FDA Clearance of IND for Ketamir-2, Novel Oral NMDA Receptor Antagonist for Neuropathic Pain

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MIRA Pharmaceuticals recently announced that the US Food and Drug Administration (FDA) cleared its Investigational New Drug (IND) application for Ketamir-2, a novel oral NMDA receptor antagonist for the treatment of neuropathic pain.¹

This IND submission consisted of a comprehensive data package of preclinical pharmacology, safety, and toxicology studies, including a pivotal neurotoxicity study in Sprague-Dawley rats which showed no evidence of brain lesions or adverse CNS effects.² This marks a key distinction from traditional ketamine, which has been associated with NMDA-linked neurotoxicity and the formation of Olney lesions in similar preclinical models. These findings were reinforced by multiple validated neuropathic pain models, in which Ketamir-2 consistently demonstrated potent analgesic effects and superior efficacy to gabapentin and pregabalin, with a reversal of pain sensitivity observed in select models. The IND also incorporated phase 1 readiness data and manufacturing documentation.

The single ascending dose portion of an international phase 1 trial at Hadassah Medical Center in Jerusalem is nearing its completion, and dose escalation is progressing smoothly. MIRA is now preparing to initiate the multiple ascending dose portion of the study, which will assess the safety, tolerability, and pharmacokinetics of repeated doses over several days. These data will help inform optimal dosing strategies.

Additionally, MIRA is moving toward a phase 2a study in diabetic peripheral neuropathy, with the goal of initiating its first US-based efficacy trial in late 2025. MIRA is also in discussions with leading US institutions to explore (1) a trial in chemotherapy-induced peripheral neuropathy, and (2) advancing the formulation development for topical Ketamir-2 for localized pain.

"This IND approval validates the strength of our preclinical data and the differentiated pharmacology of Ketamir-2," said Erez Aminov, the chairman and CEO of MIRA. "We are executing and advancing with precision and speed, and we believe Ketamir-2 may represent one of the most promising nonopioid, noncontrolled neuropathic pain treatments in development today."

Ketamir-2 has consistently demonstrated robust efficacy and safety across a range of preclinical studies, including:

• Preclinical findings showed that 300 mg/kg of Ketamir-2 achieved 60% greater efficacy over neuropathic pain treatment gabapentin in reducing chemotherapy-induced pain in just 9 days of treatment.³
• In a validated diabetic neuropathy model, investigators induced type 2 diabetes in rats using a high-fat diet and a low dose of streptozotocin, which resulted in hyperglycemia and neuropathic symptoms. By week 8, most diabetic rats exhibited sensory hypersensitivity. Ketamir-2 significantly reduced pain sensitivity, and some animals even returned to prediabetic baseline sensitivity after receiving Ketamir-2.⁴
• In head-to-head studies using the chronic constriction injury model in rats, Ketamir-2 showed 112% and 70% greater pain relief compared with FDA-approved treatments gabapentin and pregabalin, respectively.⁵
• A comprehensive neurotoxicity study confirmed absence of Olney lesions.⁶
• Data indicate that Ketamir-2 crosses the blood brain barrier with longer exposure times and greater levels of nor-Ketamir present in the brain. Additionally, following oral administration, Ketamir-2 is characterized by rapid absorption, a short half-life. and high clearance. Other select findings confirm the molecule's clean pharmacological profile and position Ketamir-2 as a differentiated and scalable alternative to existing treatments.⁷
• Ketamir-2 demonstrated antidepressant and anxiolytic-like effects in validated behavioral models, with no dissociative or psychotomimetic adverse effects.⁷

"Ketamir-2 has demonstrated consistent, potent efficacy across preclinical pain models with a clean safety profile and broad therapeutic potential. The IND approval is a testament to our scientific rigor and may pave the way for meaningful clinical translation," said Itzchak Angel, PhD, the chief scientific advisor at MIRA.

References

1. MIRA Pharmaceuticals announces FDA clearance of IND for Ketamir-2, enabling U.S. clinical trials in neuropathic pain. News release. July 29, 2025. Accessed July 30, 2025. https://www.morningstar.com/news/accesswire/1053868msn/mira-pharmaceuticals-announces-fda-clearance-of-ind-for-ketamir-2-enabling-us-clinical-trials-in-neuropathic-pain

2. MIRA Pharmaceuticals lead program Ketamir-2 shows no brain toxicity in FDA-mandated study. News release. May 6, 2025. Accessed July 30, 2025. https://finance.yahoo.com/news/exclusive-mira-pharmaceuticals-lead-program-111643050.html

3. MIRA Pharmaceuticals' Ketamir-2 shows 60% greater efficacy than FDA-approved gabapentin in reversing chemotherapy-induced neuropathic pain. News release. October 28, 2024. Accessed July 30, 2025. https://firstwordpharma.com/story/5907173

4. MIRA Pharmaceuticals announces positive results for Ketamir-2 in diabetic neuropathy animal model, reinforcing confidence ahead of phase I completion. News release. April 16, 2025. Accessed July 30, 2025. https://mirapharmaceuticals.com/mira-pharmaceuticals-announces-positive-results-for-ketamir-2-in-diabetic-neuropathy-animal-model-reinforcing-confidence-ahead-of-phase-i-completion/

5. MIRA Pharmaceuticals announces Ketamir-2 outperforms current FDA-approved neuropathic pain treatments, gabapentin and pregabalin, in preclinical study. News release. October 21, 2024. Accessed July 30, 2025. https://mirapharmaceuticals.com/mira-pharmaceuticals-announces-ketamir-2-outperforms-current-fda-approved-neuropathic-pain-treatments-gabapentin-and-pregabalin-in-preclinical-study/

6. MIRA Pharmaceuticals Reports No Brain Toxicity in FDA-Required Study of Ketamir-2, Confirming Absence of Ketamine-Linked Neurotoxicity. News release. May 7, 2025. Accessed July 30, 2025. https://www.biospace.com/press-releases/mira-pharmaceuticals-reports-no-brain-toxicity-in-fda-required-study-of-ketamir-2-confirming-absence-of-ketamine-linked-neurotoxicity

7. Angel I, Perelroizen R, Deffains W, et al. KETAMIR-2, a new molecular entity and novel ketamine analog. Front Pharmacol. 2025;16:1606976.