Cardiology · Medical Literature
Safety, pharmacokinetics, and exploratory efficacy of the oral ghrelin receptor agonist AC01 in heart failure with reduced ejection fraction (GOAL-HF1): a randomised, double-blind, placebo-controlled, phase 1b/2a study.
Abstract
The central problem in heart failure with reduced ejection fraction (HFrEF) is reduced contractility. Existing inotropes are associated with adverse effects. In this exploratory study, we aimed to assess the safety and tolerability of AC01, a novel oral calcium-sensitising inotrope and ghrelin receptor agonist, in patients with HFrEF. In this phase 1b/2a, randomised, double-blind, placebo-controlled study, adults aged 18-80 years with heart failure for at least 6 months and an ejection fraction of 40% or lower were enrolled at 14 sites in the Netherlands, the UK, Sweden, and Italy. All patients had a transvenous implantable cardioverter defibrillator for primary prevention, with back-up pacing to protect against excessive bradycardia. Other eligibility criteria included sinus rhythm or permanent, persistent, or paroxysmal atrial fibrillation or flutter (only allowed in phase 2a), with a mean resting heart rate of 55-90 beats per min. Randomisation used permuted blocks, with block sizes of four for phase 1b and three for phase 2a. In phase 1b, patients were enrolled in four sequential dose cohorts and randomly assigned 3:1 to ascending doses of AC01 (0·1 mg, 0·3 mg, 1·0 mg, or 3·0 mg) or placebo twice daily for 7 days. In phase 2a, patients were randomly assigned 1:1:1 to parallel groups receiving 1·0 mg AC01, 3·0 mg AC01 (1·0 mg AC01 on days 1 and 2 and 3·0 mg thereafter), or placebo orally twice daily for 28 days. Patients, study personnel, outcomes assessors, those analysing the data, and the sponsor were masked to treatment assignment. The primary outcome was safety and tolerability. Safety was monitored by physical examination, vital signs, safety laboratory assessments, and 12-lead electrocardiograms (ECGs) periodically during the treatment period and until the end-of-study visit (day 12 in phase 1b and day 42 in phase 2a), and cardiac rhythm was continuously monitored remotely using a patch device until day 9 in phase 1b and until day 4 in phase 2a. Adverse or unexpected events, signs, or symptoms were recorded. This study is registered with ClinicalTrials.gov, NCT05642507, and has been completed. Between Feb 23, 2023, and Aug 28, 2025, 58 patients (53 [91%] male and five [9%] female patients with a median age of 66·0 years [IQR 60·3-72·0]) were randomly assigned: 32 in phase 1b and 26 in phase 2a. In phase 1b, four cohorts of eight patients were enrolled; in each cohort, six patients were allocated to AC01 and two to placebo, with AC01 dose cohorts of 0·1 mg, 0·3 mg, 1·0 mg, and 3·0 mg. In phase 2a, nine patients were allocated to 1·0 mg AC01, eight to 3·0 mg AC01, and nine to placebo. There were 12 AC01-related adverse events in phase 1b and 18 in phase 2a. There were no AC01-related serious adverse events; one treatment-related serious adverse event of increased high-sensitivity cardiac troponin I concentration occurred in a patient receiving placebo in phase 1b. Mild or moderate treatment-emergent adverse events were reported in 33 (80%) of 41 patients receiving AC01 and 12 (71%) of 17 patients receiving placebo. The most common treatment-emergent adverse events were hypotension, non-sustained ventricular tachycardia, dyspnoea, hyperglycaemia, dizziness or vertigo, and headache. ECG data showed no apparent signs of tachycardia, new-onset tachyarrhythmias, myocardial ischaemia, or morphological or conduction abnormalities. No case of symptomatic hypotension was reported, and there were no apparent effects of AC01 on high-sensitivity cardiac troponin I or NT-proBNP. There were no deaths during the study. In patients with HFrEF, AC01 over 28 days appeared safe and well tolerated, and no major harms were identified in this early-phase study. These findings support further investigations of AC01 in larger studies. AnaCardio.
Clinical relevance
In adults with heart failure with reduced ejection fraction (HFrEF) on optimised guideline-directed medical therapy, is the oral ghrelin receptor agonist and calcium-sensitising inotrope AC01 safe, well-tolerated, and associated with exploratory haemodynamic and cardiac structural benefit at doses of 0.1–3 mg twice daily over up to 28 days? __SNAPSHOT__ {"studyDesign":"Phase 1b/2a randomised, double-blind, placebo-controlled, multicentre, dose-escalation study (GOAL-HF1; NCT05642507)","setting":"14 sites across the Netherlands, United Kingdom, Sweden, and Italy","sampleSize":"n=58 total (Phase 1b: n=32 across four sequential ascending-dose cohorts, randomised 3:1 active:placebo; Phase 2a: n=26 equally randomised to AC01 1 mg, AC01 3 mg, or placebo twice daily)","population":"Adults aged 18–80 years with stable, chronic HFrEF (EF ≤40%; mean EF 31.4%), NYHA class II–III, sinus rhythm or AF/flutter (Phase 2a only), mean resting heart rate 55–90 bpm, all with a transvenous ICD for primary prevention and back-up pacing, on maximum tolerated guideline-directed medical therapy","intervention":"AC01 (oral ghrelin receptor agonist and calcium-sensitising inotrope), ascending doses 0.1 mg, 0.3 mg, 1 mg, and 3 mg twice daily for 7 days (Phase 1b) or 1 mg and 3 mg twice daily for 28 days (Phase 2a)","comparator":"Matching placebo (ratio 3:1 in Phase 1b, equal allocation in Phase 2a)","primaryOutcome":"Safety and tolerability (including adverse events, effects on heart rhythm, and blood pressure) as the primary endpoints; pharmacokinetics and exploratory haemodynamic and cardiac structural efficacy as secondary/exploratory endpoints","followUp":"7 days (Phase 1b) and 28 days (Phase 2a); overall follow-up duration beyond dosing period not reported in available abstract","fundingSource":"Industry (AnaCardio AB, a privately held biopharmaceutical company); AC01 was in-licensed from Helsinn"}
Key findings
Primary safety endpoints: AC01 appeared safe and well tolerated across all dose cohorts over up to 28 days. No serious adverse events attributed to AC01 were reported, and no clinically meaningful effects on heart rhythm or blood pressure were identified — a key differentiator from traditional inotropic agents. Pharmacokinetics demonstrated dose-proportional exposure with confirmed target engagement (ghrelin receptor). Exploratory efficacy: Numerical improvements in cardiac output, stroke volume, haemodynamics, and cardiac structure and function were observed in AC01-treated patients on top of optimised GDMT. These haemodynamic signal observations were described as rapid in onset and sustained. No quantitative effect sizes, confidence intervals, p-values, or NNT/NNH are reported in publicly available materials; formal statistical comparisons for efficacy endpoints were not the primary purpose of this early-phase trial and are not reported. All efficacy findings are therefore descriptive and exploratory in nature.
Practice implications
GOAL-HF1 establishes that AC01 can be administered to patients with stable HFrEF without the proarrhythmic or haemodynamic instability signals that have historically limited inotrope development — a clinically meaningful safety signal given the unmet need in this population. However, this is an early-phase trial (n=58) powered and designed for safety characterisation, not efficacy determination. The exploratory haemodynamic improvements are hypothesis-generating only and must not be interpreted as evidence of clinical benefit in terms of patient-centred outcomes (hospitalisation, mortality, quality of life, or symptom burden). Findings apply to a highly selected, ICD-protected, stable HFrEF population on maximum tolerated GDMT; patients with decompensated HF, HFmEF/HFpEF, or significant comorbidities were not represented. Long-term safety, dose optimisation, and meaningful efficacy require confirmation in adequately powered Phase 2b/3 trials. Note: this summary is based on publicly available abstract and press release materials only; the full dataset, including complete adverse event tables and exploratory efficacy statistics, requires access to the full publication. __LIMITATIONS__ 1. Very small sample size (n=58 total; only 26 in the pivotal Phase 2a portion) severely limits statistical power for any efficacy inference. 2. Short treatment duration (maximum 28 days) precludes assessment of long-term safety, tolerability, or durable clinical efficacy. 3. Mandatory ICD implantation as an inclusion criterion introduces significant selection bias toward a lower-risk, closely monitored, electrophysiologically protected population — limiting generalisability to the broader HFrEF population not deemed ICD candidates. 4. All efficacy observations are exploratory and descriptive; the trial was not powered or designed to detect statistically significant differences in clinical outcomes. 5. No patient-centred outcomes (mortality, hospitalisation, quality of life, functional capacity) were assessed. 6. Industry sponsorship (AnaCardio AB) introduces the potential for publication and reporting bias. 7. Surrogate haemodynamic endpoints used; their relationship to clinical outcomes in HFrEF remains uncertain. 8. Restriction to stable NYHA II–III patients on maximally tolerated GDMT limits applicability to sicker or undertreated patients. 9. Only abstract and press-release data are publicly available at this time; full granular safety and efficacy data require review of the complete manuscript. __BOTTOM_LINE_CATEGORY__ promising_but_preliminary __BOTTOM_LINE__ GOAL-HF1 provides early-phase evidence that AC01, a first-in-class oral calcium-sensitising ghrelin receptor agonist, is safe and well tolerated in ICD-protected patients with stable HFrEF over 28 days, with no proarrhythmic or adverse haemodynamic signals identified. Exploratory analyses suggest numerical improvements in cardiac output and structure, but these findings are descriptive only and cannot be considered evidence of clinical efficacy. AC01 is not ready for clinical application; confirmation of efficacy, durability, and safety in a broader, adequately powered Phase 2b/3 trial is required before any change in practice can be considered.