may translate into a clinically meaningful impact on patients' symptoms and exercise tolerance in Phase 3."

REDWOOD-HCM: Clinical Trial Design

REDWOOD-HCM is a multi-center, randomized, placebo-controlled, double-blind, dose finding clinical trial of CK-274 in patients with symptomatic obstructive HCM (oHCM) on background medical therapy. The primary objective of the trial is to determine the safety and tolerability of CK-274. The secondary objectives are to describe the concentration-response relationship of CK-274 on the resting and post-Valsalva left ventricular outflow tract gradient as measured by echocardiography during 10 weeks of treatment, to describe the dose response relationship of CK-274, and to evaluate the plasma concentrations of CK-274 in patients with oHCM. Seventeen investigative sites in North America and Europe screened for patients to enroll in Cohort 1 and 2 of REDWOOD-HCM.

Topline results from REDWOOD-HCM include data from two sequentially conducted cohorts, Cohort 1 (n=21) and Cohort 2 (n=20) which randomized treatment of patients 2:1 to CK-274 or placebo. Patients received up to three escalating doses of CK-274 once daily (5, 10, 15 mg in Cohort 1 and 10, 20, 30 mg in Cohort 2) or placebo. Patients had an echocardiogram after two weeks of treatment at each dose to determine potential up-titration to the next higher dose. Overall, treatment duration for each patient in REDWOOD-HCM was 10 weeks with an echocardiogram conducted 2 weeks after the last dose.

REDWOOD-HCM: Topline Results

For patients on CK-274 in Cohort 1 (n=14), the average resting LVOT-G changed from 53.8 mmHg at baseline to 13.4 mmHg at 10 weeks; for patients on CK-274 in Cohort 2 (n=14) the average resting LVOT-G changed from 58.2 mmHg at baseline to 15.1 mmHg at 10 weeks; and for patients in the combined placebo group (n=13) the average resting LVOT-G changed from 52.1 at baseline to 44.0 mmHg at 10 weeks (Figure 1, p=0.0003 for Cohort 1, p=0.0004 for Cohort 2 in comparison to placebo at 10 weeks).

A photo accompanying this announcement is available at https://www.globenewswire.com/NewsRoom/AttachmentNg/46013660-2ce0-4569-871d-1708d39140b0

For patients on CK-274 in Cohort 1 (n=14) the average Valsalva LVOT-G changed from 74.4 mmHg at baseline to 38.1 mmHg at 10 weeks; for patients on CK-274 in Cohort 2 (n=14) the average Valsalva LVOT-G changed from 82.3 mmHg at baseline to 29.8 mmHg at 10 weeks; and for patients in the combined placebo group (n=13) the average Valsalva LVOT-G changed from 84.6 at baseline to 76.0 mmHg at 10 weeks (Figure 2; p=0.001 for Cohort 1, p<0.0001 for Cohort 2 in comparison to placebo at 10 weeks).

A photo accompanying this announcement is available at https://www.globenewswire.com/NewsRoom/AttachmentNg/9aca65d5-6f6e-44d5-8439-323e8c93c0f2



The average ejection fraction for patients on CK-274 in Cohort 1 (n=14) changed from 73.2% at baseline to 67.4% at 10 weeks; for patients on CK-274 in Cohort 2 (n=14) the average ejection fractionchanged from 75.4% at baseline to 64.1% at 10 weeks, and for patients in the combined placebo group (n=13) the average ejection fraction changed from 74.5% at baseline to 74.9% at 10 weeks (p=0.007 for Cohort 1, p=<0.0001 for Cohort 2 in comparison to placebo at 10 weeks).



Overall, the incidence of adverse events was similar between treatment arms. Treatment with CK-274 in REDWOOD-HCM was generally well tolerated in patients being treated with current standard of care with adverse events reported as mild or moderate in severity. There were no treatment related serious adverse events reported by investigators.

No patients who received CK-274 in Cohort 1 had an LVEF <50%. In Cohort 2, one patient with an LVEF at baseline of 58% was up-titrated to 20 mg of CK-274 and experienced transient LVEF reduction to <50% (remaining above 40%) requiring down titration. No interruptions or discontinuations of treatment with CK-274 occurred in any patients across both cohorts.

The distribution (Table 1) of patients across doses of CK-274 in REDWOOD-HCM informs dose selection for the planned Phase 3 trial with the objective to assess clinical outcomes at the lowest effective individualized dose of CK-274.

Table 1

Final Dose Achieved (N)Cohort 1 Cohort 2Placebo 5 mg 10 mg 15 mg 10 mg 20 mg 30 mgCohort 1+2 (N=41) 13 4 5 5 9 4 1

Results of REDWOOD-HCM will be submitted to a future medical conference and for publication.