THE DISCOVERY AND CLINICAL DEVELOPMENT OF (2R,6R)- HYDROXYNORKETAMINE FOR DEPRESSION AND PAIN

This symposium will present the translational development of (2R,6R)hydroxynorketamine (2R6R), a ketamine metabolite, which is currently in human phase II trials for treatment resistant depression, obsessive compulsive disorder, and neuropathic pain. The session brings together the teams responsible for the discovery, IND-enabling work, and early-phase clinical studies across two therapeutic indications, providing attendees with an end-to-end view of a novel psychopharmacologic agent advancing through the development pipeline. Dr. Todd Gould from the University of Maryland School of Medicine will describe the preclinical discovery of 2R6R’s efficacy in depression models, including mechanistic studies, pharmacology, and translational biomarkers supporting its advancement into development. He will highlight how understanding stereoisomer-specific activity and non– NMDA receptor mechanisms informed selection of 2R6R as a drug candidate with a potentially improved safety and tolerability profile relative to ketamine. Dr. Craig Thomas from the NIH National Center for Advancing Translational Sciences will detail the INDenabling program, including synthesis and formulation, PK/PD modeling, and preclinical safety findings that guided first-in-human dosing and risk-mitigation strategies. Dr. Carlos Zarate (NIH National Institute of Mental Health) will present key findings from the first-inhuman Phase I study, summarizing safety, tolerability, PK parameters, and early biomarker signals relevant to antidepressant activity, as well as the design, rationale, and progress of the treatment resistant depression Phase II trial including clinical endpoints, biomarker strategy, and anticipated next steps. Dr. Robert McCarthy, Rush University Medical Center, will present data demonstrating analgesic activity in preclinical pain models and describe the design and status of the Phase II study evaluating analgesic efficacy, durability of response, and comparative outcomes for a single infusion of 2R6R versus ketamine or saline in individuals with neuropathic extremity pain. The discussant (Dr. Dawn Ionescu, Johnson and Johnson Innovative Medicine) will integrate themes across presentations, emphasizing the translational decision-making that enabled forward progression from mechanistic discovery to human studies across two indications. The panel will address scientific, regulatory, and methodological challenges unique to developing a stereoisomeric metabolite as a therapeutic agent, including the complexities of advancing an academic and NIH intramural-led program in the absence of traditional industry sponsorship and the associated implications for scalability, regulatory interaction, and trial design. Attendees will gain an integrated understanding of how mechanistic neuroscience, biomarker-driven strategy, and rigorous clinical methodology can facilitate development of novel psychopharmacologic agents. This symposium will also underscore how coordinated collaboration among academic investigators, federal research institutes, and clinical trial centers can efficiently advance innovative therapeutics addressing substantial unmet need in both mood disorders and chronic pain. This session will be of broad interest to investigators focused on drug development in mood disorders, pain and their comorbidity as well as translational neuroscience more broadly.

Learning Objective 1: Describe the mechanistic, translational, and preclinical evidence supporting the development of (2R,6R)-hydroxynorketamine as a therapeutic candidate for depression and pain.

Learning Objective 2: Identify key clinical, regulatory, and methodological considerations in advancing (2R,6R)-hydroxynorketamine from Phase I to Phase II trials across multiple indications, including biomarker and trial-design strategies.

References

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