Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Also known as AMG 423, CK-1827452
Omecamtiv Mecarbil Matrix F1 Formulation · 5 trials · 10 indications
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.
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).
| Arm | Type | Description |
|---|---|---|
| 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. |
| 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) |
| Name | Type | Description |
|---|---|---|
| Omecamtiv Mecarbil Matrix F1 Formulation | DRUG | Modified release tablets for oral administration |
| Omecamtiv Mecarbil Matrix F2 Formulation | DRUG | Modified release tablets for oral administration |
| Placebo | DRUG | Modified release tablets matching to omecamtiv mecarbil |
| 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 |
| AMG 423 | DRUG | omecamtiv mecarbil |
Inclusion Criteria: * History of chronic heart failure (HF), defined as requiring treatment for HF for a minimum of 4 weeks prior to screening * Treated with stable, optimal pharmacological therapy for ≥ 4 weeks * History of left ventricular ejection fraction (LVEF) ≤ 40% * Elevated N-terminal proh...
Omecamtiv Mecarbil Matrix F1 Formulation is an investigational oral small molecule developed by Cytokinetics, Incorporated for left ventricular systolic dysfunction. It is a modified release oral formulation of omecamtiv mecarbil that was studied in a Phase 2 clinical trial in patients with chronic heart failure and reduced left ventricular ejection fraction.
Omecamtiv Mecarbil Matrix F1 Formulation targets cardiac myosin, specifically the MYH7, MYH6, MYH7B, MYL3, MYL2 and MYL7 proteins. It acts as a myosin activator, meaning it is designed to increase cardiac contractility by directly activating the myosin motor that drives heart muscle contraction.
Omecamtiv Mecarbil Matrix F1 Formulation is being developed by Cytokinetics, Incorporated, which trades on the Nasdaq under the ticker CYTK. Cytokinetics is a biopharmaceutical company focused on the discovery and development of muscle biology therapeutics, including cardiac muscle activators for heart failure.
Omecamtiv Mecarbil Matrix F1 Formulation is in Phase 2 clinical development. It is an investigational agent and has not been approved by the FDA. The Phase 2 program has been completed, and the formulation has been evaluated in a single completed clinical trial to date.
Omecamtiv Mecarbil Matrix F1 Formulation was evaluated in the COSMIC-HF trial, registered as NCT01786512. COSMIC-HF was a Phase 2, randomized, double-blind, placebo-controlled study of a modified release oral formulation in patients with chronic heart failure and left ventricular systolic dysfunction. It enrolled 544 patients across the United States, Australia, Belgium, Bulgaria, Canada, Czechia, Germany, Hungary, Italy, Lithuania, the Netherlands, Poland and the United Kingdom, and the trial is completed.