Safety, tolerability, and basic pharmacokinetic parameters of AUX-001, a once-daily extended release nicorandil in healthy volunteers under fasting and fed conditions

Abstract

Abstract Introduction Chronic-stable angina pectoris (CSAP) is one of the most common cardiovascular conditions in the developed world with a rising prevalence in both Europe and North America. Mounting evidence from chronic angina outcomes studies, including COURAGE, BARI, ORBITA and recently ISCHEMIA, has reemphasized optimized medical therapy (OMT) as first-line treatment for most chronic-stable angina pectoris (CSAP) patients over coronary revascularization. Yet, there has been a lack of development of new antianginal medications since 2006. To lessen polypharmacy and enable better long-term compliance in CSAP patients, AUX-001, a once-daily (QD), extended-release (ER) nicorandil is in clinical development for treating CSAP as an innovative, novel version of the immediate-release (IR) antianginal. Objective To test the safety, tolerability, and basic pharmacokinetic (PK) parameters of AUX-001 QD in fasting and fed conditions in healthy volunteers during this first-in-human phase 1a study. Methods 16 healthy adult volunteers were enrolled. Vital signs (HR, BP, respiratory rate) and any adverse events were collected during screening, pre-dose, 1, 2, 6, 12, 24-h, and 48-h post-dose and at end-of-study for the two respective periods (fasting and fed). Results Evaluable information was available on 16 patients for fasting and 15 for fed conditions with one patient excluded due to protocol violation. No patient discontinued due to safety or tolerability. No severe AEs were recorded. AEs observed during period 1 included headaches (n=12), asymptomatic hypotension (n=3), palpitation (n=1) and nasal congestion (n=1). In period 2, leading AEs were headaches (n=11), neck pain (n=1) and decreased hemoglobin (n=1). Most AEs were mild and transitory and did not trigger medical intervention or discontinuation. AUX-001 pharmacokinetics exhibited a reduced Cmax, a right-hand shift in Tmax, and an extension of T1/2 beyond 9 hours compared to the historical data of the commercially available IR nicorandil. AUX-001 had a small, temporary effect on heart rate and systolic and diastolic blood pressure but within the normal compensatory haemodynamic steady-state stability. The peak effect with the current AUX-001 prototype was at 6 hours, independent of the food effect. Conclusion AUX-001 was safe and well tolerated. Initial vasodilator-induced headaches were manageable by using simple OTC NSAIDs and led to no dropouts. No patients discontinued due to AEs or tolerability issues. There were no lasting significant haemodynamic effects of AUX-001 beyond 24hours. PK parameters of AUX-001 are characteristic of an ER formulation. Observed pharmacokinetics indicates that the achieved T1/2 is substantially longer than with IR nicorandil (~1hour vs >9h) and shows promise for a potential once daily treatment of exercise induced chronic angina.AUX-001 Study Data ESC Abstract 2024