Maryland Pao

(R,S)‐Ketamine (ketamine) is a dissociative anesthetic that also possesses analgesic and antidepressant activity. Undesirable dissociative side effects and misuse potential limit expanded use of ketamine in several mental health disorders despite promising clinical activity and intensifying medical need. (2R,6R)‐Hydroxynorketamine (RR‐HNK) is a metabolite of ketamine that lacks anesthetic and dissociative activity but maintains antidepressant and analgesic activity in multiple preclinical models. To enable future assessments in selected human indications, we report the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of RR‐HNK in a Phase 1 study in healthy volunteers (NCT04711005). A six‐level single‐ascending dose (SAD) (0.1–4 mg/kg) and a two‐level multiple ascending dose (MAD) (1 and 2 mg/kg) study was performed using a 40‐minute IV administration emulating the common practice for ketamine administration for depression. Safety assessments showed RR‐HNK possessed a minimal adverse event profile and no serious adverse events at all doses examined. Evaluations of dissociation and sedation demonstrated that RR‐HNK did not possess anesthetic or dissociative characteristics in the doses examined. RR‐HNK PK parameters were measured in both the SAD and MAD studies and exhibited dose‐proportional increases in exposure. Quantitative electroencephalography (EEG) measurements collected as a PD parameter based on preclinical findings and ketamine's established effect on gamma‐power oscillations demonstrated increases of gamma power in some participants at the lower/mid‐range doses examined. Cerebrospinal fluid examination confirmed RR‐HNK exposure within the central nervous system (CNS). Collectively, these data demonstrate RR‐HNK is well tolerated with an acceptable PK profile and promising PD outcomes to support the progression into Phase 2.