AC01, a novel oral calcium-sensitizing isotope and ghrelin receptor agonist designed to increase myocardial contractility, appeared safe and well-tolerated over a 28-day treatment period in patients with heart failure with reduced ejection fraction (HFrEF), according to results from a phase 1b/2a randomized trial published June 24 in The Lancet.

The double-blind, multicenter, international GOAL-HF1 study enrolled 58 adults (median age, 66 years; 9% women; 95% White) with NYHA class II (76%) or III (24%) HF for at least six months and an LVEF ≤40% into 1b and 2a phases. In phase 1b, 32 patients were randomized 1:1:1:1:2 to AC01 at 0.1 mg, 0.3 mg, 1.0 mg or 3.0 mg or placebo, administered twice daily over seven days. In phase 2a, 26 patients were randomized to AC01 at 1.0 mg (n=9) or 3.0 mg (n=8) or placebo (n=9) twice daily for 28 days.

Results showed there were 12 treatment-related, treatment-emergent adverse events among eight patients in phase 1b and 18 events among eight patients in phase 2a. None of these events were classified as serious, although there was one serious event among placebo patients in phase 1b (increased high-sensitivity cardiac troponin I concentration) and one among placebo patients in phase 2a (inappropriate ICD shock due to atrial fibrillation).

Within the entire cohort, 33/41 (80%) of patients in the treatment arms and 12/17 (71%) in the placebo arms reported mild (92%) or moderate (8%) treatment-emergent adverse events, with the most common being hypotension, nonsustained ventricular tachycardia, dyspnea, hyperglycemia, dizziness or vertigo, and headache. There was no treatment discontinuation due to adverse events or deaths during the study.

On ECG assessment, there was no indication of tachycardia, new-onset tachyarrhythmias, myocardial ischemia or morphological or conduction anomalies. No cases were reported of symptomatic hypotension or effects of high-sensitivity cardiac troponin I or NT-proBNP.

"AC01 appeared safe and well tolerated in patients with HFrEF, with growth hormone release consistent with target engagement and dose-proportional pharmacokinetics," write study authors Lars H. Lund, MD, PhD, et al., adding that "exploratory analyses showed numerical changes in cardiac output, stroke volume, and cardiac structure and function that warrant further evaluation."

"The study findings suggest a promising new therapeutic strategy for patients with heart failure using an oral agent aimed at increasing myocardial contractility – addressing one of the principal pathophysiological defects of the disease – without the safety concerns associated with other inotropic agents," write Clara Saldarriaga, MD, FACC, and Jairo Rendon, MD, FACC, in an accompanying editorial comment, recommending that "the safety of this medication should be tested and reproduced in patients with more severe, advanced heart failure, who are the potential target of this therapy."