ABSTRACT Respiratory depression from drug overdose, if untreated, can cause serious life-threatening complications, including respiratory arrest and death. Substance-induced respiratory depression from overdose of opioids, other central nervous system depressants such as sedatives and alcohol, and increasingly polysubstance abuse is a leading cause of mortality and has risen in parallel with the marked increase in narcotics consumption. ENA-001 is a therapeutic agent which stimulates ventilation – without reversing analgesic effects, or precipitating withdrawal – for treatment of patients with respiratory and central nervous system (CNS) depression due to opioid or polysubstance overdose in a hospital or community setting. It is a novel compound that is expected to be classified as a New Chemical Entity. The primary molecular mechanism underlying the ventilatory stimulant effects of ENA-001 appears to be functional inhibition of BK channels of the carotid bodies, thereby acting as a hypoxia-mimetic. ENA-001 has been administered to humans during four clinical studies, with a fifth underway. Following two ascending dose studies to establish a dosing range for IV infusion, a continuous infusion of ENA- 001 was shown to stimulate respiration in the presence of a strong opioid (alfentanil) while preserving the analgesic effects of alfentanil. ENA-001 maintained oxygen saturation and ETCO2 within normal range (P < 0.05, P < 0.01, respectively vs placebo) with greater MV than placebo (p < 0.01). The next stage in development is to characterize the efficacy of intramuscular (IM) and intravenous (IV) bolus injections (rapid dosing) as suitable routes of administration for suspected overdose in the clinic or community setting. In this proposal, Enalare will study the PK/PD and efficacy of IV bolus and IM ENA-001 in a population of healthy volunteers. Phase 1 is PK/PD studies using Model Informed Drug Development (MIDD) to identify initial IM and IV bolus dosing for Aim 2. The MIDD process will use existing PK and PD data from the multiple IV continuous infusion studies in humans, along with data from preclinical IM and IV bolus delivery models such as the recently completed IM bioavailability study and ongoing IM bioequivalence study, to determine dosing targets to achieve rapid attainment of effective plasma drug exposure, thus optimal therapeutic effects (efficacy), from bolus dosing. Phase 2 will be a Single Ascending Dose Study of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of ENA-001 administered as IM and IV bolus injections. The study protocol is an 8-period ascending, repeated, single dose, safety and tolerability study comparing the effects of ENA-001 with placebo in 2 panels of screened healthy volunteers. Study periods will be conducted for IM (4-periods) and IV (4-periods) bolus injections, and will be randomized, double-blinded, and placebo-controlled. The information gained from this proposal will be used to define subsequent studies of efficacy in simulations of opioid-induced respiratory depression and will give ample information on the efficacy of IM and IV ENA-001 bolus injections on ventilation and mimics, as much as possible, real-life (i.e., street) conditions.

NARRATIVE Respiratory depression caused by narcotics such as fentanyl and other substance/polysubstance overdoses (OD), is a leading cause of mortality and has risen in parallel with the marked increase in narcotics consumption in the US. ENA-001 is a novel compound that has been shown in past trials to stimulate breathing in humans with opioid-induced respiratory depression. This study establishes the effects of intramuscular and intravenous rapid injections of ENA-001 in healthy volunteers to support practical routes of administration for community OD settings.