NRx Pharmaceuticals Investigational New Drug (IND) Application for NRX-100 (Ketamine) in the Treatment of Acute Suicidality

Frequently Asked Questions from Investors

Why did NRx advance its IND in ketamine to the point of seeking New Drug Approval?
When NRx (then NeuroRx) included stabilization with ketamine prior to use of NRX-101 in its Breakthrough Therapy protocol, we expected that others would develop an FDA-labeled form of ketamine for treating acute suicidality. Unexpectedly, nasal esketamine failed to show a compelling reduction in suicidal ideation (although it did demonstrate reduction of depression among suicidal patients) and the sponsor of esketamine chose not to pursue its use in patients with bipolar depression. In January 2023, the FDA advised NRx to seek a label for use of ketamine by submitting data from adequately-controlled trials. In Sept 2023 nasal racemic ketamine (i.e. R/S ketamine) failed to demonstrate a statistically-significant reduction in suicidal ideation. Unexpectedly, NRx was left in a position where it had the only active IND for the use of ketamine in treating acute suicidality.

Does NRx have any theories that might explain the above failures?
There is no question that systemic absorption of ketamine is far more variable when ketamine is delivered to the nose than when it is delivered intravenously. This lesson was learned in 2006 when Jazz Pharmaceuticals abandoned development of intranasal ketamine for treatment of chronic pain. Absorption of ketamine from a nasal spray is highly dependent upon the positioning of the nasal applicator and is well known to be influenced by nasal congestion and other patient factors. Moreover, the antidepressant/anti-suicidality effect of ketamine may depend upon a steady state blood level in the correct zone. Indeed, this is suggested by Fava’s NIH-supported dose ranging trial and other studies.

NRx has promised its shareholders to invest their funds in the development of NRX-101 to treat CNS disorders such as bipolar depression, chronic pain, and PTSD. Isn’t this a distraction from your mission?
Our commitment to life-threatening CNS disorders has not changed. By investing a small amount of exploratory capital in the laboratory work that we performed, we have unlocked a whole new market for our shareholders. At the same time, we have recruited development partners who are facilitating our ketamine development at minimal additional cost to our shareholders.

Ketamine is a very old drug. Why won’t you have immediate generic competition?
The formulation of ketamine used in anesthesia is antiquated and problematic. First of all, it requires a pH of 2.0 to maintain ketamine in solution. Indeed, this may in part explain the surprising results with intranasal ketamine. NRx, together with its partner Nephron Pharmaceuticals, has developed a proprietary, patentable formulation of ketamine that will be far closer to a physiologic pH (pH human body levels between 7.35 to 7.45 – in the absence of pathological states). Unlike oral drugs, where functional generic substitution is permitted, such substitution is forbidden for intravenous drugs without identical formulations. This will not prevent physicians from prescribing the old generic formulation. However, those who are not practicing within the walls of a hospital must order the old formulation from compounding pharmacies. FDA has issued two letters cautioning against this practice. Moreover, once there is a legally labelled form of IV ketamine on the market, it becomes illegal for a compounding pharmacy to dispense compounded ketamine in similar dosage and route of administration.

What IP protection do you expect for your ketamine?
We anticipate 20 years of patent protection for a new formulation of IV ketamine.

How large is the potential market for infused ketamine in the US?
The CDC has stated that 3.5 million Americans form a plan to kill themselves each year. Tragically, too many of them succeed. Today, ketamine is largely available only to those able to pay out of pocket and able to locate a treatment center. Many ketamine treatment centers refuse to treat suicidal patients because of the need to maintain overnight and weekend supervision. We believe that an FDA label for ketamine, together with strict safeguards around its use, will change that scenario.

Where will NRx focus next with infused ketamine?
You never know. Innovation is in our DNA. However, we recognize that intravenous infusion is challenging in the outpatient setting. We continue to seek alternatives that will provide steady-state drug delivery in a more convenient manner.