Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Also known as Omecamtiv Mecarbil Matrix F1 Formulation, AMG 423, Omecamtiv Mecarbil Matrix F2 Formulation, Omecamtiv Mecarbil Swellable Core Technology F2, Omecamtiv Mecarbil
CK-1827452 · 12 trials · 13 indications
Efficacy of omecamtiv mecarbil compared with placebo on the risk of HF outcomes in patients with symptomatic HFrEF and severely reduced ejection fraction in the setting of guideline-directed medical therapy per local standard of care.
The effect of treatment on exercise capacity, as assessed by peak oxygen uptake, was assessed during cardiopulmonary exercise testing (CPET) with gas-exchange analysis. Cycle ergometry was the preferred modality for exercise testing; treadmill exercise testing was an acceptable alternative. Participants were to use the same testing modality for all exercise tests during the study. Whenever possible, CPET was administered by the same study personnel using the same equipment throughout the study.
The primary outcome was a composite of a heart-failure (HF) event or cardiovascular (CV) death, whichever occurred first, in a time-to-event analysis. A heart-failure event was defined as an urgent clinic visit, emergency department visit, or hospitalization for subjectively and objectively worsening heart failure leading to treatment intensification beyond a change in oral diuretic therapy. All deaths and HF events were adjudicated by an independent external clinical events committee (CEC) at the Duke Clinical Research Institute, using standardized definitions based on the recent American College of Cardiology/American Heart Association (ACC/AHA) standards for endpoint definitions in cardiovascular clinical trials. Time to cardiovascular death or first HF event was analyzed using Kaplan-Meier (KM) methods. Since the median was not calculated, the percentage of participants with a positively adjudicated event during the study is reported.
Maximum plasma concentration (C max) measured in nanograms per milliliter (ng/mL) post first dose and pre second dose on day 1. Doses are approximately 12 hours apart in cohort 1 and 3 and 8 hours apart in cohort 2.
Time of observed maximum plasma concentration (T max) measured in hours (hr) post first dose and pre second dose on day 1. Doses are approximately 12 hours apart in cohort 1 and 3 and 8 hours apart in cohort 2.
Area under the curve (AUC) measured in hours \* nanograms per milliliter (hr\*ng/mL) post first dose and pre second dose on day 1. Doses are approximately 12 hours apart in cohort 1 and 3 and 8 hours apart in cohort 2.
Maximum plasma concentration (C max) measured in nanograms per milliliter (ng/mL) post dose on day 10. Only one dose was administered on day 10 (final dose of study).
Time of observed maximum plasma concentration (T max) measured in hours (hr) post dose on day 10. Only one dose was administered on day 10 (final dose of study).
Area under the curve (AUC) measured in hours \* nanograms per milliliter (hr\*ng/mL) post dose on day 10. Only one dose was administered on day 10 (final dose of study).
The Modified Naughton Exercise Treadmill Test was employed in this study. Exercise Treadmill Test 3 (ETT-3) was performed during the last 2 hours of the 20-hour infusion of study drug or placebo. Baseline Exercise Treadmill Test (ETT-B) was performed prior to dosing.
Pooled analysis of the echocardiographic measure systolic ejection time from echocardiograms taken at all timepoints. The systolic ejection time is the period during which the aortic valve is open and blood is flowing across the valve. Echocardiograms from cohorts 1,2,3,4 and 5 (564 echocardiograms) were binned into either placebo group or 1 of 6 groups based on plasma concentration of CK-1827452.
Pooled analysis of the echocardiographic measure fractional shortening from echocardiograms taken at all timepoints. Fractional shortening is the percentage of change from baseline in the left ventricular cavity dimension with systole. Echocardiograms from cohorts 1,2,3,4 and 5 (564 echocardiograms) were binned into either placebo group or 1 of 6 groups based on plasma concentration of CK-1827452.
Continuous 12-lead digital ECG recording was performed on day 1 of each period. ECGs were analyzed by a blinded, central reader. At each specified timepoint, ten 14-second 12-lead ECG tracings were extracted from the continuous recordings. The median QT in each replicate was calculated; the mean of available medians was used as the participant's reportable value at that timepoint. QT interval was corrected for heart rate using Fridericia's correction (QTcF). Change from baseline (ΔQTcF) was calculated based on a linear mixed-effects model with period, sequence, time (categorical), treatment, and time-by-treatment interaction as fixed effects and baseline QTcF as covariate. Placebo-corrected ΔQTcF (ΔΔQTcF) was calculated as the adjusted mean ΔQTcF after OM dosing minus adjusted mean ΔQTcF after placebo. If the upper bound of the confidence interval of ΔΔQTcF was \< 10 ms for all post-dose time points, OM was to be concluded to not have a significant effect on QT interval prolongation.
Part A and Part B: Total AMG 423 pharmacokinetic parameters including area under the plasma concentration time curve (AUC) from time 0 to the time of the last quantifiable sample (AUC0-t) and maximum observed plasma concentration after dosing (Cmax).
The highest infusion rate tolerated by at least eight subjects. A dose was intolerable if: 1) the pattern of intolerance clearly distinguished active drug from placebo, or 2) the number of subjects intolerant of the dose level in question was at least 3 more than the number of subjects intolerant of placebo.
| Arm | Type | Description |
|---|---|---|
| Omecamtiv Mecarbil | EXPERIMENTAL | Participants randomized to omecamtiv mecarbil will be dosed based on their omecamtiv mecarbil plasma concentration at 25, 37.5 or 50 mg twice daily until at least 850 participants experience a HF event or CV death, whichever comes first. |
| Placebo | PLACEBO_COMPARATOR | Participants randomized to placebo will receive placebo twice daily until at least 850 participants experience a HF event or CV death, whichever comes first. |
| Placebo BID | PLACEBO_COMPARATOR | Participants will receive placebo BID. |
| 25 mg Omecamtiv Mecarbil BID | EXPERIMENTAL | Participants will receive 25 mg omecamtiv mecarbil BID. |
| 37.5 mg Omecamtiv Mecarbil BID Target Dose | EXPERIMENTAL | Participants will receive omecamtiv mecarbil 25 mg BID up to Week 4 or Week 8 and 25 mg or 37.5 mg BID after Week 4 or Week 8, based on Week 2 PK. |
| 50 mg Omecamtiv Mecarbil BID Target Dose | EXPERIMENTAL | Participants will receive Omecamtiv Mecarbil 25 mg BID up to Week 4 or Week 8 and 25 mg or 50 mg BID after Week 4 or Week 8, based on Week 2 PK. |
| Dose-escalation Cohort 1: Placebo | PLACEBO_COMPARATOR | Participants received placebo tablets twice a day (BID) for 7 days. |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 | EXPERIMENTAL | Participants received 25 mg omecamtiv mecarbil (OM) Matrix F1 (M-F1) tablets twice a day for 7 days. |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 | EXPERIMENTAL | Participants received 25 mg omecamtiv mecarbil Matrix F2 (M-F2) tablets twice a day for 7 days. |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2 | EXPERIMENTAL | Participants received 25 mg omecamtiv mecarbil swellable core technology F2 (SCT-F2) tablets twice a day for 7 days. |
| Dose-escalation Cohort 2: Placebo | PLACEBO_COMPARATOR | Participants received placebo tablets twice a day for 7 days. |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F1 | EXPERIMENTAL | Participants received 50 mg omecamtiv mecarbil M-F1 tablets twice a day for 7 days. |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F2 | EXPERIMENTAL | Participants received 50 mg omecamtiv mecarbil M-F2 tablets twice a day for 7 days. |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2 | EXPERIMENTAL | Participants received 50 mg omecamtiv mecarbil SCT-F2 tablets twice a day for 7 days. |
| Expansion Phase: Placebo | PLACEBO_COMPARATOR | Participants received placebo tablets twice a day for 20 weeks. |
| Expansion Phase: Omecamtiv Mecarbil 25 mg M-F1 | EXPERIMENTAL | Participants received 25 mg omecamtiv mecarbil M-F1 tablets twice a day for 20 weeks. |
| Expansion Phase: OM M-F1 PK-based Titration | EXPERIMENTAL | All participants received 25 mg omecamtiv mecarbil M-F1 tablets twice a day. At week 8 the dose escalated to 50 mg twice a day if the week 2 predose plasma concentration of OM was less than the predefined cutoff of 200 ng/mL. |
| Cohort 1: MR 50 mg BID | EXPERIMENTAL | Modified-release (MR) 50 mg dose of CK-1827452 twice a day (BID) for 10 days. |
| Cohort 2: IR 37.5 mg TID | EXPERIMENTAL | Immediate-release (IR) 37.5 mg dose of CK-1827452 three times a day (TID) for 10 days. |
| Cohort 3: MR 100 mg BID | EXPERIMENTAL | Modified-release (MR) 100 mg dose of CK-1827452 twice a day (BID) for 10 days |
| Mid Dose CK-1827452 or Placebo | EXPERIMENTAL | CK-1827452 I.V. infusion for 2 hours at 24mg/hr followed by 18 hours at 6mg/hr or placebo, followed by 6 days three times a day oral dose and a final single oral dose |
| High Dose CK-1827452 or Placebo | EXPERIMENTAL | CK-1827452 I.V. infusion for 2 hours at 48mg/hr followed by 18 hours at 11mg/hr or placebo, followed by 6 days three times a day oral dose and a final single oral dose |
| Cohort 1 | EXPERIMENTAL | 4 treatment periods with a 2 hour infusion. The 4 treatment periods consist of 3 escalating dose levels of CK-1827452 and 1 placebo treatment randomized into the dose escalation sequence. Treatment periods occur at least 7 days apart. |
| Cohort 2 | EXPERIMENTAL | 4 treatment periods with a 2 hour infusion. The 4 treatment periods consist of 3 escalating dose levels of CK-1827452 and 1 placebo treatment randomized into the dose escalation sequence. Treatment periods occur at least 7 days apart. |
| Cohort 3 | EXPERIMENTAL | 4 treatment periods with a 24 hour infusion. The 4 treatment periods consist of 3 escalating dose levels of CK-1827452 and 1 placebo treatment randomized into the dose escalation sequence. Treatment periods occur at least 7 days apart. |
| Cohort 4 | EXPERIMENTAL | 4 treatment periods with a 24 hour infusion. The 4 treatment periods consist of 3 escalating dose levels of CK-1827452 and 1 placebo treatment randomized into the dose escalation sequence. Treatment periods occur at least 7 days apart. |
| Cohort 5 | EXPERIMENTAL | 2 treatment periods with a 72 hour infusion. The 2 treatment periods are randomly assigned and consist of 1 dose level of CK-1827452 (with dose de-escalation possible depending on tolerability) and 1 placebo treatment. Treatment period 2 occurs at least 7 days after the conclusion of period 1. |
| Part A | EXPERIMENTAL | After an overnight fast of at least 10 hours participants received a single oral dose of 25 mg omecamtiv mecarbil on Day 1. |
| Part B | EXPERIMENTAL | Participants with a maximum observed plasma OM concentration ≤ 350 ng/mL in Part A were randomly assigned to receive a single dose of each the following 3 treatments in one of six treatment sequences: * Placebo * 50 mg omecamtiv mecarbil * 400 mg moxifloxacin Each treatment was separated by a washout of at least 7 days. |
| Group 1 | EXPERIMENTAL | End Stage Renal Diseas (ESRD) requiring hemodialysis |
| Group 2 | EXPERIMENTAL | Normal renal function (eGFR \>or = 80mL/min/1.73m\^2) |
| Group 3 | EXPERIMENTAL | Mild decrease in GFR (eGFR 60-79 mL/min/1.73m\^2) |
| Group 4 | EXPERIMENTAL | Moderate decrease in GFR (eGFR 30-59 mL/min/1.73m\^2) |
| Group 5 | EXPERIMENTAL | Severe decrease in GFR (eGFR 15-29 mL/min/1.73m\^2) |
| Group 6 | EXPERIMENTAL | Normal renal function (eGFR \>or = 80mL/min/1.73m\^2) |
| Dose-escalation Cohort 1 | EXPERIMENTAL | 4 treatment periods consisting of a 2 hour placebo infusion (single blind) followed by a 6 hour infusion of study drug or placebo. Each subject will receive 3 active ascending doses of study drug and 1 dose of placebo randomized into the sequence of escalating doses in a double-blind manner. Treatment periods occur at least 7 days apart. |
| Dose-escalation Cohort 2 | EXPERIMENTAL | 4 treatment periods consisting of a 2 hour placebo infusion (single blind) followed by a 6 hour infusion of study drug or placebo. Each subject will receive 3 active ascending doses of study drug and 1 dose of placebo randomized into the sequence of escalating doses in a double-blind manner. Treatment periods occur at least 7 days apart. |
| Dose-escalation Cohort 3 | EXPERIMENTAL | 4 treatment periods consisting of a 2 hour placebo infusion (single blind) followed by a 6 hour infusion of study drug or placebo. Each subject will receive 3 active ascending doses of study drug and 1 dose of placebo randomized into the sequence of escalating doses in a double-blind manner. Treatment periods occur at least 7 days apart. |
| Dose-escalation Cohort 4 | EXPERIMENTAL | 4 treatment periods consisting of a 2 hour placebo infusion (single blind) followed by a 6 hour infusion of study drug or placebo. Each subject will receive 3 active ascending doses of study drug and 1 dose of placebo randomized into the sequence of escalating doses in a double-blind manner. Treatment periods occur at least 7 days apart. |
| Name | Type | Description |
|---|---|---|
| Omecamtiv Mecarbil (OM) | DRUG | Oral Tablet |
| Placebo | DRUG | Oral Tablet |
| Omecamtiv Mecarbil | DRUG | Oral omecamtiv mecarbil twice daily for up to 20 weeks with dose level determined by periodic blood testing |
| Standard of Care | DRUG | Participants were required to be optimally managed with standard of care therapies for chronic HF (eg, beta blockers, renin angiotensin aldosterone system inhibitors), consistent with regional clinical practice guidelines, unless contraindicated. |
| 25 mg Omecamtiv Mecarbil | DRUG | oral tablet |
| 37.5 mg Omecamtiv Mecarbil | DRUG | oral tablet |
| 50 mg Omecamtiv Mecarbil | DRUG | oral tablet |
| Omecamtiv Mecarbil Matrix F1 Formulation | DRUG | Modified release tablets for oral administration |
| Omecamtiv Mecarbil Matrix F2 Formulation | DRUG | Modified release tablets for oral administration |
| Omecamtiv Mecarbil Swellable Core Technology F2 | DRUG | Modified release tablets for oral administration |
| CK-1827452 | DRUG | 50 mg MR CK-1827452 BID for 10 days |
| CK-1827452 24mg and 6 mg iv infusion | DRUG | I.V. infusion for 2 hours at 24mg/hr followed by 18 hours at 6mg/hr |
| CK-1827452 12.5mg capsule | DRUG | 12.5mg oral immediate release capsule |
| CK-1827452 48 mg and 11 mg iv infusion | DRUG | I.V. infusion for 2 hours at 48mg/hr followed by 18 hours at 11mg/hr |
| CK-1827452 25mg capsule | DRUG | 25mg oral immediate release capsule |
| Placebo iv infusion | DRUG | Matching placebo iv infusion |
| Placebo capsule | DRUG | Matching placebo oral immediate release capsule |
| Moxifloxacin | DRUG | 400 mg moxifloxacin oral tablet |
| AMG 423 | DRUG | omecamtiv mecarbil |
Inclusion Criteria: Adult patients who meet all the following criteria at screening may be included in the study: * Are between ≥ 18 years and ≤ 85 years at the signing of informed consent * Have a history of chronic HFrEF, defined as requiring treatment for HF for a minimum of 3 months prior to s...
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CK-1827452 is an investigational small molecule being studied for the treatment of heart failure. It has been evaluated in Phase 2 clinical trials in patients with stable heart failure, including those with ischemic cardiomyopathy and angina. It is not approved for any indication and remains in clinical development.
CK-1827452 is being developed by Cytokinetics, Incorporated, which trades on the Nasdaq under the ticker CYTK. The company has sponsored the Phase 2 clinical program evaluating the drug in heart failure and related cardiovascular conditions.
CK-1827452 is in Phase 2 clinical development. All three of its registered trials were Phase 2 studies, and all three are now completed. There are currently no active trials of CK-1827452, and the drug is investigational rather than approved.
CK-1827452 has been evaluated in three completed Phase 2 trials: NCT00941681, which studied oral pharmacokinetics in stable heart failure; NCT00682565, which assessed intravenous and oral dosing in ischemic cardiomyopathy and angina; and NCT00624442, which studied infusion in stable heart failure. Total enrollment across these trials was 174 patients.
CK-1827452 was studied in randomized, double-blind, controlled Phase 2 trials. The program enrolled 174 patients with heart failure and related conditions across sites in the United States, Georgia, Russia, and the United Kingdom. Trials evaluated both oral and intravenous infusion formulations of the drug.