NRx Pharmaceuticals Investigational New Drug (IND) Application for NRX-101 in the Treatment of Complicated Urinary Tract Infections

Frequently Asked Questions from Investors

Why is NRx venturing outside of CNS disease into an area where the Company has limited expertise?
In a sense, we did not seek this indication in Complicated Urinary Tract Infection (cUTI), it sought us.  When we set out to develop D-cycloserine (DCS) and Lurasidone in 2014 to treat life-threatening CNS disorders, we knew DCS was an antibiotic, but assumed its time had passed in favor of the well-known and commonly-used generation of antibiotics.  However, over the ensuing ten years, resistant pathogens that were once a problem in hospitalized patients with multiple morbidities have become a public health crisis in otherwise healthy people. When we decided to test NRX-101 against the pathogens that most frequently hospitalize and kill Americans, we were actually surprised that it had retained potency over 70 years of use.

NRx has promised its shareholders to invest their funds in the treatment of 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 leveraged the investment we already made to develop and manufacture NRX-101 at no additional cost to our shareholders.

It seems surprising that DCS should be useful for treating brain disorders and also as an antibiotic
Nature can be surprising in that way and this is far from the first time. Actually, the first serotonin-targeted antidepressants (the mono-amine oxidase inhibitors) were also derived from antibiotics.  In the case of DCS, the molecule is structurally similar to alanine – an amino acid that is essential to the bacterial cell wall. When DCS is incorporated into the bacterial cell wall instead of alanine, the cell wall becomes permeable and the bacterium dies.  It happens that DCS also binds to a specific site on the NMDA receptor because of its structural similarly to glycine, a different amino acid.

How does NRx plan to finance this new area of endeavor?
As we have commented previously, we envision the use of NRX-101 as an antibiotic to fall outside our core mission.  Accordingly, we invite discussion with potential partners and investors whose mission encompasses the infectious disease space. As we have planned for our initiative related to intravenous ketamine, we anticipate establishing a spinoff company that will initially be owned by NRx Pharmaceuticals and by current shareholders of NRx Pharmaceuticals through a share dividend and a royalty trust.  While NRx and its shareholders may be diluted over time, current NRx shareholders will have the option to further invest in this endeavor through the spinout structure, should they choose to do so.

Why has the FDA been so cooperative in allowing you to enter an area where you have no prior expertise?
First of all, our work in this area has been guided by Dr. Michael Manyak, an internationally-recognized Professor of Urology, Immunology, and Tropical Medicine who was previously the Global Medical Director for the urology franchise of GlaxoSmithKline. Our regulatory and manufacturing leads, Drs. Gordin and Panicucci have extensive prior experience in this area and our Chief Business Officer, Matt Duffy began his career at Pfizer in the Infectious Disease area.  Thus, we serendipitously assembled a team for our CNS initiative that had deep roots in infectious disease and whose expertise is apparent to FDA.

From the FDA’s perspective, the Agency recognized the emerging public health crisis related to antibiotic resistance more than 20 years ago and enlisted the support of Congress through the Qualified Infectious Disease Program more than 10 years ago.  Unfortunately, the FDA’s predictions have come to pass in that 20% of Urinary Tract Infections are now classified as Complicated UTI and that percentage is increasing.  The work we did to demonstrate FDA-compliant manufacturing of NRX-101 was on file at FDA when we submitted the cUTI IND and the laboratory work done at Charles River Laboratories was performed to the Good Laboratory Practices (GLP) standards of the FDA.

DCS is a very old drug.  Why won’t you have immediate generic competition?
We are not developing DCS to treat cUTI, we are developing NRX-101, a combination of DCS and lurasidone, where we hold Composition of Matter patent protection. Although DCS is a potent antibiotic, the same NMDA properties that underlie its effectiveness in treating depression, chronic pain, and PTSD, are known to cause mild hallucinations, which is a well-known and expected side effect of NMDA inhibition. In the course of developing NRX-101, we demonstrated that lurasidone and other 5-HT2a antagonist drugs can block those CNS side-effects, potentially making DCS a newly-useful antibiotic.

Aside from the patent protection afforded to us, the Qualified Infectious Disease Product (QIDP) program provides sponsors with five years of FDA market exclusivity over and above the market exclusivity afforded by achieving a new label indication under the FDA 505.b.2 pathway.  Thus, if NRX-101 is successful as an antibiotic, it will enjoy initial protection from generic competition for some time. Contrary to popular belief, DCS is not a generic drug in the US.  It is an innovative drug that no longer enjoys patent protection. While a generic entrant could file an ANDA against Seromycin (the marketed version of DCS), access to the Seromycin label would not give a generic entrant the ability to market for treatment of cUTI and would leave patients with the well-known CNS side effects of DCS.

Do you have plans for what to do when your IP protections runs out?
We are, in fact, working on a follow-on version of DCS that will have longer half-life in the bloodstream and urinary tract, perhaps enabling once-a-day dosing. This would also extend our patent life.

What will NRx think of next?
You never know. Innovation is in our DNA.