Safety and tolerability of the M2 muscarinic acetylcholine receptor modulator BAY 2413555 in heart failure with reduced ejection fraction in the REMOTE-HF study.

BAY 2413555 is a novel selective and reversible positive allosteric modulator of the type 2 muscarinic acetylcholine (M2) receptor, aimed at enhancing parasympathetic signaling and restoring cardiac autonomic balance for the treatment of heart failure (HF). This study tested the safety, tolerability and pharmacokinetics of this novel therapeutic option. REMOTE-HF was a multicenter, double-blind, randomized, placebo-controlled, phase Ib dose-titration study with two active arms. Study participants had an established diagnosis of HF with NYHA Class I-III and LVEF ≤ 45%. Patients were required to have an implanted cardiac defibrillator (ICD) or cardiac resynchronization therapy (CRT) device because of the potential for bradycardia or AV conduction delay, which may be induced by BAY 2413555. The study period included a screening and run-in period, followed by a treatment period of over 28 days, consisting of two parts, A and B, comprising 14 days each. Participants were randomized into 1 of 3 arms: a placebo arm and two BAY 2413555 arms-one receiving 1.25 mg in both Part A and Part B (BAY 1.25 mg-1.25 mg) and the other receiving 1.25 mg in Part A followed by 5 mg in Part B (BAY 1.25 mg-5 mg). The primary safety endpoint was the number of participants with treatment-emergent adverse events (TEAEs). Secondary endpoints included number of participants with high degree AV block or symptomatic pauses/ bradycardia and changes from baseline in resting heart rate after 2 and 4 weeks of dosing with BAY 2413555. Changes from baseline in heart rate recovery (HRR) at 1 and 2 min after exercise testing and chronotropic reserve (CR) were also assessed. Of the anticipated 129 participants, 22 participants were randomized: 7 to placebo, 8 to BAY 1.25 mg-1.25 mg, and 7 to BAY 1.25 mg-5 mg. The study was terminated early based on new and unexpected preclinical findings from a chronic animal toxicology study in monkeys in which evidence of increased vascular inflammation was observed, leading to a no longer favorable risk-benefit balance for the intended long-term (i.e., life-long) treatment of heart failure patients. Comparable adverse events were not encountered in REMOTE-HF. Overall, until the termination of the study, BAY 2413555 was safe and well tolerated, with no deaths or TEAEs leading to discontinuation, and no symptomatic bradycardia or AV blocks observed. There was a larger change in the mean HRR at 60 s in the pooled BAY 2413555 treatment arms in Part A (1.25 mg) compared to the placebo (+ 7.3 vs. -6.7 bpm), indicating enhanced cardiac parasympathetic activity. Administration of 1.25 mg and 5 mg BAY 2413555 was safe and well tolerated in both active treatment arms, with no concerning safety findings observed. However, due to the limited number of subjects resulting from early termination, the results should be considered with caution and viewed as exploratory. There were promising signs of target engagement, providing grounds for further exploration of the mechanism.