NA-1

NA-1, designated nerinetide in clinical development and also known by its research name Tat-NR2B9c, is a synthetic, cell-permeant eicosapeptide composed of the 11-residue cell-membrane transduction domain of the human immunodeficiency virus type 1 (HIV-1) Tat protein fused to the nine C-terminal residues of the GluN2B (NR2B) subunit of the N-methyl-D-aspartate (NMDA) glutamate receptor. The compound was designed to inhibit the protein-protein interaction between postsynaptic density protein 95 (PSD-95) and the GluN2B subunit, thereby uncoupling NMDA receptor activation from the downstream excitotoxic signaling cascade that drives neuronal injury in ischemic stroke and related conditions, without blocking normal NMDA receptor ion channel function or calcium influx. The foundational discovery was reported by Aarts et al. in Science in 2002, demonstrating that perturbation of the NMDA receptor-PSD-95 interaction reduced excitotoxic neuronal death in vitro and focal ischemic brain damage in rats. Subsequent preclinical work extended the neuroprotective efficacy to nonhuman primates, where Cook et al. (2012) demonstrated greater than 50 percent reduction in stroke volume in cynomolgus macaques subjected to transient middle cerebral artery occlusion and treated with Tat-NR2B9c at 2.6 mg/kg intravenous. The compound was advanced into clinical development by NoNO Inc., a Toronto-based biotechnology company founded by the originating investigator Michael Tymianski. The Phase 2 ENACT trial (Hill et al. 2012, Lancet Neurology) in 185 patients undergoing endovascular aneurysm repair demonstrated safety and a significant reduction in the number of procedure-related ischemic infarcts on diffusion-weighted magnetic resonance imaging. The Phase 3 ESCAPE-NA1 trial (Hill et al. 2020, Lancet) in 1105 patients with acute ischemic stroke undergoing endovascular thrombectomy did not meet its primary endpoint of improved 90-day modified Rankin Scale outcomes in the overall population, but a pre-specified subgroup analysis revealed a clinically meaningful 9.5 percent absolute benefit in patients who did not receive concurrent alteplase, with subsequent mechanistic work demonstrating that plasmin generated by alteplase degrades the nerinetide peptide in vivo. The Phase 3 ESCAPE-NEXT trial (2025, Lancet) in 850 patients undergoing thrombectomy without prior thrombolysis did not confirm the subgroup benefit. The Phase 2 FRONTIER trial (2025, Lancet) in 532 patients with suspected acute cerebral ischemia treated by paramedics in the prehospital setting demonstrated safety and feasibility but did not meet primary efficacy endpoints. Pharmacokinetically, nerinetide exhibits a plasma half-life of approximately 5 to 10 minutes following intravenous bolus administration, consistent with rapid peptide clearance by endogenous proteases and tissue distribution. The clinical dose is 2.6 mg/kg intravenous (maximum 270 mg) administered as a single infusion. The safety profile across all clinical trials has been favorable, with adverse event rates comparable to placebo; the only notable signal is a small excess of serious hypotension events immediately following infusion. This monograph reviews the chemistry, structure, and synthesis of nerinetide; the PSD-95 inhibitory mechanism in molecular detail; the pharmacokinetic profile; the preclinical neuroprotection evidence across species; the complete clinical trial record; sourcing and quality considerations; reconstitution and handling; stack-interaction considerations; the adverse event and safety record; and a comparative assessment of five PSD-95 pathway neuroprotective candidates against nerinetide on five competency standards.