Pharmacokinetics Study of AMG 423 in Healthy Subjects and Subjects With Various Degrees of Renal Insufficiency

Study Overview
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Brief Summary
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A phase 1, open-label study in subjects with normal renal function and subjects with various degrees of renal insufficiency, including patients with end-stage renal disease (ESRD) requiring hemodialysis. The primary objective is to evaluate the single-dose PK of AMG 423 in subjects with various degrees of renal insufficiency, including patients with end-stage renal disease requiring hemodialysis.

Detailed Description
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This study was conducted by Amgen as the IND holder, with Cytokinetics as a collaborator. Due to the termination of the collaboration agreement between Amgen and Cytokinetics in May 2021 and subsequent transfer of the omecamtiv mecarbil IND from Amgen to Cytokinetics, Cytokinetics is now listed as the sponsor.

Official Title
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An Open-label, Single-dose Study of the Safety, Tolerability, and Pharmacokinetics of AMG 423 in Healthy Subjects and Subjects With Various Degrees of Renal Insufficiency and Effect of Hemodialysis on AMG 423 Pharmacokinetics

Conditions
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Heart Failure

Intervention / Treatment
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* Drug: AMG 423


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men or women ≥18 years of age Laboratory test values (clinical chemistry and hematology)within normal limits, (other than test values out of the normal range for subjects with CKD [groups 1 and 3 through 5]), or clinically acceptable to the investigator and sponsor at screening and day -3 Free of any clinically significant disease or condition(s) (other than that consistent with CKD for subjects in groups 1 and 3 through 5) that require a physician's care and/or would interfere with the evaluations, procedures, or participation in the study per the investigator's discretion; Exclusion Criteria: Subjects whose second MDRD eGFR result during the screening period is not within 10% of the first eGFR result Subjects who have received a functioning renal transplant within the past year Subjects with ESRD who do not have a functioning hemodialysis access Subjects with hemodynamic instability during hemodialysis Subjects whose renal insufficiency is due to active autoimmune renal disease Subjects with renal insufficiency or ESRD requiring hemodialysis and Troponin I > upper limit of normal (ULN) at screening or day -3 Subjects with history of heart disease or unstable angina within the last 3 months Subjects with uncontrolled diabetes (Hb1Ac > 8%) and/or subjects who are able but unwilling to adhere to the required fasting intervals

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1<br>End Stage Renal Diseas (ESRD) requiring hemodialysis | Drug: AMG 423<br>* omecamtiv mecarbil<br>|
| Experimental: Group 2<br>Normal renal function (eGFR >or = 80mL/min/1.73m^2) | Drug: AMG 423<br>* omecamtiv mecarbil<br>|
| Experimental: Group 3<br>Mild decrease in GFR (eGFR 60-79 mL/min/1.73m^2) | Drug: AMG 423<br>* omecamtiv mecarbil<br>|
| Experimental: Group 4<br>Moderate decrease in GFR (eGFR 30-59 mL/min/1.73m^2) | Drug: AMG 423<br>* omecamtiv mecarbil<br>|
| Experimental: Group 5<br>Severe decrease in GFR (eGFR 15-29 mL/min/1.73m^2) | Drug: AMG 423<br>* omecamtiv mecarbil<br>|
| Experimental: Group 6<br>Normal renal function (eGFR >or = 80mL/min/1.73m^2) | Drug: AMG 423<br>* omecamtiv mecarbil<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AMG 423 Pharmacokinetic Parameters | 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). | Twenty time points, up to eight days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Other Total AMG 423 PK Parameters | Total AMG 423 pharmacokinetic parameters including but not limited to terminal phase half life (t1/2) and time of maximum AMG 423 plasma concentration (tmax), AUC from time 0 to infinity (AUCinf) and apparent plasma clearance (CL/F) for Part A and Part B; | Twenty time points, up to eight days | 
| AMG 423 Dialysis Clearance | AMG 423 dialysis clearance (CLd) for ESRD subjects in Part A; | Hours 4, 5, 6, 7 & 8 post-dose | 
| AMG 423 Metabolites | AMG 423 metabolites (M3 and M4) pharmacokinetic parameters including but not limited to AUC0-t, AUCinf, AUC metabolite to parent ratios, Cmax, tmax and t1/2, if appropriate. | Twenty time points, up to eight days | 
| Safety | Secondary safety endpoints are subject incidence of adverse events and clinically significant changes in vital signs, physical examinations, clinical laboratory tests and ECGs. | Up to 46 days, including a 28 day screening period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heart, Failure, Renal, Insufficiency, Cardiac, Kidney, Hemodialysis, Impairment, omecamtiv mecarbil, cardiac myosin activator, CK-1827452