A Double-blind, Randomized, Placebo-controlled, Multicenter, Dose Escalation Study to Select and Evaluate an Oral Modified Release Formulation of Omecamtiv Mecarbil in Subjects with Heart Failure and Left Ventricular Systolic Dysfunction

Systolic heart failure is a clinical syndrome marked by impaired cardiac
contractility. Omecamtiv mecarbil (AMG 423) is a novel small molecule that
increases cardiac contractility by directly activating myosin in the heart
muscle. In contrast to currently available inotropes, AMG 423 achieves its
effects without increasing myocyte calcium transients, myocardial oxygen uptake
or heart rate.

The primary objectives of this study are to select an oral modified release
(MR) formulation and dose of omecamtiv mecarbil for in subjects with HF and
left ventricular systolic dysfunction and to characterize itspharmacokinetics
(PK) after 20 weeks of treatment.

This study consists of a dose escalation phase to select 1 of 3 oral omecamtiv
mecarbil formulations studied in 2 dose escalation cohorts, followed by an
expansion phase to evaluate 20 weeks of administration of the selected
omecamtiv mecarbil formulation at 2 dose levels, compared with placebo. In each
of the dose escalation cohorts, approximately 40 subjects will be randomized to
receive 1 of the 3 formulations of omecamtiv mecarbil BID (25-mg BID cohort 1;
50-mg BID cohort 2) or placebo BID for 7 days. If necessary to achieve an
effective plasma concentration in subjects with HF, a third cohort may be added
to test some or all of the omecamtiv mecarbil formulations at the dose of 75 mg
BID before proceeding to the expansion phase. In the expansion phase,
approximately 450 subjects will be randomized into 1 of 3 treatment groups to
receive the selected formulation of omecamtiv mecarbil at 1 of 2 dose levels,
or placebo. It is expected that the dose levels in the expansion phase will be
25 mg and 50 mg BID. Dose levels of 50 mg and 75 mg BID may be selected if a
third dose escalation cohort at 75 mg BID is conducted. Treatment in the
expansion phase is for 20 weeks. PK and safety data will be reviewed in a Dose
Level Review Meeting (DLRM) before enrollment into the next cohort is
initiated.

In total, up to approximately 570 subject in 125 centers will be randomized.
The Netherlands will only participate in cohort 2 (and 3 if applicable) and in
the expansion phase.

With protocol amendment #4 a titration step has been added to the 50 mg arm in
the expansion phase. The total treatment duration has therefore been amended
from 12 weeks to 20 weeks, with an end of study visit at week 24.

Protocol amendment #4:
Subjects randomized to omecamtiv mecarbil 50 mg BID target dose will initiate
administration at 25 mg BID until week 8. These subjects will start
administration at 50 mg BID at the week 8 visit only if the week 2 predose
omecamtiv mecarbil plasma concentration is < 200 ng/mL. Subjects with week 2
predose PK >= 200 ng/mL, or for which a week 2 PK value is not available in time
for dose adjustment, will continue administration at 25 mg BID until the end of
study participation. Subjects randomized to placebo or to 25 mg BID will
receive the assigned IP throughout the study.

Dose escalation phase cohort 1: 25 mg BID omecamtiv mecarbil (1 of the 3 oral
formulations) or placebo 7 days
Dose escalation phase cohort 2: 50 mg BID omecamtiv mecarbil (1 of the 3 oral
formulations) or placebo 7 days
Dose escalation phase cohort 3: 75 mg BID omecamtiv mecarbil (1 of the 3 oral
formulations) or placebo 7 days
Enrollment expansion phase: 25 or 50 mg BID omecamtiv mecarbil (1 formulation)
or placebo 20 weeks

The following procedures will be performed according to the ''Schedule of
Assessments'' (protocol page 39 and 41): physical examination, vital signs,
ECG, and blood sampling in both escalation phase and expansion phase. Moreover
a serum pregnancy will be done at the screening and end of study visit in both
phases. In the expansion phase echocardiograms will also be performed at
screening, week 12 and 20. In the expansion phase PROs/ClinROs will need to be
completed at certain visits.

In the escalation phase patients will need to come to the hospital 10 times. In
the expansion phase patients will need to come to the hospital 8 times. In
between, patients will be contacted by phone. The visits on day 1 and 7 of the
escalation phase and on week 2 and 12 of the expansion phase will take the
whole day. Patients may stay over for the night.

For adverse events of AMG423, please see question E9.