105: ENA-001, a Novel BK-channel Blocker, Enhances Hypoxic Ventilatory Sensitivity and Alleviates Propofol-induced Respiratory Effects in Healthy Volunteers

Statement of Purpose, Innovation or Hypothesis: During procedural sedation, the risk of respiratory depression and airway obstruction rises due to drug interference with ventilatory control. Predicting the onset, duration, or severity of respiratory events is challenging due to various factors such as individual drug sensitivity, pulmonary and central nervous system dysfunction, underlying diseases, and concomitant medications. Therefore, the appropriate use and management of medications during procedural sedation is crucial to ensure patient safety and optimize recovery outcomes including the adoption of agnostic respiratory stimulants. ENA-001 is being developed as an agnostic therapy for treating respiratory depression in procedural patients. ENA-001 is a fast acting and short duration intravenous agent that acts by partially blocking BKCa²⁺ (Maxi K channels) in the carotid body to stimulate respiration. Previous reports have demonstrated the ability of ENA-001 to stimulate ventilation in healthy subjects and significantly counteract ventilation suppression by the opioid alfentanil.

Description of Methods & Materials: In this randomized, double-blinded, placebo-controlled, three-period crossover phase 1b study, the effect of two intravenous doses of ENA-001 on propofol-induced respiratory depression was investigated in 14 healthy volunteers. Each period involved intravenous infusion of ENA-001 or placebo for 270 minutes (ENA-001 low dose: 33.3 µg.kg^-1.min^-1 for 10 min followed by a continuous infusion of 6.7 µg.kg^-1.min^-1 for 260 min; ENA-001 high dose: 33.3 µg.kg^-1.min^-1 for 20 min followed by a continuous infusion of 18.3 µg.kg⁻¹.min⁻¹ for 250 min). During each period, the loading dose of ENA-001 or placebo was followed by three blocks in which participants received intravenous placebo or propofol in a predetermined order (open label): placebo – propofol low dose – propofol high dose (targeting plasma concentration of 600 and 1200 ng/mL, respectively). During the infusions, Bispectral Index (BIS) and cardiovascular parameters were continuously monitored. The primary endpoint was the acute hypoxic ventilatory response (AHR), assessed during each propofol block at normal and high end-tidal CO₂ concentration. Safety parameters were included as secondary endpoints.

Data & Results: ENA-001 high dose significantly increased AHR compared to placebo (the lower dose did not show a significant difference). Propofol inhibited AHR, with an even greater effect on the hypercapnic response. ENA-001 high dose blunted the propofol effect, maintaining AHR comparable to pre-propofol values. There were no differences in BIS between treatment groups, and no serious adverse events occurred during the study. The most common adverse event attributed to ENA-001 was mild infusion site pain. Blood pressure, heart rate, and cardiac index increased during hypoxic measurements, but did not significantly differ versus placebo. Changes in clinical laboratory values and ECG were similar across treatments.

Interpretation, Conclusion or Significance: These findings suggest that ENA-001 high dose significantly increases AHR while maintaining a favorable safety profile, even when co-administered with clinically relevant plasma concentrations of propofol. ENA-001 demonstrates potential as a respiratory stimulant in clinical settings, effectively enhancing ventilation without inducing antagonistic effects with other drugs.

Disclosures: This study was funded by Enalare Therapeutics Inc.  Drs. Dahan, Gould, Pergolizzi, and Colucci received consultancy fees from
Enalare Therapeutics Inc. Dr. Miller is an employee of Enalare Therapeutics Inc. The other authors declare no competing interests.

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