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Mechanism of Action & Combination Treatment of our Investigational Drugs*

*These drugs are not approved for the indications discussed below

NMDA regulates the speed of thoughts
Too little NMDA activity > Increased Ideation, hallucinations, psychosis
Too much NMDA activity > Reduced Ideation, depression, suicide

NRX-101’s proprietary dual-mechanism of action targets the NMDA and 5-HT2a receptors – two key receptors in the brain.

The NMDA receptor is a glutamate receptor found in nerve cells.  It is critical to the memory function as it controls signaling from neuron to neuron.  NMDA also directly regulates a calcium ion channel that controls the rate of ideation (formation of new ideas) in the brain.

D-cycloserine, one of the active ingredients in NRX-101, targets the NMDA receptor and modulates NMDA activity, potentially fostering a normal pace of thought generation. Multiple human studies have demonstrated that administration of D-cycloserine triggers an antidepressant effect. However, our research indicates that the treatment requires administration with an antipsychotic to counteract the psychomimetic side effects.

The 5-HT2a receptor is a G protein-coupled receptor and a member of the serotonin family. It is known for its role in mediating certain antipsychotic effects. Lurasidone, the other active ingredient in NRX-101, is a 5-HT2a antagonist that is currently approved as an antipsychotic, and for use in bipolar depression. Laboratory studies have shown that Lurasidone and other 5-HT2a antagonists have an unexpected synergistic effect with D-cycloserine, potentially enhancing the antidepressant effect while minimizing the potential psychomimetic (hallucinations) side effects. A phase 2 human study has shown results consistent with this finding.

NRX-101’s proprietary combination of D-cycloserine and Lurasidone is designed to be administered orally, daily for approximately six weeks following an initial, single infusion of NRX-100 (ketamine). The company believes that this therapeutic approach may offer an oral, outpatient treatment with the potential to significantly extend NRX-100’s (ketamine) antidepressant/anti-suicidal effect.

Combination Treatment

Scientific rationale supports the approach of combining an NMDA antagonist, such as D-cycloserine, with additional therapeutic mechanisms in the treatment of Bipolar Depression in patients with Acute Suicidal Ideation/Behavior (ASIB). This is crucial due to the fact that despite the substantial promise shown by D-cycloserine in the treatment of depression and schizophrenia, the treatment must be administered with an antipsychotic to counteract certain potential side effects.


5-HT2a Receptor Antagonist

One key potential combination target that has shown promise in counteracting the side effects of D-cycloserine is the 5-HT2a receptor, a G protein-coupled receptor and a member of the serotonin family.  It is known for its role in mediating certain antipsychotic drugs. Studies have demonstrated that deceased suicidal and other depressed patients have had more 5-HT2a receptors than normal patients, indicating that the increased presence of 5-HT2a receptors may play a role in depression.

Lurasidone (Latuda®), a 5-HT2a antagonist, is currently approved as an antipsychotic and for bipolar depression. However, in animal akathisia studies, it was discovered that lurasidone and other 5-HT2a antagonists have an unexpected synergistic effect with D-cycloserine, potentially enhancing the antidepressant effect while minimizing the potential psychomimetic side effects.

The synergistic effects of NMDA and 5-HT2a antagonists in the rat akathisia model are described in detail in several US and ex-US patent filings.  The combination of lurasidone (and other 5HT2a antagonists) and D-cycloserine led to a significant reduction in akathisia compared to control and to lurasidone alone.  Akathisia is defined as a state of agitation, distress, and restlessness that is an occasional side-effect of antipsychotic and antidepressant drugs.

The inclusion of ketamine, an FDA-approved anesthetic, in a combination treatment for acute suicidal crisis in bipolar depression is also supported by scientific research. Like D-cycloserine, ketamine works by targeting the NMDA receptor.  Clinical research has demonstrated that by blocking the NMDA channel, ketamine rapidly reduces depression and suicidality in people with bipolar disorder.

Despite these promising clinical findings, ketamine is not FDA-approved for the treatment of bipolar depression or the reduction of suicidality.  Ketamine’s antidepressant/anti-suicidal activity is short-lived. Treatment of bipolar depression in patients with ASIB would therefore require repeat infusions of ketamine. However, ketamine administration is associated with hallucinations and other psychomimetic side effects, and could require 1-2 weekly visits of the patient to a treatment center.


Investigational Sequential Drug Treatment Regimen

NRx Pharma believes that, if approved, its investigational, sequential treatment regimen consisting of single induction of NRX-100 (ketamine), followed by daily, oral NRX-101 (fixed-dose combination of D-cycloserine and lurasidone), may offer patients a rapid-onset antidepressant/anti-suicidal effect (NRX-100), potentially maintained by an oral, outpatient therapy (NRX-101).

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NRX-100/NRX-101

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Scientific Publications