September 20, 2023
Dear Shareholders,Following our presentation at the HC Wainwright Investor’s Conference and our recent press release announcing a data collaboration giving NRx access and rights to patient level data from the landmark KETIS study (KETIS BMJ), shareholders have reached out with questions regarding our plans for developing and marketing Ketamine. We will answer these questions as time and data allow:
1. What is the relevance of the French KETIS study to our clinical development plans in Bipolar Disorder?
Although our primary objective is to develop NRX-101 as a safe, oral, home use medicine to treat suicidal bipolar depression, we believe the ketamine data from France to be highly relevant for two reasons:
First, our initial Breakthrough Therapy Designation identifies the use of NRX-101 in Acute Suicidality in Bipolar Depression following initial stabilization with ketamine or other approved therapy. While we are focusing our efforts on the larger market of patients who are suicidal but do not require hospitalization at the time of treatment, we remain committed to helping those who are suicidal to the point where they require hospitalization as well. Those are the patients who demonstrated substantial benefit in the recently-published STABIL-B trial and whose data the FDA reviewed in its award of Breakthrough Therapy Designation. In January, the FDA advised us that if we want to be able to label our drug for this subgroup, a New Drug Application for ketamine would be required. In our view, the findings of the French KETIS study represent landmark findings that deserve the FDA’s full consideration. The findings, in our view, confirm the earlier clinical trial conducted by Grunebaum and co-workers at Columbia University in New York, in which ketamine demonstrated a similarly significant reduction in both suicidality and depression, compared to placebo, among patients with both bipolar and major depression. 
Secondly, we believe the KETIS study demonstrates that ketamine, an NMDA antagonist drug, is far more effective in reducing suicidality among patients with bipolar depression than among those with major depressive disorder. As you know from the literature and from our many communications, while bipolar depression represents perhaps a 10% subgroup of those with depression, patients with bipolar depression are far more likely to take their lives and traditional antidepressants are not shown to be of benefit in this aspect of the disease. Indeed, SSRI antidepressants are known to provoke suicide in people with bipolar depression.
The results of the KETIS study are dramatic. The Odds Ratio associated with ketamine vs. placebo in the subgroup with bipolar depression was 14, compared to the far smaller effect of ketamine (Odds Ratio of 1.3) in those with major depressive disorder and those with other forms of depression (Odds Ratio of 1.3 and 3.7 respectively). Thus, Prof. Abbar and his colleagues may have demonstrated for the first time that bipolar depression responds particularly well to NMDA-antagonist drugs compared to major depressive disorder. We caught a hint of this in the STABIL-B trial, where we saw a mean difference of 7.7 points on the Montgomery Asberg Depression Rating Scale (MADRS) between NRX-101 and lurasidone, whereas most successful antidepressants in major depressive disorder demonstrate a MADRS differences of about half that magnitude, generally when compared to placebo. Naturally, the small size of the STABIL—B trial demands caution in extrapolating from these findings.
Thus, the French KETIS trial gives us the first evidence – to our knowledge – that NMDA antagonist drugs such as ketamine and D-cycloserine may be more effective in treating bipolar depression than in treating major depressive disorder and provide us with additional enthusiasm for pursuing the development on anti-NMDA drugs for the treatment of these patients whose only approved therapy today remains electroconvulsive therapy.
It’s important to recognize that a trial of this complexity could not have been performed by a private company, certainly not by a small biotech. These findings, collected at substantial cost to the French government and its institutions amplify the earlier findings from two NIH-sponsored trials in the US.,
2. What basis do we have to believe that D-cycloserine may have a ketamine-like effect
We have no basis to expect that D-cycloserine (DCS) will work as quickly as ketamine to reduce depression or suicidality in bipolar depression. Ketamine is a highly potent direct-acting NMDA channel blocker. However, it is also well known to be highly addictive, hallucinogenic and neurotoxic. Further, it can cause acute blood pressure elevation, cannot be given by mouth, and must be administered in a clinic setting under direct supervision of a physician, with the patient restricted from driving for 12 hours. DCS, on the other hand, is not neurotoxic, not addictive, and when formulated in NRX-101 with lurasidone, has not been shown to cause hallucinations. From a simplistic perspective, ketamine is like putting a cork in the NMDA channel to block the flow of ions, while DCS is more like turning a valve to slow the flow in a pipe.
We do, however, have two interesting sets of data that compare the effectiveness of ketamine to those of DCS that are shared in the public domain but which we have not compared in a communication such as this.
The first evidence comes from the various laboratory studies that are used to validate potential antidepressant effects. There are extensive data in laboratory tests in which DCS has a ketamine-like effect. A more intriguing finding, however, comes from recently published data in which Magnetic Resonance Spectroscopy is used to measure glutamate levels in the brains of patients with depression who are treated with ketamine and DCS. MR Spectroscopy is a method by which an MRI machine is used to measure levels of specific chemicals in the human brain. Previously, we demonstrated to the FDA that DCS alters levels of glutamate in the brain, which is why we were awarded a biomarker letter of support for NRX-101. The effect of NRX-101 on brain glutamate levels was shown to be comparable to the effect of ketamine on brain glutamate levels. However, this does not demonstrate efficacy of NRX-101; efficacy can be demonstrated in clinical trials such as our ongoing Phase 2b/3 trial. That trial is now enrolling its last 14 patients. However, the intriguing glutamate finding, together with KETIS data gives us additional reason to hope that NMDA antagonist drugs, such as DCS, may produce a ketamine-like effect without the side effects of ketamine.
3. What is the patient need for ketamine from NRx?
We believe there are various improvements in the delivery/process/access to IV ketamine that may provide benefits to patients and caregivers. These likely entail legal and regulatory filings as well as inventions that may be suitable for patent filing. However, development of racemic intravenous ketamine for treatment of acute suicidality in bipolar depression is not our primary business focus.
Our primary focus is the development of oral NRX-101 for treatment of bipolar depression, chronic pain, and in the future, PTSD. We do, however, believe that these data on the use of ketamine to achieve rapid stabilization will be of supportive value in applying NRX-101 to treatment of the most acute patients and of important mechanistic value in continuing to demonstrate that NMDA antagonist drugs are key to the treatment of depression and suicidality in bipolar depression.
As discussed, ketamine alone, NRX-100, is a potentially important treatment for Suicidal Bipolar Depression; it is also a potentially enabling therapy for use of NRX-101 in this group of people. Currently, approved forms of ketamine are not allowed for use in Suicidal Bipolar Depression. While this may not be a broad commercial opportunity, we strongly believe that some form of ketamine must be available for this Orphan subset of patients in acute need.
As always, thank you for your continued support of NRx as we pursue our mission of Bringing Hope to Life.
 Grunebaum MF, Ellis SP, Keilp JG, Moitra VK, Cooper TB, Marver JE, Burke AK, Milak MS, Sublette ME, Oquendo MA, Mann JJ. Ketamine versus midazolam in bipolar depression with suicidal thoughts: A pilot midazolam-controlled randomized clinical trial. Bipolar Disord. 2017 May;19(3):176-183. doi: 10.1111/bdi.12487. Epub 2017 Apr 28. PMID: 28452409.
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 Dong Z, Grunebaum MF, Lan MJ, Wagner V, Choo TH, Milak MS, Sobeih T, Mann JJ, Kantrowitz JT. Relationship of Brain Glutamate Response to D-Cycloserine and Lurasidone to Antidepressant Response in Bipolar Depression: A Pilot Study. Front Psychiatry. 2021 Jun 2;12:653026. doi: 10.3389/fpsyt.2021.653026. PMID: 34149476; PMCID: PMC8208505.
 Milak MS, Rashid R, Dong Z, Kegeles LS, Grunebaum MF, Ogden RT, Lin X, Mulhern ST, Suckow RF, Cooper TB, Keilp JG, Mao X, Shungu DC, Mann JJ. Assessment of Relationship of Ketamine Dose With Magnetic Resonance Spectroscopy of Glx and GABA Responses in Adults With Major Depression: A Randomized Clinical Trial. JAMA Netw Open. 2020 Aug 3;3(8):e2013211. doi: 10.1001/jamanetworkopen.2020.13211. PMID: 32785636; PMCID: PMC7424409.