Clinical pharmacology of AZD9977, a novel, selective mineralocorticoid receptor (MR) modulator without K plus -sparing properties

Abstract Background and purpose Excessive MR activation is implicated in the pathogenesis of cardiovascular disease. MR antagonists (MRA) are effective and key guideline-directed therapy in patients with heart failure (HF) with reduced ejection fraction. However, clinical adverse events due to hyperkalaemia and a decline in renal function significantly restricts the treatment. AZD9977 is a novel, non-steroidal selective MR modulator that, compared with MRA, displays a differentiated MR-binding pattern and cofactor recruitment profile, and exerts similar organ protective effects to eplerenone with minimal effects on urinary electrolyte handling. Methods We performed a randomized, placebo-controlled, single-blind phase 1 study to evaluate the safety, tolerability and pharmacokinetics of oral AZD9977 in healthy men. Three sequential ascending dose cohorts were evaluated, and participants received either AZD9977 (n=6) or placebo (n=3) for 8 days. AZD9977 target doses of 50mg bid, 150mg bid and 300mg bid were explored based on a model predicted dose range comparable to and exceeding the target receptor occupancy levels achieved with approved MRA drugs. The dose of AZD9977 50mg bid is predicted to be equipotent to spironolactone 25mg daily. Results 27 healthy male subjects aged 23–45 years completed the study. All doses of AZD9977 were well tolerated with no safety concerns identified. A total of 7 adverse events occurred in 4 participants (22.2%) receiving AZD9977 and 8 events occurred in 6 participants (66.7%) receiving placebo, none severe or resulting in withdrawal from the study. Rapid absorption of AZD9977 was observed with median Tmax values ranging from 0.5 to 0.8-hours post-dose and approximate dose proportional kinetics between 50 to 300 mg twice daily, as measured by AUCτ and Cmax. Steady-state levels in plasma were generally reached within 3–4 days. Target engagement was confirmed by a robust dose-dependent rise in mean serum aldosterone levels between Day −1 and Day 7 (Placebo = 43±172pmol/L, AZD9977 50mg bid = 132±83pmol/L, 150mg bid = 447±242pmol/L, 300mg bid = 808±330pmol/L; Figure 1). AZD9977 had no effect on blood pressure or heart rate and did not alter serum electrolyte levels, urinary Na+ excretion, log urinary Na+/K+ ratio (Figure 2), estimated GFR, or urine volumes when compared to placebo-treated subjects. Figure 1 and Figure 2 Conclusion These observations in humans are consistent with pre-clinical studies, demonstrating robust MR-receptor engagement without changes in serum K+ and renal electrolyte handling. These characteristics could potentially realise the therapeutic benefit of MR blockade with a low risk of hyperkalaemia. This hypothesis is currently being tested clinically in a head-to-head trial of AZD9977 versus spironolactone in patients with HF and impaired renal function (NCT03682497). Acknowledgement/Funding The study was Sponsored and funded by AstraZeneca