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 abuseis 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 precipitatingwithdrawal - for treatment of patients with respiratory and central nervous system (CNS) depression due toopioid or polysubstance overdose in a hospital or community setting. It is a novel compound that is expected tobe classified as a New Chemical Entity. The primary molecular mechanism underlying the ventilatory stimulanteffects of ENA-001 appears to be functional inhibition of BK channels of the carotid bodies, thereby acting as ahypoxia-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 theanalgesic 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 developmentis to characterize the efficacy of intramuscular (IM) and intravenous (IV) bolus injections (rapid dosing) as suitableroutes of administration for suspected overdose in the clinic or community setting. In this proposal, Enalare willstudy the PK/PD and efficacy of IV bolus and IM ENA-001 in a population of healthy volunteers. Phase 1 isPK/PD studies using Model Informed Drug Development (MIDD) to identify initial IM and IV bolus dosing for Aim2. The MIDD process will use existing PK and PD data from the multiple IV continuous infusion studies inhumans, along with data from preclinical IM and IV bolus delivery models such as the recently completed IMbioavailability study and ongoing IM bioequivalence study, to determine dosing targets to achieve rapidattainment 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 andPharmacodynamics of ENA-001 administered as IM and IV bolus injections. The study protocol is an 8-periodascending, repeated, single dose, safety and tolerability study comparing the effects of ENA-001 with placeboin 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 fromthis proposal will be used to define subsequent studies of efficacy in simulations of opioid-induced respiratorydepression and will give ample information on the efficacy of IM and IV ENA-001 bolus injections on ventilationand mimics, as much as possible, real-life (i.e., street) conditions.
Public Health Relevance Statement: 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.
Project Terms: