CLINICAL DEVELOPMENT OF (2R,6R)-HYDROXYNORKETAMINE: ONGOING TRIALS IN TRD AND OCD AND PHASE 1 SAFETY, TOLERABILITY, AND PK/PD RESULTS IN HEALTHY VOLUNTEERS

(R,S)-Ketamine is a dissociative anesthetic with analgesic and antidepressant effects, but its dissociative adverse effects and misuse liability limit broader use despite promising efficacy. (2R,6R)-hydroxynorketamine (RR‑HNK), a ketamine metabolite, lacks anesthetic and dissociative properties in preclinical models while retaining antidepressant and analgesic activity. We report the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of RR‑HNK from a Phase 1 study in healthy volunteers. The trial comprised 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) design, each administered as 40‑minute intravenous infusions to mirror common ketamine dosing for depression. RR‑HNK was well tolerated across all dose levels, with no serious adverse events. Measures of dissociation and sedation showed no anesthetic or dissociative effects within the examined range. PK analyses in both SAD and MAD parts demonstrated dose‑proportional increases in exposure. As a PD measure—motivated by preclinical findings and ketamine’s known effects on gamma‑band oscillations—quantitative EEG showed increases in gamma power in some participants at lower to mid doses. Cerebrospinal fluid sampling confirmed central nervous system exposure. RR‑HNK is being investigated for treatment‑resistant depression (TRD), pain, and obsessive‑compulsive disorder (OCD). Ongoing studies include: (1) an OCD trial with 1:1:1 randomization to 0.25 mg/kg RR‑HNK, 0.5 mg/kg RR‑HNK, or placebo (IV saline), with change in OCD severity measured by the Yale–Brown Obsessive‑Compulsive Scale (Y‑BOCS); and (2) a single‑site, randomized, double‑blind, placebo‑controlled, crossover study in TRD evaluating two weeks of IV RR‑HNK (0.25–2.0 mg/kg), an enhancer of synaptic glutamate release. Exploratory biomarkers include gamma oscillatory power and other spectral metrics with MEG, resting‑state and task‑based functional connectivity with fMRI, and prefrontal glutamate and other metabolites measured using 7T ^1H‑MRS. These Phase 1 findings and ongoing trials support further evaluation of RR‑HNK as a non‑dissociative candidate therapy for TRD, pain, and OCD.

References

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