Phase Ib/IIa Trial With AC01 in Patients With HFrEF

Key Inclusion Criteria, Dose Escalation Phase: * Male and female out-patients of any ethnicity, between 18-80 years (inclusive), with stable HFrEF. * Chronic HF for at least 6 months duration defined by history with current NYHA class II-III severity. * LVEF ≤40% by TTE more than 6 months before screening and again at screening (screening measurement confirmed by echocardiography core lab). * Sinus rhythm with mean resting heart rate 55-90 bpm. * Cardiac Index 0.5-2.4 measured by Innocor at screening and Day -1. Screening measurement confirmed by core lab. * Transvenous ICD for primary prevention in place and active (as long as it is not subcutaneous). * Optimal guideline-based medical therapy for HFrEF as judged by the Investigator, at stable doses for ≥2 weeks with no intention to change dosing during trial duration. Key Exclusion Criteria, Dose Escalation Phase: * Any cardiac rhythm that does or could interfere with ECG or TTE interpretation, including but not limited to permanent or persistent atrial fibrillation or flutter or paroxysmal atrial fibrillation or flutter with an episode in the last 3 months, frequent premature ventricular contractions, or atrial or ventricular pacing * Ongoing or planned mechanical circulatory support, treatment with any IV vasoactive drugs (vasodilators, inotropes, or vasopressors) or diuretics, and/or dialysis or hemofiltration or ultrafiltration. * Probable alternative explanations for symptoms or signs (e.g., but not limited to, known primary cardiomyopathy \[hypertrophic, constrictive, restrictive, infiltrative, congenital\]). Primary uncorrected hemodynamically significant valve disease, right-sided HF not due to left-sided HF. * History of aborted cardiac arrest (cardiac arrest in the setting of myocardial infarction is allowed). * Hospitalized for HF or received IV diuretics, vasodilators, or inotropes for HF ≤30 days. * Clinical diagnosis of acute coronary syndrome or stroke ≤30 days. * PCI or percutaneous valve intervention ≤30 days or planned. * Angina pectoris ≤30 days. * Any cardiovascular procedure planned during study duration. * Hospitalized or unplanned visit to the emergency department for any reason in last 30 days; patient is eligible 30 days from discharge from hospital. * Use of any drugs or substances known to be strong inducers of CYP3A4 enzyme within 28 days prior to the first dose of study drug and/or planned to be used during the overall study period until the day after the final dose of study drug (e.g., rifampin, phenytoin). * eGFR by CKD-EPI \<30 mL/min/1.73 m2 at screening or at Day -1. * Serum or plasma potassium \<3.5 or \>5.2 mEq/L at screening or at Day -1. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>3 times upper limit of normal (ULN) or total bilirubin \>2 times ULN at screening or at Day -1 or known cirrhosis or severe liver or pancreatic disease, or Gilbert's syndrome. * Any condition that in the opinion of the Investigator may interfere with adherence to, or makes patient not suitable for, entry into the study. * Mean systolic blood pressure \<90 mmHg or \>140 mmHg, sitting after at least 5 minutes rest at screening or at Day -1. * Any of the following ECG findings at screening or at Day -1: atrial or ventricular pacing, QTcF \>450 ms for males and \>470 ms for females, AV block I with PQ \>240 ms, AV block II or III. In the case of non-paced QRS prolongation \>120 ms, the QTcF is allowed to be up to but not greater than 470 ms. Key Inclusion Criteria, Cohort Expansion Phase: * Male and female out-patients of any ethnicity, between 18-80 years (inclusive), with stable HFrEF. * Chronic HF for at least 6 months duration defined by history with current NYHA class II-III severity. * LVEF ≤40% by TTE more than 6 months before screening and again at screening (screening measurement confirmed by echocardiography core lab). * Sinus rhythm or permanent, persistent or paroxysmal AFF (AFF at screening capped at ≥25% of enrolled patients) with mean resting heart rate 55-90 bpm measured as part of vital signs, at screening and on Day -1. Mean defined as mean of 3 separate measurements 1 minute apart. * Transvenous ICD for primary prevention in place and active (i.e., subcutaneous ICD not accepted). * Optimal guideline-based medical therapy for HFrEF as judged by the Investigator, at stable doses for ≥2 weeks with no intention to change dosing during trial duration. Key Exclusion Criteria, Cohort Expansion Phase: * Any cardiac rhythm other than AFF that does or could interfere with ECG or TTE interpretation, including but not limited to \>20% of ventricular contractions on ECG strips being premature ventricular contractions including doublets, triplets, bigeminy or trigeminy, or atrial or ventricular pacing. * Ongoing or planned mechanical circulatory support, treatment with any IV vasoactive drugs (vasodilators, inotropes, or vasopressors) or diuretics, and/or dialysis or hemofiltration or ultrafiltration. * Probable alternative explanations for symptoms or signs (e.g., but not limited to, known primary cardiomyopathy \[hypertrophic, constrictive, restrictive, infiltrative, congenital\]). Primary uncorrected hemodynamically significant valve disease, right-sided HF not due to left-sided HF. * History of aborted cardiac arrest (cardiac arrest in the setting of myocardial infarction is allowed). * Hospitalized for HF or received IV diuretics, vasodilators, or inotropes for HF ≤30 days. * Clinical diagnosis of acute coronary syndrome or stroke ≤30 days. * PCI or percutaneous valve intervention ≤30 days or planned. * Angina pectoris ≤30 days. * Any cardiovascular procedure planned during study duration. * Hospitalized for cardiovascular or other disease in last 30 days as per Investigator discretion; patient is eligible 30 days from discharge from hospital. * Use of any drugs or substances known to be strong inducers of CYP3A4 enzyme within 28 days prior to the first dose of study drug and/or planned to be used during the overall study period until the day after the final dose of study drug (e.g., rifampin, phenytoin). * eGFR by CKD-EPI \<30 mL/min/1.73 m2 at screening. * Serum or plasma potassium \>5.2 mEq/L at screening. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>3 times upper limit of normal (ULN) or total bilirubin \>2 times ULN at screening or at Day -1 or known cirrhosis or severe liver or pancreatic disease, or Gilbert's syndrome. * Any condition that in the opinion of the Investigator may interfere with adherence to, or makes patient not suitable for, entry into the study. * Mean systolic blood pressure \<90 mmHg or \>140 mmHg, sitting after at least 5 minutes rest at screening or at Day -1. * Any of the following ECG findings at screening or at Day -1: atrial or ventricular pacing, QTcF \>450 ms for males and \>470 ms for females, AV block I with PQ \>240 ms, AV block II or III. In the case of non-paced QRS prolongation \>120 ms, the QTcF is allowed to be up to but not greater than 470 ms.