(1149) ENA-001, a BK-Channel Blocker, Stimulates Breathing Without Analeptic Side Effects

Introduction: The use of anesthetics may result in depression of the hypoxic ventilatory response (HVR). Since there are no receptor-specific antagonists for most anesthetics, there is the need for agnostic respiratory stimulants, that increase respiratory drive irrespective of its cause. ENA-001 stimulates ventilation by acting at carotid BKCa2+ channels and is being developed as such agnostic therapy for the treatment of respiratory depression. It has been previously reported that ENA-001 increased minute ventilation (MV) in healthy subjects and reduces arterial pCO2 in alfentanil-induced. respiratory depression.

Methods: In this randomized cross-over trial, 14 male and female healthy volunteers were randomized to receive placebo, low dose (6.7 µg/kg/min) and high dose (18.3 µg/kg/min) ENA-001 on 3 separate occasions. Isohypercapnic HVR (MV increase in L/min per % SpO2 decrease) and was measured on each occasion during a fixed sequence of placebo, followed by low- and high-dose propofol infusion, targeting plasma concentrations of 600 and 1200 ng/mL, respectively. During infusion, Bispectral Index (BIS) and cardiovascular parameters were continuously measured.

Results: ENA-001 high dose resulted in a significant treatment effect versus placebo on AHR (estimate of the difference: 0.575 L/min/% (95% confidence interval (CI) 0.407-0.744), p< 0.0001), whereas ENA 001 low dose versus placebo was not significantly different (0.144 (95% CI: -0.024 - 0.312), p=0.0897). Propofol inhibited the AHR but concurrent administration of a high dose of ENA-001 caused the AHR to remain comparable to pre-propofol values. There was no difference in BIS between treatments and no clinically meaningful difference on cardiovascular response was observed after treatment with ENA-001 versus placebo.

Conclusions: The data from this study showed that treatment with high dose ENA-001 significantly increased the AHR compared to placebo, both with and without co-administration of clinically relevant plasma concentrations of propofol. ENA-001 did not impact propofol-induced sedation while also maintaining a favorable safety profile. These finding support that ENA-001 is a respiratory stimulant with potential for use in clinical practice, inducing stimulation of MV without antagonizing other drugs.