Safety, tolerability, and pharmacokinetics of oral Ketamir-2, a novel selective NMDA receptor antagonist: results of a first-in-human Phase 1 study
Itzchak Angel, Yoseph Caraco, Chana Sternberg, Maor Wanounou, Simha Blotnick, Waseem Mujahed, Erez Aminov
September 29, 2026 DOI: 10.22541/authorea.15009655/v1 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized, double-blind, placebo-controlled Phase 1 trial |
|---|---|
| Sample size | 57 |
| Population | Healthy adults |
| Interventions | Ketamir-2 placebo |
| Dose | single ascending doses 50-600 mg; once-daily 150-600 mg for 5 days |
| Duration | Single doses or once-daily dosing for 5 days |
| Measures | Bowdle VAS, KSET, C-SSRS |
| Key findings | Oral Ketamir-2 was well tolerated at single doses up to 600 mg and daily doses up to 600 mg for 5 days, with adverse events in 37.2% of active versus 50.0% of placebo participants and no serious, Grade 3 or higher, psychotomimetic, abuse-related, or suicidality signals. The authors report that 300 and 600 mg exposures meet or exceed concentrations associated with efficacy in preclinical chemotherapy-induced peripheral neuropathy models, supporting progression to Phase 2a. |
Abstract
Background: Ketamine, a high-affinity NMDA receptor antagonist, is used off-label for neuropathic pain but has limited clinical utility due to poor oral bioavailability, narrow therapeutic window, and dissociative effects. Ketamir-2 is a novel low-affinity, phencyclidine-site-selective NMDA antagonist (IC50 ~100 µM versus ketamine's low single-digit µM), designed to retain analgesic activity while reducing dissociative liability.
Objective: Evaluate the safety, tolerability, and pharmacokinetics of oral Ketamir-2 in a first-in-human Phase 1 study (MIRA-001).
Methods: Randomized, double-blind, placebo-controlled study in 57 healthy adults. Participants received single ascending doses (50–600 mg) or once-daily doses (150–600 mg for 5 days) with 3:1 randomization to Ketamir-2 or placebo. Safety assessments included treatment-emergent adverse events, vital signs, electrocardiography, and psychotomimetic/suicidality screening (Bowdle VAS, KSET, C-SSRS). Plasma and urine pharmacokinetics were characterized for Ketamir-2 and its major metabolite, Norketamir.
Results: Ketamir-2 was well tolerated across all doses. Adverse events occurred in 37.2% of active and 50.0% of placebo participants with no dose-dependent trend. No serious adverse events, Grade ≥3 events, or meaningful psychotomimetic, abuse-related, or suicidality signals were observed. Ketamir-2 demonstrated rapid absorption (Tmax 1.0–2.5 hours), dose-dependent exposure, and no clinically meaningful accumulation over 5 days. Norketamir showed dose-proportional exposure and longer half-life (6.4–8.6 versus 2.5–7.2 hours).
Conclusions: Oral Ketamir-2 demonstrated favorable safety, tolerability, and pharmacokinetic profiles at doses up to 600 mg. Exposures at 300 and 600 mg meet or exceed concentrations associated with efficacy in preclinical chemotherapy-induced peripheral neuropathy models, supporting progression to Phase 2a.