Abstract 1238: Ketamir-2, a novel oral ketamine analogue for chemotherapy-induced peripheral neuropathy.

Abstract Background: Ketamir-2 is a next-generation ketamine analogue designed to improve oral bioavailability and safety relative to existing ketamine-based pain therapies. It acts as a low-affinity N-methyl-D-aspartate (NMDA) receptor antagonist with selective binding to the phencyclidine (PCP) site, a mechanism believed to underlie its analgesic potential while reducing dissociative effects. Methods and Results: In preclinical studies, oral administration of Ketamir-2 (pamoate salt) produced significant analgesic activity across established rodent models of neuropathic pain, including the Chung spinal nerve ligation model in rats and the paclitaxel-induced mechanical allodynia model in mice. In both models, Ketamir-2 demonstrated superior efficacy compared with oral ketamine and the standard neuropathic pain agents pregabalin and gabapentin, which served as positive controls. Pharmacological profiling confirmed robust oral bioavailability and lack of P-glycoprotein (P-gp) substrate activity, supporting its efficient penetration across the blood-brain barrier—an essential property for central nervous system (CNS) therapeutics. Notably, Ketamir-2 exhibited a favorable safety profile with no evidence of dissociative or psychedelic side effects typically observed with ketamine. Clinical Development: Results from the first-in-human (FIH) study will be presented. This randomized, double-blind, placebo-controlled Phase 1 trial, conducted at the Clinical Pharmacology Unit of Hadassah Medical Center, evaluated the safety, tolerability, and pharmacokinetics of Ketamir-2 in healthy adult volunteers. A total of 56 participants were enrolled across single-ascending-dose (SAD) and multiple-ascending-dose (MAD) cohorts. Conclusions: These findings support Ketamir-2 as a promising oral NMDA-receptor modulator for the treatment of chemotherapy-induced peripheral neuropathy (CIPN) and other neuropathic pain disorders, offering a differentiated profile combining efficacy, safety, and oral convenience. Citation Format: Itzchak Angel, Erez caraco Yoseph, Aminov. Ketamir-2, a novel oral ketamine analogue for chemotherapy-induced peripheral neuropathy abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1238.