The actions of NP10679 are enhanced in conditions of slightly acidic pH, such as those in brain areas attacked by stroke. This attribute provides greater safety margins for NP10679 in stroke compared to other NMDA therapies that failed previously in the disorder. This feature is critical since those failures may be attributed, in part, to narrow safety margins limiting exposure of tested compounds.
NP10679 is neuroprotective in a preclinical model of stroke, and its potential therapeutic value in stroke is supported by a recent Phase 3 study demonstrating positive effects of a peptide inhibitor (NA-1) of the NMDA receptor (GluN2B). NP10679, however, has a number of potential advantages over NA-1 – most notably in the area of drug-drug interaction that enables it to retain activity in the presence of the standard of care, tissue plasminogen factor (TPA), for ischemic stroke. Furthermore, Phase 1 clinical studies of NP10679 have revealed an excellent half-life (~17 hours) and none of the side effects typically observed in NMDA receptor antagonists. These properties suggest a favorable profile for NP10679 for the treatment of stroke.
Subarachnoid Hemorrhage (SAH)
Treatment of patients following subarachnoid hemorrhage (SAH) caused by a ruptured aneurysm is another potential indication for NP10679 in the context of brain ischemia. Vasospasm occurring during the week following SAH in a substantial portion (~35%) of such patients produces ischemic damage. The efficacy of our pH-dependent GluN2B receptor antagonists has been established in an animal model of ischemic injury induced by SAH. NP10679 also demonstrated excellent drug-like properties in our Phase 1 trial that make it an attractive candidate for prophylactic treatment following SAH.
Severe Peri-Operative Pain
Decades of preclinical work reveal beneficial effects of NMDA receptor blockers for pain. Studies of animal models reveal that NMDA receptor activation contributes to acute expression of pain, as well as the development of persistent pain far outlasting the acute insult. While opiates are often the drugs of choice to treat pain, symptomatic relief is accompanied by the development of tolerance and, with time, dependence. Both create the potential for subsequent abuse and other down-stream negative consequences.
Ketamine, a pan-NMDA inhibitor, is effective in reducing opiate use in acute severe pain, but undesirable behavioral effects and unfavorable pharmacokinetics limit its usefulness. We believe NP10679 has the potential to replace ketamine as a treatment for peri-operative pain and provide a better tolerated therapy with improved drug-like properties.
Treatment of major depressive disorder unresponsive to antidepressant drugs is an important unmet medical need associated with increased risk of suicide. The FDA recently approved esketamine for treatment-resistant depression, the first novel class of antidepressants approved in decades. The seriousness of the disorder enabled approval of esketamine, a pan-NMDA blocker, despite negative side effects that include frequent, unsettling “out of body” experiences, which are also referred to as dissociative effects.
Clinical studies of GluN2B-specific NMDA blockers, however, have shown efficacy without the dissociative effects. With a similar lack of dissociative effects and favorable pharmacokinetics, NP10679 is an appealing candidate for treatment-resistant depression.