Glutamate is the primary excitatory neurotransmitter in the central nervous system and binds to postsynaptic glutamate receptors, including N-methyl-D-aspartate (NMDA) receptors. NMDA receptors play a crucial role in synaptic plasticity, which is important for learning and memory. However, in the setting of ischemia (stroke) or brain injury, overactivation of these receptors can lead to excitotoxicity, a process that damages or kills neurons. Although excitotoxicity represents an important therapeutic target to improve outcomes in patients suffering a traumatic or ischemic brain injury, prior clinical trials have been limited by the on-target adverse effects of non-selective NMDA antagonists. NP10679 selectively inhibits the GluN2B subunit of NMDA receptor, but has no effect on GluN2A, GluN2C, or GluN2D subunits. This selectivity is beneficial because it provides effective neuroprotection and avoids the side effects associated with non-selective inhibition of all NMDA receptors regardless of subunit composition. Furthermore, extrasynaptic NMDA receptors that contain the GluN2B subunit may be involved in processes that can lead to excitotoxicity under pathological conditions, and selectively targeting this subset of receptors would mitigate those potentially harmful effects.
The unique pH-sensitive nature of NP10679 means that it becomes more active under acidic conditions, which is relevant in the context of brain injury or disease because localized regions undergoing injury develop local tissue acidosis. Thus, NP10679 can potentially be used to prevent or minimize neuronal damage caused by abnormally high concentrations of extracellular glutamate that arise in injured tissue. This is important in conditions such as stroke, traumatic brain injury, subarachnoid hemorrhage, and certain neurodegenerative diseases, in which extracellular fluid becomes acidic due to anaerobic metabolism and failure to remove CO2. The resulting NMDA receptor-mediated excitotoxicity is a major mechanism contributing to secondary neuronal damage. The selective and pH-sensitive characteristics of NP10679 make it a promising candidate for treating various neurological conditions because it is designed to be active in regions of injury without causing strong NMDA receptor inhibition (and thus side effects) in adjacent healthy brain tissue. Ongoing research is exploring its efficacy and safety in different disease contexts, such as the treatment of acute brain injuries, epilepsy, and chronic neurodegenerative diseases, as well as prophylactic use in at-risk populations, such as individuals who suffered subarachnoid hemorrhage, an initial stroke, or patients undergoing cardiac bypass surgery. As with any drug, the safety and efficacy of NP10679 is of primary concern. Clinical trials and rigorous testing are necessary to determine its suitability for use in humans, including understanding any potential side effects or interactions with other medications.
In a new study published in the peer-reviewed journal Clinical Pharmacology in Drug Development by Drs. Robert Zaczek, Ray Dingledine, George Koszalka, Stephen Traynelis and led by Professor Daniel Laskowitz from Duke University, the authors conducted a Phase 1 clinical trial of NP10679 that implemented a comprehensive and methodical approach to evaluate this new neuroprotective agent’s pharmacokinetic profile, safety, and tolerability.
The authors divided the trial into two phases: Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD). Each phase was designed to assess different aspects of the drug’s profile in healthy volunteers. For the SAD Phase, their objective was to assess the safety, tolerability, and pharmacokinetics of a single dose of NP10679 delivered by intravenous infusion. This was a randomized, double-blind, placebo-controlled single-dose, dose-escalation trial. The study included six escalating dosing cohorts, with dosages ranging from 5 mg to 200 mg. Sentinel Dosing Adaptive Design was used, where the first two subjects (1 active, 1 placebo) were dosed and observed for 48 hours before dosing the remaining subjects in the cohort. The authors reviewed safety/tolerability and pharmacokinetic data before escalating to the next dose level.
The second (MAD) phase aimed to evaluate the safety and pharmacokinetics of NP10679 on repeated dosing until a steady state blood level was reached. Similar to the SAD study, this phase was also randomized, double-blind, and placebo-controlled. The doses included 25 mg, 50 mg, and 100 mg per day. Subjects received single 75 mL IV infusions of NP10679 or placebo over 30 minutes for five consecutive days. Subjects were observed in the clinic through 48 hours post-dose on the last day, with follow-up visits thereafter. The authors assessed treatment-emergent adverse events (TEAEs), physical examinations, infusion site examinations, laboratory findings, neuropsychiatric assessments, vital signs, and subject-reported tolerability. They also monitored neurobehavioral effects associated with NMDA antagonism, using standardized assessments, including the Hamilton Depression Rating Scale, Mini-Mental Status Examination, as well as assessments of anxiety or dissociative states. The authors coded all adverse events and tabulated them by dose level, system organ class, and preferred term. The data revealed that the most common treatment-emergent adverse event was mild somnolence, particularly on day 1 at higher dose levels, that was readily reversed by, for example, simply speaking the subject’s name. Other TEAEs such as dizziness, headache, and tremor were noted but deemed not to impact subject safety. To estimate the pharmacokinetic profile, blood samples were drawn at various intervals post-dose in both the SAD and MAD studies and liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays were used to quantify NP10679 in plasma samples. Descriptive pharmacokinetic parameters were calculated based on plasma concentrations of NP10679 using noncompartmental analysis.
In conclusion, the outcomes of the first NP10679 trial in humans are significant for several reasons. Firstly, the drug’s safety profile was remarkably favorable. Adverse effects were minimal, with only mild somnolence observed at higher doses. This finding is important, considering the well-known side effects associated with NMDA receptor antagonists, such as cognitive dysfunction and dissociative phenomena. Moreover, the pharmacokinetic data revealed a promising half-life that supports once-daily dosing, which is a crucial factor for enhancing patient compliance and therapeutic effectiveness. Notably, the study hints at NP10679’s potential as a prophylactic agent, particularly for conditions like aneurysmal subarachnoid hemorrhage (aSAH), where it could offer neuroprotection during the vulnerable period following an aneurysm rupture. Beyond its immediate clinical applications, the trial’s findings have broader implications. The success of NP10679 underscores the feasibility of developing targeted neuroprotective therapies with minimized systemic side effects. Its pH-dependent mechanism of action opens new avenues for drug development, suggesting that similar strategies could be employed in other neurological disorders. This represents an innovative approach in the field of neuroprotection, offering a targeted and potentially safer method to mitigate the harmful effects of excitotoxicity in various neurological disorders. Further research and clinical trials on NP10679 will be essential to fully understand its potential and limitations.
Zaczek R, Traynelis SF, Dingledine R, Koszalka GW, Laskowitz DT. Phase 1 Clinical Results for NP10679, a pH-sensitive GluN2B-selective N-methyl-d-aspartate Receptor Inhibitor. Clin Pharmacol Drug Dev. 2023;12(7):706-717. doi: 10.1002/cpdd.1217.