Dear Colleagues and Investors,
In light of recent findings related to serotonin and its role in depression, investors have asked us to provide more specific information on the primary target addressed by D-cycloserine, a component of NRX-101. D-cycloserine is believed to decrease the activity of the brain’s NMDA receptor. The role of D-cycloserine was addressed in the recent CEO message to shareholders at the annual meeting held on July 18, 2022 and is addressed in greater detail in the Company’s 10K and investor presentations. Considerable attention in the press has been directed to the role of ketamine in treating depression and its role in stimulating growth of new connections between the brain cells associated with higher level thoughts. One of the two components of NRX-101, D-cycloserine inhibits the NMDA receptor in a manner similar to ketamine and importantly, is believed to have a more favorable side effect profile with less potential for addiction and neurotoxicity.
Investors wanting to learn more about current scientific thinking regarding the effects of NMDA-inhibiting drugs on the brain might wish to read the 2019 Scientific American article, “Behind the Buzz: How Ketamine Changes the Depressed Patient’s Brain,” and similar articles in the science press that attempt to explain this relatively new chemical mechanism for treating depression, PTSD, and other unmet medical needs.
NRx Pharmaceuticals completed a multicenter clinical trial, the Sequential Therapy for Treatment of Severe Bipolar Depression (STABIL-B) study in which participants presenting for emergency care with Severe Bipolar Depression and Acute Suicidal Ideation or Behavior (ASIB) were randomly allocated to an infusion of ketamine vs. placebo. Those who stabilized on ketamine (as defined by remission on both depression and suicidality) and who were discharged from emergency care were then offered a random assignment to NRX-101 (a fixed-dose combination of D-cycloserine and lurasidone) vs. lurasidone alone. Because of the life-threatening nature of ASIB, we and the U.S. Food and Drug Administration (FDA) agreed to use an active, standard of care comparator and not a placebo for the outpatient component of this trial. On the basis of these data, the FDA awarded Breakthrough Therapy Designation to NRX-101 for the treatment of Severe Bipolar Depression in patients with Acute Suicidal Ideation and Behavior (ASIB) after initial stabilization with ketamine or other effective therapy.
The preliminary findings of the study were presented at the American College of Neuropsychopharmacology as a peer-reviewed poster. The abstract (W134) was published in the journal Neuropsychopharmacology. Results of the STABIL-B trial are now being submitted for peer review as a full-length scientific article.
Subsequent to the completion of the STABIL-B study, NRx collaborated with scientists at Columbia University to explore whether biochemical changes in the brain that are triggered by administration of NRX-101 could be measured with Magnetic Resonance Spectroscopy, a technique that uses a High Strength Magnetic Resonance Imaging device to measure the level of specific molecules – in this case glutamate and glutamine levels – in the brain rather than simply creating images of the brain. Those scientists have previously demonstrated that ketamine, a well-known NMDA antagonist antidepressant, affects brain glutamate and glutamine levels in the brain (collectively known as Glx) in a manner that is correlated with decreased levels of depression (Milak et. al. 2020). The investigators demonstrated a statistically-significant correlation between reduced levels of brain glutamate and reduced levels of depression (r—0.83; P=0.04) and concluded these preliminary pilot results require replication but provide further support for a link between antidepressant effect and a decrease in glutamate by the NMDAR antagonist class of antidepressants.
Please note that “negative correlation” is a scientific term that correlates a decrease in one variable with a corresponding decrease in another variable and is not meant to imply a clinical value judgment. The Glx analysis was proposed in a biomarker Letter of Intent to the FDA Biomarker qualification program, based on which the FDA issued a Biomarker Letter of Support stating that “published and nonpublished data submitted by NeuroRx to FDA suggests that measurement of Glx has the potential to be developed as a pharmacodynamic biomarker…There is evidence that NMDA-blocking drugs may result in increased Glx, but this effect has not been observed in drugs targeting the serotonin pathway.”
Sources are linked and attached below.
Jonathan Javitt, MD, MPH
NRx Pharmaceuticals, Inc.
Link to Abstract W134:
Daniel Javitt*, Andrew Nierenberg, Sanjay Mathew, Richard Shelton, Jonathan Javitt, Robert Besthof, Rohini Chitra, John Carlos Diaz, Marisa Gorovitz
Columbia University, New York, New York, United States
Relationship of Brain Glutamate Response to D-Cycloserine and Lurasidone to Antidepressant Response in Bipolar Depression: A Pilot Study
Zhengchao Dong1,2, Michael F. Grunebaum1,2, Martin J. Lan1,2, Vashti Wagner 2, Tse-Hwei Choo1,3, Matthew S. Milak1,2, Tarek Sobeih4, J. John Mann1,2,5 and Joshua T. Kantrowitz 1,6,7*
1 Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY, United States, 2 Molecular Imaging and Neuropathology, New York State Psychiatric Institute, New York, NY, United States, 3 Mental Health Data Science, New York State Psychiatric Institute, New York, NY, United States, 4 Information Sciences, Nathan Kline Institute, Orangeburg, NY, United States, 5 Department of Radiology, College of Physicians and Surgeons, Columbia University, New York, NY, United States, 6 Psychotic Disorders, New York State Psychiatric Institute, New York, NY, United States, 7 Information Sciences, Nathan Kline Institute, Orangeburg, NY, United States
N-methyl-D-aspartate glutamate-receptor (NMDAR) antagonists such as ketamine have demonstrated efficacy in both major depressive disorder (MDD) and bipolar disorder depression (BP-D). We have previously reported that reduction in Glx (glutamate + glutamine) in the ventromedial prefrontal cortex/anterior cingulate cortex (vmPFC/ACC), measured by proton magnetic resonance spectroscopy (1H MRS) at 3T during a ketamine infusion, mediates the relationship of ketamine dose and blood level to improvement in depression. In the present study, we assessed the impact of D- cycloserine (DCS), an oral NMDAR antagonist combined with lurasidone in BP-D on both glutamate and Glx. Subjects with DSM-V BP-D-I/II and a Montgomery-Asberg Depression Rating Scale (MADRS) score>17, underwent up to three 1H MRS scans. During Scan 1, subjects were randomized to receive double-blind lurasidone 66mg or placebo. During Scan 2, all subjects received single-blind DCS 950mg + lurasidone 66mg, followed by 4 weeks of open label phase of DCS+lurasidone and an optional Scan 3. Five subjects received lurasidone alone and three subjects received placebo for Scan 1. Six subjects received DCS+lurasidone during Scan 2. There was no significant baseline or between treatment-group differences in acute depression improvement or glutamate response. In Scan 2, after a dose of DCS+lurasidone, peak change in glutamate correlated negatively with improvement from baseline MADRS (r = −0.83, p = 0.04). There were no unexpected adverse events. These preliminary pilot results require replication but provide further support for a link between antidepressant effect and a decrease in glutamate by the NMDAR antagonist class of antidepressants.
Keywords: N-methyl-D-aspartate, glutamate, MRS—1H nuclear magnetic resonance spectra, biomarker, bipolar depression, D-Cycloserine, lurasidone
Front. Psychiatry 12:653026.doi: 10.3389/fpsyt.2021.65
 Milak MS, Rashid R, Dong Z, et. al. Assessment of Relationship of Ketamine Dose With Magnetic ResonanceSpectroscopy of Glx and GABA Responses in Adults With Major Depression. A Randomized Clinical Trial.JAMA Network Open 2020;3(8):e2013211. doi:10.1001/jamanetworkopen.2020.13211
 Dong Z, Grunebaum MF, Lan MJ, et. al., Relationship of brain glutamate response to D-cycloserine and lurasidone to antidepressant response in bipolar depression: A pilot study. Frontiers in Psychiatry 2021;12 Article 653026