What changed in this filing

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Item 1. Business

2024-03-29 compared with 2023-03-31 · 518 added, 349 removed, 667 unchanged (57% of the section changed)

Company Overview

NRx is a clinical-stage pharmaceutical company which develops, through its wholly-owned operating subsidiary, NeuroRx, Inc., (“NeuroRx”), novel therapeutics for the treatment of central nervous system disorders.

Our strategy is to apply innovative science to known molecules in the pursuit of therapies for high unmet needs, including lethal conditions.

The company’s patent estate contains broad disclosure of the synergistic combination of NMDA and 5-HT2A antagonist drugs in the treatment of mental health disorders and chronic pain.

The Company’s foundation product, NRX-101 (D-cycloserine/lurasidone), is being studied initially for the treatment of bipolar depression in patients with suicidality, has been awarded Fast Track designation, Breakthrough Therapy designation, a Special Protocol Agreement (SPA), and a Biomarker Letter of Support by the U.S.

Food and Drug Administration (the “FDA”).

To the Company’s knowledge, NRX-101 is the only oral antidepressant demonstrated to reduce suicidal ideation in a phase 2 trial.

Company Overview and History

NRx is a clinical-stage bio-pharmaceutical company which develops and will distribute, through its wholly-owned operating subsidiaries, NeuroRx, Inc., (“NeuroRx”) and HOPE Therapeutics, Inc.

(“HOPE”), novel therapeutics for the treatment of central nervous system disorders including suicidal depression, chronic pain, and PTSD.

NeuroRx is organized as a traditional Research and Development (“R&D”) company, whereas HOPE is organized as a Specialty Pharmaceutical (SpecPharma) company intended to distribute ketamine and other therapeutic options to clinics that serve patients with suicidal depression and PTSD.

The 2023 fiscal year was one of extraordinary growth and transition for NRx.

During the year the Company restructured its management to overcome challenges in capital formation, clinical trial enrollment, and corporate growth, in a manner that resulted in demonstrable milestones for 2023 and a company that we believe to be poised for growth in 2024.

Those milestones achieved in 2023 and through the date of this filing include:

Recruitment of a new management team under the leadership of Jonathan Javitt, MD, MPH (the Company’s Founder and Chairman) and Stephen Willard, JD, (CEO and Director), comprised of individuals with demonstrated success in the design, recruitment, and analysis of clinical-stage drug development, together with demonstrated commercial success in the marketing and sales of commercial stage pharmaceuticals.

This management team includes a new Chief Financial Officer, Chief Business Officer, Director of Clinical Research, Head of Regulatory Affairs, Head of Scientific Affairs, and a new Chief Medical Lead for urology.

Establishment of a drug development partnership with Alvogen, Inc., a $4 billion US-based pharmaceutical company and Lotus Pharmaceutical Company, LTD (1975.TW), an Asia Pacific-based pharmaceutical company to jointly develop NRX-101 for the treatment of suicidal bipolar depression, while leaving NRx in a position to continue innovative drug development of its pharmaceutical assets for other indications.

The partnership provides for up to an aggregate of $330 million in commercial stage milestone payments together with a double-digit royalty on net sales worldwide.

Publication of the world’s first clinical trial (the STABIL-B trial) to demonstrate sustained remission from acute suicidality and depression in patients with Bipolar Disorder, using NRX-100 (ketamine) for induction of remission and NRX-101 (D-cycloserine/lurasidone) for maintenance of that remission.

Results of this trial were the basis for FDA’s award of Breakthrough Therapy Designation.

Completion of patient data collection and data lock in the first clinical trial to study patients with suicidal bipolar depression treated in the outpatient setting under the leadership of Prof.

Andrew Nierenberg of Harvard/Mass General Hospital with no unexpected Serious Adverse Events.

The category of suicidal patients recruited in this trial have previously been excluded from the clinical trials of all known oral antidepressants.

Top line data are expected in April 2024.

Replacement of the Company’s traditional study site-based approaches to clinical trial recruitment with an internet/AI-based nationally-focused clinical trial recruitment strategy, in partnership with 1-N-Nealth, Inc., a digital marketing organization.

This approach resulted in a 300% increase in successful clinical trial enrollment in 2023 compared to 2022.

Achievement of >94% rater concordance through conclusion of the trial, a measure that substantially exceeds current industry standards.

Removal of the Company’s solid dose (for oral medications) manufacturing platform from Shanghai with re-establishment of solid dose manufacturing in partnership with Alcami, Inc.

(North Carolina, USA).

Submission and successful review of the NRX-101 FDA manufacturing file (i.e.

“Module 3” of a New Drug Application) and completion of a Type C Chemical Manufacturing Controls (“CMC”) meeting with FDA for NRX-101.

Company now has more than 1 million oral doses manufactured to commercial standards in its warehouse and is expecting five years of room temperature shelf stability.

Establishment of a sterile products drug development and manufacturing partnership with Nephron Pharmaceuticals, Inc.

(West Columbia, SC), an FDA-inspected facility.

Under this partnership NRx is both manufacturing ketamine in a novel abuse- and diversion-resistant presentation and developing new forms of ketamine designed for improved tolerability and clinical effectiveness based on prior inventions patented by the Company’s founder (US 5494901).

The Company has now manufactured its first commercial batch of ketamine in a novel diversion-resistant packaging presentation and is expecting at least two years of room temperature shelf stability.

Completion (through March 2024) of capital formation initiatives that achieved greater than 50% reduction in the corporate indebtedness and raised $9.2 million in new capital during FY 2023 with $7.8 million of additions to working capital during Q1 2024 to support the Company’s drug development initiatives, while rotating the shareholder base away from technically-oriented hedge funds and towards growth-oriented investors and corporate partners.

Improvement in negative Earnings per Share to ($0.40) in FY 2023 vs ($0.60) in prior 12 month period.

Management projects positive cash flow by year-end 2024 via partnerships and HOPE Therapeutics activities.

Implementation of a clinical trial quality control system for psychiatry trials designed to identify data quality problems and noncompliant (and potentially fraudulent) study patients at clinical trial sites.

Demonstration of 94% concordance between clinical trial endpoints as measured at study sites compared to measurement of those same endpoints by the Company’s central rating team under the leadership of veteran psychologist/psychometricians from the University of Pennsylvania.

Expansion of the Company’s patent portfolio and regulatory licenses to include the use of NRX-101 to treat Chronic Pain, approval of an Investigational New Drug application (“Study May Proceed”) from the US Food and Drug Administration (“FDA”), and licensure of US Patent 8,653,120 for use of D-Cycloserine to treat Chronic Pain together with the recruitment of its inventor, Prof.

Vania Apkarian of Northwestern University as a consultant to the Company.

Activation of the Company’s previously-dormant drug development activities related to ketamine (NRX-100), based on FDA feedback.

Establishment of data-sharing partnerships with a French government hospital consortium and with Columbia University (New York, NY) to license patient-level data from two clinical trials demonstrating safety and efficacy of ketamine for treating acute suicidal depression in support of a New Drug Application to the FDA.

Formation of HOPE Therapeutics, a Specialty Pharmaceutical company that aims to develop and market both ketamine and related digital therapeutics to extend and augment the effect of ketamine in treating suicidal depression, a condition for which the only currently approved therapy is hospitalizations and electroshock therapy.

Identification of NRX-101, the company’s lead drug for CNS disorders as a potent antibiotic for treatment of Complicated UTI and Pyelonephritis, with demonstration of in-vitro (i.e.

laboratory effectiveness) against antibiotic-resistant urinary tract pathogens resulting in FDA award of Qualified Infectious Disease Product and Fast Track designations by the FDA together with Priority Review status for this indication.

Partnership with the Foundation FondaMental (Paris, FR) and its Founder/CEO, Prof.

Marion Leboyer to develop the first disease-modifying drug to treat schizophrenia and autism.

Six scientific publications:

two papers documenting the preclinical safety of NRX-101, namely that NRX-101 does not cause neurotoxicity 1 nor does it lead to self-administration 2 , NRX-101 shows antimicrobial activity against uropathogens that cause complicated urinary tract infection (cUTI) 3 , a position paper on NRX-101 in the treatment of chronic pain 4 , the development and testing of a psychometric assessment monitoring system to improve concordance in psychiatric clinical trials 5 , and the Phase 2 STABIL-B clinical trial results.

Continued active prosecution of 16 filed patent applications and 48 issued patents around the world providing broad disclosure of the synergistic combination of NMDA and 5-HT 2A antagonist drugs in the treatment of mental health disorders and chronic pain.

NRX-101 is covered by four families of U.S.

and foreign patents, including a composition of matter patent (U.S.

and foreign patents, including a

composition of matter patent (U.S.

10,583,138 and foreign counterparts).

Suicidal Bipolar Depression was chosen as an initial target for NRX-101 because of the well-defined population and extraordinary unmet medical need associated with this condition.

However, non-clinical and clinical evidence suggests that DCS-based medicines may have broad use in the treatment of Post-traumatic Stress Disorder (PTSD) and Chronic Pain, in addition to their use in treatment of depression.

These indications collectively affect more than 50 million Americans.

Although DCS has been known for more than 70 years as an anti-infective, its propensity to cause psychedelic effects, together with challenges in maintaining drug stability, limited its use clinical use and by the year 2000, DCS was rarely used in the United States.

NRx has licensed U.S.

Patent 8,653,120 for use of D-Cycloserine to treat Chronic Pain as an expansion of that portfolio .

HOPE has received term sheets for more than $60 million in funding from new investors upon public listing and is expected to be spun out as a separate company to be owned by NRx, current NRx shareholders, and new investors upon completion of final audit and financial statements.

IND for NRX-101 in the treatment of Complicated Urinary Tract Infection (cUTI) is based on in vitro data just accepted for peer-reviewed publication in Antibiotics, an MDPI journal.

On the basis of these findings, FDA granted Qualified Infectious Disease Product (QIDP), Fast Track and Priority Review designations NRx is seeking a clinical phase partner for this multi-hundred million dollar indication.

Elected nationally recognized attorney in highly regulated industries, and healthcare specialist, Janet Rehnquist, Esq., to the Company’s Board of Directors.

Management has taken action to restore Nasdaq listing compliance and seeking to combat illegal naked shorting of NRx securities.

The Company has two lead compounds today, NRX-100, a proprietary presentation of ketamine and NRX-101, a patented fixed-dose combination of D-cycloserine and lurasidone.

Both products have Fast Track designation from the U.S.

Food and Drug Administration (“FDA”) for the treatment of suicidal bipolar depression.

NRX-101 additionally has Breakthrough Therapy Designation and a Biomarker Letter of Support from the FDA for this purpose.

To the Company’s knowledge, NRX-101 is the only oral antidepressant demonstrated to reduce suicidal ideation in a phase 2 trial.

For mechanistic reasons unrelated to its central nervous system N-methyl-D-aspartate (“CNS NMDA”) antagonist properties, NRX-101 interferes with cell wall formation in certain bacteria, rendering it a potent antibiotic and is demonstrated to kill certain treatment-resistant urinary tract bacteria.

Accordingly, NRX-101 has been awarded Qualified Infectious Disease Product Designation and Fast Track Designation by the FDA to treat Complicated Urinary Tract Infection and Pyelonephritis.

Our strategy is to apply innovative science to known molecules in the pursuit of therapies for high unmet needs, including lethal conditions (NeuroRx) and to distribute ketamine and ancillary therapies to qualified clinics and practitioners who treat patients with suicidal depression (HOPE).

The Company has announced plans to spin off HOPE to a freestanding company, half of which will be owned by the Company and half by individual shareholders.

NeuroRx was founded in 2015 by Professors Jonathan Javitt, MD, MPH and Daniel Javitt, PhD, MD, as a privately-funded R&D company targeting psychiatry drug development and attracted sufficient capital to enter phase 2b/3 research in 2016.

Over the subsequent three years it formulated and manufactured clinical supplies of NRX-101, initiated and completed the STABIL-B trial and established the first Special Protocol Agreement issued by the FDA Division of Psychiatry Products to conduct a confirmatory trial of NRX-101 following induction with NRX-100 in hospital Emergency Department patients with acutely suicidal bipolar depression.

That trial was initiated in November 2019 and suspended in February 2020 because of the COVID pandemic lockdown.

In March 2020 NeuroRx was asked to undertake clinical drug development of intravenous Aviptadil, a synthetic form of human Vasoactive Intestinal Peptide (VIP), by Relief Therapeutics, AG (Relief, Switzerland:

In December 2020, NeuroRx was approached by Big Rock Partners Acquisition Corporation, a special purpose acquisition company (“BRPA”) (Nasdaq:BRPA) about a potential business combination.

On May 24, 2021, BRPA consummated the Agreement and Plan of Merger (as amended, the “Merger Agreement”) with NeuroRx, and Big Rock Merger Corp., a Delaware corporation and wholly owned, direct subsidiary of BRPA (“Merger Sub”).

Pursuant to the Merger Agreement, on May 24, 2021 (the “Closing Date”), which has been accounted for as a reverse recapitalization, Merger Sub was merged with and into NeuroRx, with NeuroRx surviving the merger (the “Merger” and, together with the other transactions contemplated by the Merger Agreement, the “Business Combination”).

On the Closing Date, BRPA changed its name to NRX Pharmaceuticals, Inc.

(“NRx Pharmaceuticals” or the “Company”).

The Company’s ticker symbol was changed to “NRXP.”

The Company formulated Aviptadil (later named Zyesami ® ) for human administration and achieved FDA clearance to initiate the first human trial for treatment of COVID-19 Respiratory Failure in 10 weeks from project inception to first

patient treated.

A company-sponsored randomized, double-blind clinical trial of Aviptadil vs.

placebo demonstrated a 50% reduction in mortality compared to placebo among patients on ventilators for COVID-19 together with dramatic reductions in inflammatory markers (cytokines) and improvement in chest x-ray findings.

These results caused Zyesami to be selected from among 5,000 candidate drugs as the only investigational compound tested in the ACTIV-3 Critical Care arm of the NIH nationwide program to test novel drugs for COVID-19.

The Company additionally formed a partnership with the Israel Institute for Biological Research (IIBR) to test a novel COVID vaccine (BriLife ® ), which NRx committed to test in clinical trials to be conducted in the Caucasus region.

Unfortunately, IIBR did not succeed in manufacturing BriLife to the Good Manufacturing Practices (GMP) standards required by FDA, the European Medicines Authority (EMA) and other strict regulators, preventing the clinical initiation of the BriLife project.

The COVID lockdown ended in March 2022 and the Company’s Board unanimously voted to return NRx’s focus to CNS drug development and to recruit a new Chief Executive Officer with legal and business skills that would complement the scientific strength of the Company’s Founder, Chairman, and Chief Scientist.

Subsequently, in June 2022, the NIH trial announced futility in its attempt to replicate the survival benefit reported for Aviptadil in patients on ventilators for COVID-19 and subsequently disclosed its failure to fully treat 30% of those randomized to Aviptadil.

The trial could not be restarted because it was unrecruitable in the aftermath of the pandemic.

In December 2022, the Company agreed to return all Aviptadil assets to Relief in exchange for a commitment by Relief to use commercially-reasonable efforts to develop Aviptadil and to pay NRx more than $30 million in royalties and milestones from its future success, if any.

In July 2022, the Company recruited Mr.

Stephen Willard, JD, a Presidentially-commissioned member of the U.S.

National Science Board as CEO and a member of the Company’s Board of Directors, with Dr.

Javitt continuing in his leadership role Chief Scientist.

In December 2023, the Company’s reorganized Board of Directors re-elected Dr.

Javitt as its Chairman.

At the same time, the Company announced its plan to form HOPE Therapeutics as a specialty pharmaceutical company to develop a clinical market for ketamine and other treatments for suicidal depression.

Recent Developments

February 2024 Offerings

On February 27, 2024, we entered into an underwriting agreement (the “Underwriting Agreement”) with EF Hutton LLC (the “Representative”), as the representative of the several underwriters named therein (the “Underwriters”), relating to an underwritten public offering (the “February 2024 Public Offering”) of 5,000,000 shares of the Common Stock.

The public offering price for each share of Common Stock was $0.30, and the Underwriters purchased the shares of Common Stock pursuant to the Underwriting Agreement at a price for each share of Common Stock of $0.276.

On February 28, 2024, the February 2024 Public Offering closed (the “Closing Date”).

Aggregate gross proceeds from the February 2024 Public Offering were approximately $1.5 million, before deducting underwriting discounts and commissions and estimated expenses payable by the Company.

Pursuant to the Underwriting Agreement and the engagement letter, dated as of February 22, 2024, by and between the Company and the Representative, the Company agreed to issue to the Representative in connection with the February 2024 Public Offering, a warrant to purchase up to a number of shares of Common Stock representing 5.0% of the shares of Common Stock and any Option Shares (as defined below) sold, at an initial exercise price of $0.33 per share, subject to certain adjustments (the “Underwriter’s Warrant”).

On February 28, 2024, the Company issued to the Representative the Underwriter’s Warrant to purchase up to 250,000 shares of Common Stock (the “Underwriter Warrant Shares”).

The Underwriter’s Warrant is exercisable six months following the date of the Underwriting Agreement and terminates on the five-year anniversary of the date of the Underwriting Agreement.

Pursuant to the Underwriting Agreement, the Company also granted the Representative a 45-day option to purchase up to an additional 750,000 shares (the “Option Shares”) of the Common Stock on the same terms as the Shares sold in the Offering (the “Over-Allotment Option”).

On March 5, 2024, the Underwriters exercised (“Overallotment Exercise”) the Over-Allotment Option to purchase an additional 750,000 shares of Common Stock.

In connection with the Overallotment Exercise, we issued an additional Underwriter’s Warrant to purchase up to 37,500 shares of Common Stock.

The Overallotment Exercise closed on March 6, 2024.

On February 29, 2024, we entered into a securities purchase agreement with an investor providing for the issuance and sale of 2,700,000 shares of Common Stock and warrants to purchase up to 2,700,000 shares of Common Stock (the

“February Warrants”) at a price of $0.38 per share of Common Stock and accompanying warrant, which represents a 26.7% premium to the offering price in February 2024 Public Offering.

The Common Stock and the February Warrants were offered pursuant to a private placement (the “February 2024 Private Placement”) under Section 4(a)(2) of the Securities Act of 1933, as amended (the “Securities Act”).

The February Warrants will have an exercise price of $0.38 per share, are initially exercisable beginning six months following the date of issuance and will expire 5 years from the date of issuance.

The aggregate net cash proceeds to the Company from the February 2024 Private Placement were approximately $1.0 million.

NRx Products in Development

NRX-101 is a combined NMDA/5-HT 2A -targeted medicine designed to address both depression and suicidal ideation, consisting of a patented, oral, fixed dose combination of D-cycloserine (DCS) and lurasidone.

Although DCS has been known for more than 70 years as an anti-infective, its propensity to cause psychedelic side-effects, together with challenges in maintaining drug stability, limited its use clinical use and by the year 2000, DCS was rarely used in the United States.

The critical doses of DCS required to achieve a clinical effect in treatment of these conditions was not understood, prior to NRx’s recent patented discoveries.

The discovery that the psychedelic effects of DCS can be attenuated by the concomitant use of serotonin-targeted drugs creates a new life for this promising molecule, whose use was previously limited by hallucinogenic effects.

The key discovery by Daniel Javitt that the psychedelic side-effects of DCS can be attenuated by the concomitant use of serotonin-targeted drugs creates a new life for this promising molecule, whose use was previously limited by hallucinogenic effects.

The manufacture of DCS was similarly limited by propensity to form inactive dimers and trimers of the cycloserine ring and no modern manufacturing program was undertaken over the past 50 years.

The Company has now modernized the required analytic methodology, achieved control over impurities as required for modern commercial drug manufacture, and solved the stability challenges in a manner that achieved five-year shelf stability in the Company’s phase 2 program and is on track to replicate that stability at commercial scale.

These advances by the Company potentially open a broad area of drug development that is enabled by NRx’s extensive worldwide portfolio of 90 patents, 48 of which have been issued and the remainder remain under prosecution.

Prior to its 2021 public offering and Nasdaq listing, the Company attracted private capital sufficient to complete a phase 2 trial that earned Breakthrough Therapy Designation and a Special Protocol Agreement from the FDA but was not in a position to develop or manufacture NRX-101 at scale for broad clinical research.

Following its initial public offering and two rounds of fundraising in 2021 and 2022, the Company had resources to transfer its offshore phase 2 drug development to a US manufacturing site, aligned with the FDA on manufacturing and CMC requirements for NRX-101, and for the first time produced ample supplies of NRX-101 in multiple dosage forms to support broad clinical trials and safety databases.

The Company is now poised to complete a registration trial for NRX-101 in the treatment of Suicidal Bipolar Depression and to explore its broader use in the treatment of depression, PTSD and chronic pain.

NRx Products in Development

Currently, there are numerous atypical antipsychotic drugs targeting the 5-HT2A receptor approved for treatment of bipolar depression.

However, all are known to increase a side effect known as akathisia, which is closely linked to suicidal ideation and behavior, and all carry a black box warning on the label regarding the potential for increased risk of suicide.

In contrast, DCS has been demonstrated in at least two clinical trials (Nierenberg 2022 i , Chen 2019 ii ) to reduce suicidal ideation, a finding also demonstrated for ketamine (Abbar 2022 iii , Grunebaum 2017 iv ).

In contrast, DCS has been demonstrated in at least two clinical trials (Nierenberg 2022 6 , Chen 2019 7 ) to reduce suicidal ideation, a finding also demonstrated for ketamine (Abbar 2022 8 , Grunebaum 2017 9 ).

Because its effect is synergistic to the antidepressant effects of serotonin-targeted drugs and because of the specific effect on suicidal ideation, the NMDA receptor of the brain is increasingly viewed as a key target for treating depression and suicidality.

To the Company’s knowledge, NRX-101 is the first investigational medicine to advance to Phase 3 for severe bipolar depression in patients with Acute Suicidal Ideation and Behavior (“ASIB”).

To the Company’s knowledge, NRX-101 is the first investigational medicine to advance for severe bipolar depression in patients with Acute Suicidal Ideation and Behavior (“ASIB”).

A safe, oral medicine for suicidal depression represents a key unmet medical need because the only currently approved treatment for this condition today is electroconvulsive therapy (ECT).

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2 Although it may have psychedelic effects when given as monotherapy, psychedelic effects of DCS have not been seen in four different studies where DCS was administered together with serotonin-targeted drugs.

Javitt additionally discovered and patented the finding that DCS is a mixed NMDA agonist/antagonist and a critical dose of DCS must be administered (in the region of 400mg – 500mg per day) in order to access its NMDA antagonist properties.

This finding explains the failure of DCS to demonstrate clinical effects in a number of published trials at lower doses.

This finding explains the failure of DCS to demonstrate clinical effects in a number of published trials at lower doses, where it acts as an agonist at the NMDA receptor.

Although development of NRX-101 began in 2015, when NeuroRx, Inc.

4 unchanged sentences

Moreover, registrational studies require either that the trial be conducted with commercial grade investigational product or compel the sponsor to conduct subsequent bridging studies to prove biological equivalence to commercial grade product.

In March 2022, the Company executed a tender process and selected Alcami (Wilmington, NC) as its manufacturing partner.

In March 2022, the Company executed a tender process and selected Alcami, Inc.

(“Alcami”) (Wilmington, NC) as its manufacturing partner.

Technology transfer was accomplished within 3 months and a first phase 3/commercial-scale batch was completed by August 2022.

In October 2022 sufficient stability data were collected to submit the manufacturing information (IND Module 3) to FDA, which was reviewed without negative comment.

The Company submitted a briefing document to FDA detailing the CMC and stability approach as part of a Type C meeting process.

On January 10, 2023, FDA provided written feedback in lieu of a Type C meeting in dictating alignment with the FDA regarding its proposed registration manufacturing and stability plan.

On February 14, 2023, the Company announced its receipt of the written minutes of a Type B meeting held with the FDA held on January 11, 2023, to outline the clinical & preclinical requirements for registration of NRX-101.

In January 2023, the Company achieved alignment with the FDA on its proposed registration manufacturing and stability plan in a Type C meeting.

In February 2023, the Company aligned with FDA in a Type B meeting to outline the clinical & preclinical requirements for registration of NRX-101.

Overall, the FDA suggested expanding the safety data base of NRX-101 to allow for chronic/intermittent use of NRX-101, as well as a broadening of the addressable population of the indication (under the SPA or otherwise) to patients with severe bipolar depression and recent acute suicidality regardless of how the initial stabilization was achieved.

This broader indication would enable the Company to potentially demonstrate the use of NRX-101 to maintain stabilization from acute suicidality in patients stabilized either with ketamine (NRX-100) or with other standard of care therapeutic approaches.

FDA encouraged the Company to request a Breakthrough Therapy Planning Meeting for NRX-101, which we intend to accomplish in second quarter of 2023.

We initiated a new registrational study of NRX-101 for the treatment of severe bipolar depression with ASIB, a potentially lethal condition that currently takes the lives of thousands of Americans each year, after initial stabilization with NRX-100 (described below).

We intend to use newly manufactured material that was manufactured using the expected commercial process.

On January 3, 2023, the Company announced that its first clinical trial sites had been contracted for this study.

Patient recruitment has not yet started for this study.

We are also conducting a clinical study for the treatment of severe bipolar depression in patients with sub-acute suicidal ideation and behavior (“SSIB”), an indication to which we now refer as “Suicidal Treatment Resistant Bipolar Depression.” The US population of patients with Suicidal Treatment Resistant Bipolar Depression is estimated to be between 700,000 and 1,000,000 people.

The DSMB reviewed the unblinded results of the first 50 patients randomized and treated in this study.

The DSMB found no futility signal at this stage of the trial.

Similarly, no safety signals were identified in association with NRX-101 and the DSMB recommended that enrollment in the trial continue as planned.

According to the study's statistical analysis plan, the failure to identify futility requires that a numerical advantage of the investigational drug relative to the comparator treatment must be observed by the DSMB.

The DSMB will continue to monitor safety and efficacy in the trial.

Based on the DSMB findings, together with the recent completion of Phase 3 commercial stage manufacture of NRX-101, the Company has upgraded the ongoing trial to a Phase 2b/3 trial whose results may be used in a future registrational filing, should the primary endpoint be met.

Based on the comments and guidance from the FDA in its recent Type B meeting regarding the registrational Acute Suicidality trial and a potentially broader indication, as well as the guidance it received from the DSMB regarding the ongoing Phase IIb/3 clinical study of NRX-101 for the treatment of severe bipolar depression in patients with SSIB, the Company is evaluating changes to its registrational program for NRX-101 and will seek to consolidate patients originally expected to enroll in the in the ASIB study into the currently enrolling Phase IIb/3 trial.

FDA encouraged the Company to request a Breakthrough Therapy Planning Meeting for NRX-101.

In late 2022 we confronted the challenges associated with recruiting suicidal patients in the traditional clinical trial site model.

We learned that the “suicidality state” is sufficiently transient that simply having trial sites offer our therapy to existing databases of known patients with bipolar disorder was both insufficient to attract sufficient numbers of patients to a clinical trial and overly prone to attracting participants seeking secondary gain.

We implemented an artificial intelligence (“AI”) based national recruitment strategy designed to identify and recruit participants who are sincerely looking for the potential benefit offered by NRX-101.

We paired this with a distributed clinical trial model developed by Science37, Inc., where traveling nurses are able to visit prospective clinical trial participants who are then treated by their own physicians, rather than relying on our ability to identify participants who live within traveling distance of a “bricks and mortar” study site.

Thus, in order to achieve clinical trial feasibility for an enormously complex and potentially lethal disease, in 2023 we invented and demonstrated a new model of clinical trial recruitment and implementation.

Psychiatry trials succeed or fail based on a high degree of confidence that psychometric ratings are implemented in a reliable manner that is consistent from one study site to the next.

An entire industry has emerged of third party rating companies that seek to achieve this consistency on behalf of sponsors.

Unfortunately, the lag time between site-rating and central rating is inconsistent with achieving real-time quality control.

Accordingly we developed in internal capability to review a study site rating within 24 hours, using an in-house team of master raters.

The industry standard has traditionally allowed a 10% difference between site raters and third party rating companies as the standard for “concordance” and has allowed a 90% concordance rate between study sites and central raters.

We tightened that standard to allowing only 5% difference between site raters and central master raters and demonstrated that 94% concordance could be maintained, with the exception of one study site that was excluded from the study and replaced at the direction of our Independent Data Safety and Monitoring Committee early in the study (prior to any data unblinding) for failure to maintain rating quality.

We applied the above technologic infrastructure to our clinical trial of NRX-101 for the treatment of severe bipolar depression in patients with sub-acute suicidal ideation and behavior (“SSIB”), an indication we now call “Suicidal Treatment Resistant Bipolar Depression.” Between 700,000 and 1,000,000 Americans suffer from Suicidal Treatment Resistant Bipolar Depression and 25,000 – 50,000 kill themselves each year.

In March 2023, the independent Data Safety Monitoring Board (reviewed the patients enrolled and determined no futility signal, which means that they observed a potential numerical advantage of NRX-101 over comparator.

Based on the comments and guidance from the FDA in its recent Type B meeting regarding the registrational Acute Suicidality trial and a potentially broader indication, as well as the guidance it received from the DSMB regarding the ongoing Phase 2b/3 clinical study of NRX-101 for the treatment of severe bipolar depression in patients with SSIB, the Company is evaluating changes to its registrational program for NRX-101 and will seek to consolidate patients originally expected to enroll in the ASIB study into the currently enrolling Phase 2b/3 trial.

This would potentially allow registration of NRX-101 for Suicidal Treatment-Resistant Bipolar Depression, regardless of the mechanism of stabilization.

With the FDA’s guidance to enroll patients for the acute (SPA) study in the outpatient setting only after stabilization, the design of this trial has effectively converged with the currently enrolling phase IIb/3 trial;

patients within both groups are deemed to have treatment resistant bipolar depression with suicidality.

This broader indication may also offer significant advantages in commercialization, while negating the need for a separate NDA for ketamine in Suicidal stabilization.

We expect top-line data from this consolidated trial in the first quarter of 2024.

We expect top-line data from this consolidated trial in the second quarter of 2024.

Lastly, the Company will also continue exploring early signal-finding studies in PTSD and chronic pain.

NRX-100 is racemic ketamine, which is a generic anesthetic that has shown efficacy in some clinical studies of depression and suicidality.

NRX-100 is racemic ketamine that is FDA-approved as a generic anesthetic.

NRX-100 has shown efficacy in some clinical studies of depression and suicidality.

12 In the Company’s STABIL-B Study, NRX-100 was used for the initial stabilization of patients with bipolar depression who were also acutely suicidal, prior to receiving NRX-101 or lurasidone.

The Company has opened an Investigational New Drug (IND) file with the FDA for the purpose of developing ketamine as a rapid induction agent in the treatment of Severe Bipolar Depression with Acute Suicidal Ideation and Behavior.

The FDA awarded Fast Track Designation to this use.

Although the Company did not initially plan to develop ketamine as a monotherapy for rapid treatment of suicidal depression, the FDA guided NRx to do so in January 2023.

Because of the urgent need, the company elected to license data from several well-controlled, publicly funded clinical trials that had not been submitted to the FDA and to prepare those data in the rigorous patient-level electronic form that is required for FDA review of clinical trial data.

These trials demonstrate clear benefit of ketamine over both placebo and active comparator (midazolam), as well as non-inferiority of ketamine to the standard of care electroconvulsive therapy.

The Company similarly entered into a manufacturing contract with Nephron Pharmaceuticals (West Columbia, SC) to create a proprietary formulation of ketamine for commercial sale.

The company expects to file a New Drug Application for ketamine through its HOPE Therapeutics division in 1H 2024 and to achieve a 2024 FDA review date (“PDUFA” date) of this application.

Zyesami (Aviptadil)

Between March 2020 and mid-2022, the Company engaged in the development of Aviptadil acetate (ZYESAMI®) for the treatment of respiratory failure in COVID-19 under a collaboration agreement signed with Relief Therapeutics Holdings, AG.

ZYESAMI initially showed promise when administered intravenously to patients with acute respiratory failure and demonstrated a statistically significant 2-fold decrease in mortality when administered in a randomized, prospective clinical trial.

Significant improvement in survival and recovery was additionally demonstrated by Youssef in a prospective open-label trial conducted at Houston Methodist Hospital.

These results were published by Youssef and coworkers in the peer reviewed literature.

v This finding was deemed “hypothesis generating” by the US FDA because mortality was the declared secondary endpoint of the clinical trial and the primary endpoint, recovery from respiratory failure, was deemed to be near (P=0.08) but not sufficiently significant to warrant Emergency Use Authorization.

Significant improvement in survival was demonstrated in a well-controlled multicenter trial.

13 This finding was deemed “hypothesis generating” by the US FDA because mortality was the declared secondary endpoint of the clinical trial and the primary endpoint, recovery from respiratory failure, was deemed to be near (P=0.08) but not sufficiently significant to warrant Emergency Use Authorization.

The study further documented immediate improvement in levels of blood oxygen and decrease in inflammatory cytokines, evidence of biological activity.

A subsequent large multicenter conducted by the US National Institutes of Health was halted for futility in May 2020.

Thus far, the NIH has not published results of the clinical trial.

Two additional trials were conducted with inhaled aviptadil for treatment of earlier stages of respiratory failure.

One trial, conducted by the Biomedical Advanced Research Development Authority of the US Department of Health and Human Services was similarly halted after hitting a futility endpoint.

A second trial, sponsored by NRx was suspended following the first DSMB review of data for lack of funding under the Relief collaboration agreement.

In 2022, we suspended our efforts to develop the pharmaceutical product, aviptadil acetate for all indications.

The NIH published report revealed that approximately 1/3 of participants who were randomized to receive Aviptadil were not fully treated at the NIH study sites.

Because the trial only considered an intent to treat analysis, this failure to treat a large number of participants may have contributed to the finding of futility.

In 2022, we suspended our efforts to develop the pharmaceutical product, Aviptadil acetate for all indications as part of an agreement with Relief Therapeutics, the original developer of Aviptadil.

On December 20, 2022, the Company transferred to Relief all of the assets it used in its Aviptadil development program.

Relief now has the exclusive right to control, and the obligation to use commercially reasonable efforts to develop and commercialize, an aviptadil product.

Relief now has the exclusive right to control, and the obligation to use commercially reasonable efforts to develop

and commercialize, an Aviptadil product.

If successful, Relief is obligated to pay NeuroRx (i) milestone payments should Relief successfully obtain commercial approval of an Aviptadil product (whether for COVID-19 or any other indication) and (ii) royalties based on a percentage of future sales of an Aviptadil product (whether for COVID-19 or any other indication), up to a maximum of $30 million in the aggregate.

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for at least two years.

Following the closing, Relief and NeuroRx dismissed their pending litigation.

Background of the CNS Portfolio

Our CNS portfolio is based upon fundamental scientific discoveries of Daniel Javitt, MD, PhD, a Professor of Psychiatry at Columbia University and co-founder of NRx.

Additional Potential Psychiatry Products

Our intellectual property estate enables us to pursue additional combinations of known molecules, including dextromethorphan, d-methadone, and other named NMDA antagonists.

Most patients with depression have major depressive disorder (MDD).

Additionally, PTSD is an area of high unmet need for which there are very few pharmacological treatment options.

PTSD can also be associated with suicidality and depression, in particular severe PTSD.

Whereas episodes of depression in bipolar disorder are episodic and tend to resolve in two to three months, depression is a chronic feature of MDD, and it can also be associated with PTSD.

NRX-102, is a potential new product in which we expect to pair a fixed dose combination of DCS with Mirtazapine, a currently approved antidepressant.

In the 2013 Phase 2 study, clinical data demonstrate the potential efficacy of DCS in combination with an SSRI antidepressant versus an SSRI antidepressant alone in treating patients with treatment resistant MDD.

We expect to resume the exploratory preclinical development of NRX-102.

Further, we have identified additional 5-HT2A antagonists that may be appropriately paired with DCS.

We are also further guided by preclinical data disclosed in our patents and publications which demonstrates that DCS may inhibit the akathisia induced by SSRI antidepressants.

Existing clinical data have shown DCS to be a useful initial therapeutic agent with which to target the glycine site on the NMDA receptor.

However, DCS has mixed agonist/antagonist effects and its antagonist properties are only manifest at high doses of DCS.

We have identified other small molecule NMDA antagonists that are effective at lower doses and may be paired with 5-HT2A antagonists to yield a dual-targeted pro-drug.

Accordingly, we plan to explore design initiatives to develop candidate prodrugs that will expand on the dual-targeted properties of NRX-101 and NRX-102.

NRX-201/202 will target bipolar depression and MDD/PTSD, respectively, and are anticipated to replace the DCS component of NRX-101/102 with a molecule that is more specifically targeted than DCS at the same glycine site target.

Our patent portfolio includes issued and pending claims for many such dual-targeted combinations.

Background of the Portfolio

Our portfolio is based upon fundamental scientific discoveries of Daniel Javitt, MD, PhD, a Professor of Psychiatry at Columbia University and co-founder of NRx.

In 1987, Daniel Javitt discovered the role of blocking the brain’s NMDA receptor (a molecule on the surface of brain cells) in producing psychosis.

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a once popular drug of abuse frequently added to cannabis) caused acute psychosis in a high proportion of users.

Daniel Javitt discovered that phencyclidine exerted its psychotogenic action by blocking the NMDA receptor and devoted the balance of his ongoing career to studying the brain chemistry of schizophrenia, depression, and related disorders.

Daniel Javitt discovered that phencyclidine exerted its psychotogenic action by blocking the NMDA receptor and devoted the balance of his subsequent career to studying the brain chemistry of schizophrenia, depression, and related disorders.

Daniel Javitt is one of the most widely published scientists in molecular psychiatry.

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The discovery has led to a broad patent portfolio now owned by us and to the development of NRX-101, the first investigational drug specifically targeting bipolar depression with suicidality.

History of our development of NRX-100/101

NRx was founded in 2015 by Drs.

Jonathan Javitt and Daniel Javitt to develop drugs that aim to treat psychiatric disorders based on the initial discovery of the phencyclidine binding site on the NMDA receptor and the role of NMDA antagonists in schizophrenia and experimental psychosis.

Javitt subsequently discovered a synergistic effect when NMDA antagonists are combined with inhibitors of the brain’s 5-HT2A receptor (e.g., SSRI antidepressants and atypical antipsychotic drugs).

This synergy has now been demonstrated in both laboratory rodent behavioral experiments and in multiple Phase II clinical trials and resulted in a Composition of Matter patent awarded in the U.S.

Javitt subsequently discovered a synergistic effect when NMDA antagonists are combined with inhibitors of the brain’s 5-HT2A receptor (e.g., SSRI antidepressants and atypical

antipsychotic drugs).

This synergy has now been demonstrated in both laboratory rodent behavioral experiments and in multiple Phase 2 clinical trials and resulted in a Composition of Matter patent awarded in the U.S.

and multiple foreign jurisdictions.

Javitt subsequently observed that when patients with depression were treated with DCS, an NMDA antagonist, in combination with antidepressants, they manifested increased antidepressant effect, but did not exhibit the hallucinations and other NMDA effects previously reported with DCS.

He further observed that DCS appeared to reduce some of the antidepressant side effects (akathisia) common to all known serotonin-targeted anti-depressants.

He further observed that DCS appeared to reduce some of the antidepressant side effects (akathisia) common to all known serotonin-targeted antidepressants.

Figure 1 Synergistic composition of matter in which drugs that inhibit the NMDA receptor block the akathisia caused by serotonin-targeted drugs and serotonin-targeted drugs, in turn, block the psychedelic effects of NMDA inhibitors.

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See “Summary of NRx Material In-licensing Obligations — NRX-100/101 — Sarah Herzog Memorial Hospital License Agreement” for more information.

NRX-101 for the Treatment of Acute Suicidal Ideation and Behavior (ASIB)

Background on the Indication

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Some epidemiological study data suggests that over the course of 5 years, approximately 1 in 5 patients suffering from bipolar depression may attempt suicide or have serious thoughts about attempting suicide.

The overall rate of death by suicide among bipolar patients is approximately 10-30 fold greater than that of the general population.

The overall rate of death by suicide among bipolar patients is approximately 10 to 30-fold greater than that of the general population.

Those who have attempted suicide are at significantly higher risk to experience another suicide attempt or die by suicide.

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Despite its lethal characteristics, there are no approved pharmacologic treatments for patients with ASIB in bipolar depression.

As a result, ECT, often combined with inpatient psychiatric care, remains the only FDA-approved treatment for patients with ASIB in bipolar depression, despite ECT’s well-documented side effects that include memory loss and confusion, along with its high cost.

As a result, electroconvulsive therapy (ECT, colloquially known as “shock therapy” or “electroshock therapy”), often combined with inpatient psychiatric care, remains the only FDA-approved treatment for patients with ASIB in bipolar depression, despite ECT’s well-documented side effects that include memory loss and confusion, along with its high cost.

In recent years, several combined D2/5-HT2a antagonists have been shown to have efficacy in treating bipolar depression (olanzapine/ fluoxetine combination, quetiapine, lurasidone, cariprazine, lumateperone) with treatment guidelines endorsing common use as first-line standard-of-care treatment in acute bipolar depression.

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Thus, ASIB in bipolar depression represents a major unmet medical need that must frequently be treated with voluntary or involuntary hospitalization under highly supervised conditions and in some cases the use of ECT.

Whereas all approved drugs for depression act primarily through monoaminergic mechanisms, the serendipitous discovery that ketamine can have a rapid and profound effect on depression and suicidality led to the realization that the glutamate system and the N-methyl-D-aspartate receptor (“NMDAR”) may also play an important role in depression and suicidality.

In our Phase IIb/III registrational study, acutely suicidal and depressed bipolar patients will receive a single low dose of IV ketamine to determine clinical response.

Patients who respond with an acute improvement of suicidality and depressive symptoms to ketamine (NRX-100), in a separate study will receive NRX-101 orally twice daily for up to six weeks to determine if NRX-101 may prolong the resolution of depressive symptoms and time to clinical relapse versus lurasidone.

NMDAR-based Treatment for Bipolar Depression

NRX-101 is a dual-targeted sequential therapy regimen (the “NRx Pharmaceuticals Sequential Therapy”) originally consisting of an initial stabilization treatment with NRX-100 (intravenous ketamine) followed by 6-week treatment with NRX-101 (combined DCS and lurasidone).

The treatment is intended for rapid stabilization of individuals with ASIB related to acute exacerbation of depressive symptoms in individuals with bipolar disorder, followed by longer term stabilization to permit resolution of the crisis.

The drug is intended for treatment of both depression and ASIB in individuals with an acute depressive decompensation in bipolar disorder.

Rationale for NRX Sequential Treatment

NRX-100 is an intravenous infusion of ketamine administered to enable an initial rapid stabilization of patients with bipolar depression who are acutely suicidal.

Once a patient who initially was acutely suicidal is sufficiently stable NRX-101 is administered.

NRX-101 is a fixed-dose combination oral capsule composed of DCS and lurasidone used to maintain remission from acute suicidality in acutely depressed bipolar patients.

Congruent with our strategy of applying innovative science to known molecules, the NRx Sequential Therapy takes advantage of the unique synergistic confluence of three FDA-approved drugs with long histories of use:

DCS, lurasidone and ketamine.

In our Phase 2b/study, acutely suicidal and depressed bipolar patients received a single low, i.e., subanesthetic dose of IV ketamine to determine clinical response.

6 Patients who responded with an acute improvement of suicidality and depressive symptoms to ketamine (NRX-100 received NRX-101 orally twice daily for up to six weeks).

Rationale for NRX-101 in ASIB

NRX-101 is a fixed-dose combination oral capsule composed of DCS and lurasidone used to reduce acute suicidality symptoms in patients with bipolar depression.

DCS is a broad-spectrum antibiotic approved for the treatment of tuberculosis (Seromycin, or Cycloserine).

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However, these were not pursued further at the time because of the liability of DCS to induce significant psychotomimetic side effects when given at high dose.

Preclinical Observations

The interaction of DCS with the NMDA receptor was first demonstrated in 1989, leading to some interest in NMDAR blockers as potential antidepressant treatments.

For example, both DCS and the related compound ACPC were shown to be active in mice, using the forced swim test for depression.

Cross-species translation of DCS effects is based upon plasma level, such that NMDAR antagonist effects are observed consistently at plasma levels >25 μg/ml (~250 μM).

This plasma level is achieved in rodents with doses >30 mg/kg and in humans with doses >10 mg/kg.

Evidence for functional target engagement at these doses comes from 1) rodent behavioral studies, 2) clinical studies of DCS in schizophrenia, and 3) clinical studies of DCS in depression.

Effects of DCS on NMDAR activation were first evaluated in 1990 by Hood et al., 1989 who noted inhibition of NMDAR activation by DCS at doses similar to our proposed active dose.

These effects were subsequently confirmed by Watson et al., 1990, and the issue of high-dose antagonist effects of DCS were extensively discussed by Lanthorn et al., 1994.

The majority of rodent behavioral studies conducted with DCS used doses of DCS of 30 mg/kg produced significant dose-dependent anxiolytic effects in the fear-potentiated startle assay that were similar to those produced by the known NMDAR glycine-site antagonist 7-chlorokynurenate.

The authors state as follows:

“…the results of the present study show that D-cycloserine exhibits anxiolytic activity at higher doses, an effect consistent with antagonist activity,” and also argue for potential effectiveness of DCS in treatment of anxiety- and fear-related disorders including generalized anxiety disorder or PTSD.

Early Clinical Results

High-dose (>500 mg) DCS was subsequently shown to reduce persistent depressive symptoms in patients with MDD who were depressed despite treatment with approved antidepressant agents.

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It is also approved for the treatment of schizophrenia in adults and patients 13-17 years of age.

Ketamine HCl is a dissociative, rapid-acting general anesthetic for intravenous or intramuscular injection, approved for surgical anesthesia.

Ketamine has shown in multiple randomized clinical trials the potential to rapidly reduce depressive symptoms and suicidal ideation.

However, the clinical effect has been demonstrated to diminish three to seven days post-dose when used intravenously and two days post-dose when the S-enantiomer is delivered intranasally.

Ketamine is classified as a schedule III substance under the Controlled Substances Act, due to its potential for addiction.

Whereas ketamine is a direct NMDA channel blocker, which binds to the phencyclidine binding site, DCS in high doses has an NMDA-antagonist effect mediated through interaction with the glycine binding site.

This effect is apparently unrelated to its properties as an anti-infective.

By combining the potential of DCS to extend the anti-depressant effects of ketamine with the antipsychotic properties of lurasidone, the NRx Pharmaceuticals Sequential Therapy has the potential to stabilize individuals with bipolar depression during acute crisis and address a serious medical need.

Ketamine HCl, infused at 0.5 mg/kg IV over 40 minutes has been shown to induce acute reductions in suicidality and depression in patients with bipolar depression, relative to control.

Numerous reports have documented approximately a 50% reduction in the MADRS and up to a 75% reduction in suicidality following a single infusion of ketamine in patients with suicidal ideation and depression.

While the long-term repeat use of ketamine for psychiatric indications may be concerning to some, DCS, when combined with Selective Serotonin Reuptake Inhibitor (“SSRI”) antidepressants in patients with treatment resistant depression, and when combined with atypical antipsychotics, in particular lurasidone, has shown separation from control and ability to maintain remission from suicidality and depression over 6 weeks with oral use.

Figure 2 Effect of DCS on persistent depressive symptoms in MDD, when added to existing anti-depressants (Heresco-Levy et.

Preclinical Observations

Cross-species translation of DCS effects is based upon plasma level, such that NMDAR antagonist effects are observed consistently at plasma levels >25 μg/ml (~250 μM).

This plasma level is achieved in rodents with doses >30 mg/kg and in humans with doses >10 mg/kg.

Evidence for functional target engagement at these doses comes from 1) rodent behavioral studies, 2) clinical studies of DCS in schizophrenia, and 3) clinical studies of DCS in depression.

Effects of DCS on NMDAR activation were first evaluated in 1990 by Hood et al., 1989 who noted inhibition of NMDAR activation by DCS at doses similar to our proposed active dose.

These effects were subsequently confirmed by Watson et al., 1990, and the issue of high-dose antagonist effects of DCS were extensively discussed by Lanthorn et al., 1994.

The authors state as follows:

DCS, when combined with Selective Serotonin Reuptake Inhibitor (“SSRI”) antidepressants in patients with treatment resistant depression, and when combined with atypical antipsychotics, in particular lurasidone, has shown separation from control and ability to maintain remission from suicidality and depression over 6 weeks with oral use (Figure 2).

Figure 2 Proportion of responders (≥50% improvement on 21-item Hamilton Depression Scale (HAMD) during 6 week adjuvant treatment with D-Cycloserine (N=13) and placebo (N=13) p=0.04.

Heresco-Levy et.

Preclinical Safety

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The combination of the drugs for the NRx Pharmaceuticals Sequential Therapy (DCS, lurasidone, and ketamine) were tested according to this protocol and found to have no evidence of neurotoxicity (Figure 3) demonstrating safety factors of 4-fold, 16-fold and 7.4-fold for ketamine, DCS, and lurasidone, respectively.

vi Each of the proposed drugs has a long history of safe use in humans, and their adverse event profiles are well characterized.

Figure 3 Rodent neurotoxicity study showing “Olney lesions” induced by the NMDAR channel blocker MK-801 (right).

No significant neurotoxicity was observed for DCS (left).

Each of the proposed drugs has a long history of safe use in humans, and their adverse event profiles are well characterized.

Figure 3 Rodent neurotoxicity study showing “Olney lesions” induced by the NMDAR channel blocker MK-801 (left).

No significant neurotoxicity was observed for maximum nonlethal dose of 2000 mg/kg of NRX-101 (center) or for ketamine at 12.5 mg/kg followed by NRX-101 (right).

Figures 2,3,4 of Jordan et al., 2022 1

Direct channel-blocking NMDAR-targeted antidepressants have shown substantial propensity for addiction and abuse liability, a propensity that has not been seen with glycine site modulators.

This propensity may be related to theories that have been advanced indicating that such agents also bind opiate receptors.

This propensity may be related to theories that

have been advanced indicating that such agents also bind opiate receptors.

DCS has also been investigated in a drug-abuse liability assay using intravenous self-administration.

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DCS did not significantly replace ketamine in this assay, consistent with lack of reported clinical abuse despite >50 years of clinical use.

Figure 4 Relative effects of DCS and ketamine on rodent self-administration, showing a significant difference between ketamine and DCS, and no significant difference between DCS and saline.

Psychogenics, Inc.

Phase IIb/III Clinical Trial - Sequential Therapy (NRX-100 Followed by NRX-101) for the Treatment of Acute Suicidal Ideation and Behavior in Bipolar Depression:

Figure 4 Number of self-administered infusions in different treatments groups.

S-ketamine largely substituted for ketamine, meanwhile DCS did not show any sign of substitution for ketamine at any dose.

(N = 12 per group;

not significant and ****:

P < 0.0001 compared to ketamine treatment).

Sapko et al., 2023 2

Licensure of a US Patent to Support Use of NRX-101

The Company has entered into a License Agreement with Apkarian Technologies to in-license US Patent 8,653,120 that claims the use of D-cycloserine for the treatment of chronic pain in exchange for a commitment to pay milestones and royalties as development milestones are reached in the field of chronic pain.

The patent is supported by extensive nonclinical data and early clinical data that suggest the potential for NMDA antagonist drugs, such as NRX-101 to decrease both chronic pain and neuropathic pain while potentially decreasing craving for opioids.

The Company has signed an agreement with Dr.

Vania Apkarian, Professor of Physiology, Anesthesia, Surgery, and Neuroscience Institute, Northwestern University Feinberg School of Medicine to join the NRx Pharmaceuticals Scientific Advisory Board (SAB).

As of December 31, 2023, the Company has recorded $0.2 million worth of expenses relating to the licensure of the patent recorded in research and development expense on the Consolidated Statements of Operations and Comprehensive Loss.

Should the Company succeed in serving 10% of the cUTI market, the Company believes that the potential royalty stream from NRX-101 has potential to exceed $1 billion annually.

Phase 2 Clinical Trial - Sequential Therapy (NRX-100 Followed by NRX-101) for the Treatment of Acute Suicidal Ideation and Behavior in Bipolar Depression:

the STABIL-B Study

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Response to Stage 1 was defined as 25% improvement in BDM, and C-SSRS 3 or less.

Responders to Stage 1 were entered into a 6-week double-blind comparison study of NRX-101 vs.

Responders to Stage 1 were entered into a 6-week double-blind

comparison study of NRX-101 vs.

lurasidone alone.

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lurasidone alone for maintenance of improvement and prevention of relapse following initial successful IV ketamine treatment.

Target doses were used of 950 mg for DCS and 66 mg for lurasidone.

Target doses were 950 mg for DCS and 66 mg for lurasidone.

Both compounds were titrated upwards over the initial 5-days of treatment.

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Secondary endpoints included suicidality, as reflect in both C-SSRS score and clinician-rated global suicidality impression score (“CGI-SS”) and relapse.

Study Results

22 subjects entered Stage 1.

17 were assigned to IV ketamine (NRX-100) and 5 to saline.

All subjects showed significant response to treatment and were entered into Stage 2.

Data were analyzed for the 17 subjects who responded to IV ketamine in Stage 1.

All subjects showed significant response to treatment and entered into Stage 2.

Stage 2 data were analyzed for the 17 subjects who responded to IV ketamine in Stage 1.

These subjects were randomized to either NRX-101 (n=12) or lurasidone alone (n=5).

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P=0.15) on MMRM analysis.

Change in depression score during Stage 1 and Stage 2 of the STABIL-B study.

All subjects improved significantly in Stage 1.

In Stage 2, subjects assigned to NRX-101 showed no significant worsening of depression, or reversion toward pre-Study 1 baseline.

By contrast, significant worsening was observed in the lurasidone alone group.

The mean difference in BDM score through day 42 was 7.7 points (P=0.032 between groups), which was considered a statistically large effect (d=1.60).

Nierenberg 2022

Table 1 Change in scores related to suicidal ideation and intent (C-SSRS and CGI-SS) during stage 2 of the STABIL-B study.

When scores are analyzed using “Last Observation Carried Forward” (LOCF) a statistically significant difference favoring NRX-101 vs.

lurasidone is observed.

(Graph) Primary Endpoint for those infused with ketamine vs.

placebo in phase I (n=22) and those who responded to ketamine in phase I and were randomized in Phase 2 to receive either NRX-101 or lurasidone (n=17).

Table depicts primary and secondary endpoints for those randomized in Phase 2 (n=17).;

Nierenberg et al., 2023 6

No significant treatment-related safety issues were observed in either group, and no deaths were reported in the study.

Plasma DCS levels achieved during the study were within the range expected based on prior human PK studies.

Study Interpretation

Overall, these results support continued development of NRX-101 for maintenance of clinical benefit in both depression and suicidality following initial successful treatment with IV ketamine.

Significant group differences were observed on LOCF analysis for both depressive symptoms, which was the prespecified primary endpoint, and for suicidality, which was a pre-specified key secondary endpoint.

For suicidality, significant LOCF differences were observed both for formal suicidality ratings obtained by certified raters and for clinical impression recorded by the treating physician, suggesting clinically meaningful effect.

The differences were significant in the MMRM analyses, suggesting an effect size in excess of 1.5, which if replicated would exceed the effect size seen with currently approved antidepressants.

To increase the likelihood of a successful follow-on trial, NRx powered the phase 2 trial to detect an effect size of 0.72, approximately have the effect size observed in the STABIL-B study.

This power analysis suggested a sample size of at least 62 patients and the Company adopted a final sample size of 72 patients to allow for dropouts and losses to follow up.

Thus, the magnitude of expected between-group differences suggested that a sample size of 72 subjects would be sufficient to achieve clinical significance if half the effect size seen in the STABIL-B is observed.

Study Summary

We initiated a clinical research program of NRX-101 during the second half of 2017 under an FDA IND application that was granted Fast Track designation by the FDA in August 2017 and upon presentation of the results was granted Breakthrough Therapy designation by the FDA in November 2018.

This was the first clinical trial (to the Company’s knowledge) to demonstrate a decrease in both depression and suicidality with an antidepressant regimen.

Upon presentation of the results was granted Breakthrough Therapy designation by the FDA in November 2018.

In April 2018, the FDA granted a Special Protocol Agreement (SPA).

We completed a Phase II clinical trial (the STABIL-B trial) of NRX-101 in 22 patients with severe bipolar depression and Acute Suicidal Ideation and Behavior (ASIB) following initial stabilization with a single dose of ketamine (NRX-100) and saw a statistically significant reduction in depression (P=0.04) and suicidal ideation (P=0.02) compared to lurasidone alone over 42 days of treatment.

If this statistically-significant advantage is replicated in the Phase IIb/III clinical trial, under the terms agreed to with the FDA in our Special Protocol Agreement, or in a similar design as per the latest FDA guidance, we aim to submit an NDA to the FDA for the regulatory approval and commercialization of NRX-101 in the U.S.

in 2023 and will evaluate our ability to submit to regulatory agencies in other regions or countries.

We believe our products are urgently needed by patients because no current serotonin-targeted antidepressant (such as SSRI drugs) or atypical antipsychotic (e.g., the D2/5HT2A drugs) has been shown to decrease suicidal ideation in patients with bipolar depression or PTSD.

Moreover, drugs in these classes bear an FDA-mandated warning regarding the potential increased risk of suicide in vulnerable patients, and to monitor all antidepressant-treated patients for the increased risk of suicide.

Ketamine has been shown to decrease suicidal ideation because of its NMDA-blocking properties, but is known to be hallucinogenic, addictive, potentially neurotoxic, and not administrable by mouth.

The only FDA-approved therapy for patients with suicidal bipolar depression remains electroconvulsive therapy (“ECT”), a treatment that is known to be effective, but to have a large number of serious side effects, and is very disruptive to the lives of these individuals.

Analysis of the STABIL-B trial showed a statistically significant reduction in depression and suicidal ideation vs.

the control group over 42 days.

We commenced a pivotal Phase IIb/III clinical trial under an FDA Special Protocol Agreement of our lead product candidate, NRX-101, in 2019 and paused that study due to the pandemic.

During this pause we advanced the commercial manufacture of NRX-101, transferring the manufacture from China to the USA.

We concluded this transfer and have now generated clinical supplies of NRX-101 using the expected commercial manufacturing process.

In 2022 we initiated a Phase II trial of NRX-101 in patients with bipolar depression with SSIB.

As of late October 2022, this study is using these new manufactured clinical supplies.

In January of 2023 we announced the initiation of a new Phase IIb/III clinical study under the SPA agreement.

On February 13, 2023, we issued a press release announcing the receipt of the written minutes and feedback received from the FDA in a Type B meeting held on January 11, 2023.

Based on these results, the Company commenced a pivotal Phase 2b/3 clinical trial under an FDA Special Protocol Agreement of our lead product candidate, NRX-101 in 2019 but suspended that trial in February 2020 because of the lockdown of study sites caused by the COVID pandemic.

The encouraging results of the trial suggested a possible use of NRX-101 without prior administration of ketamine in patients with subacute suicidality being treated in the outpatient setting.

Phase 2b/3 Clinical Trial - A Randomized, Double-Blind Controlled Comparison of NRX-101 to Lurasidone for Adults with Bipolar Depression and Subacute Suicidal Ideation or Behavior

During the COVID pause we advanced the commercial manufacture of NRX-101, transferring the manufacture from China to the USA.

The Company completed this transition in 2022 and generated clinical supplies of NRX-101 in 2023 using the expected commercial manufacturing process.

In 2022 we initiated a Phase 2 trial of NRX-101 in patients with bipolar depression with SSIB.

However, recruitment using traditional study site-based recruitment methods was inadequate to enroll study participants and in early 2023 the Company charged Zachary Javitt with designing and implementing an internet/AI-based national recruitment strategy.

In February 2023, we received feedback received from the FDA in a Type B meeting held on January 11, 2023.

FDA guided the Company to broaden the overall clinical program of NRX-101 to include safety data that would enable the chronic/intermittent use of NRX-101, in accordance with the ICH requirements.

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with Bipolar Disorder on a long-term basis.

The Company is evaluating the timing and cost of expanding its clinical program to access this larger population, as well as the overall guidance provided by the FDA.

Phase IIb/III Clinical Trial - NRX-101 for the Treatment of Severe Bipolar Depression and Subacute Suicidal Ideation or Behavior

Our Phase IIb/III study was originally aimed at investigating the effects of NRx Pharmaceuticals Sequential Therapy with IV ketamine (NRX-100) following by combined DCS + lurasidone (NRX-101) vs.

ketamine-lurasidone alone.

Based on this feedback, the Company partnered with Alvogen and Lotus to plan a far larger phase 3 initiative than originally contemplated for a significantly larger patient market.

The phase 2b/3 trial already in progress was reconfigured to an effect-size targeted trial.

This study uses a more rapid titration schedule for DCS than was used in STABIL-B, which permits proposed therapeutic dosing levels to be obtained more rapidly.

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The objective of the study is to replicate findings from both the Kantrowitz et al., 2015 17 study (NMDA Antagonists in Bipolar Depression;

NCT01833897) and the STABIL-B trial showing rapid remission of symptoms on initial ketamine treatment, followed by maintained improvement throughout the 6-week NRX-101 treatment period.

The primary hypotheses are that NRX-101 will be superior to lurasidone alone in maintenance of remission following initial successful stabilization with ketamine, as reflected both in a significant between-group separation on depression and suicidality scores as rated by the MADRS and C-SSRS scales, and in prevention of clinician-rated relapse.

The study is being conducted under a SPA with the FDA, and the treatment has been granted breakthrough status.

The study’s targeted enrollment of 72 subjects aged between 18-65 who will be randomized 2:1 to NRX-101 vs.

Recruitment was halted in February 2020 due to concerns about COVID-19.

Because of this pause, and our upcoming readiness of commercial drug supply, we are in the process of initiating a new study with the

same protocol, though we are now evaluating this based on the latest FDA feedback.

Business/ Company Overview) This study will be using the aforementioned new drug supply manufactured in the U.S.

In the recent (January 11, 2023) Type B meeting with the Psychiatric Products Division (PPD) of the FDA, the PPD suggested broadening the recruitment of the study to include “recently suicidal” patients stabilized with ketamine and other standard of care approaches in order to broaden the potential label that might be assigned should NRX-101 demonstrate superiority over lurasidone in maintaining remission from depression and suicidal ideation.

NCT01833897) and the STABIL-B trial 6 showing rapid remission of symptoms with a 6-week oral course of NRX-101 without prior use of ketamine.

The primary hypotheses are that NRX-101 will be superior to lurasidone alone in establishing and maintaining remission from depression and suicidality, as reflected both in a significant between-group separation on depression and suicidality scores as rated by the MADRS and C-SSRS scales, and in prevention of clinician-rated relapse.

In Q1 2024, the study met its target enrollment of 74 adult subjects randomized 1:1 to NRX-101 vs.

The clinical protocol and statistical analysis plan for this trial are available on clinicaltrials.gov NCT NCT03396068 ( https://storage.googleapis.com/ctgov2-large-docs/92/NCT03395392/Prot_SAP_000.pdf ).

Type C Meeting Guidance Received on January 10, 2023 from the FDA on the Chemistry, Manufacturing and Controls (CMC) Aspects of the NRX-101 Program

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Accordingly, all clinical trials and expanded access programs being conducted with NRX-101 are now being conducted with investigational product manufactured to commercial standards.

Minutes from the Company’s Type B Meeting with the U.S.

Food and Drug Administration’s Division of Psychiatry Products Held on January 11, 2023

The purpose of the meeting was to discuss requirements for submission of a New Drug Application for NRX-101.

FDA noted in written correspondence that the Special Protocol Agreement (SPA), granted in April 2019 remains in effect.

Additionally, the FDA suggested during the meeting that a broadening of the addressable population of the indication (under the SPA or otherwise) to patients with severe bipolar depression and Recent Acute Suicidality regardless of how the initial stabilization was accomplished could represent a more straightforward development program.

This broader indication would enable the Company to potentially demonstrate the use of NRX-101 to maintain stabilization from suicidality in patients stabilized either with ketamine or with other standard of care therapeutic approaches.

FDA noted that, should the results of such a study be driven primarily by subjects stabilized with ketamine, a New Drug Application for ketamine would also be required.

The FDA further guided the Company to broaden the study of NRX-101 to allow for chronic/intermittent treatment of patients with Bipolar Depression and suicidality.

This could enable a pathway for the use of NRX-101 by a broader segment of the approximately 7 million individuals in the U.S.

with Bipolar Disorder on a long-term basis.

A portion of this population is already being addressed in the Company’s ongoing phase 2 trial, which recently passed its first Data Safety Monitoring Board (DSMB) safety review.

Based on this guidance, the Company is considering expanding its current phase 2 clinical trial to a potential registration study now that the manufacture of phase 3/commercial-stage NRX-101 has been completed.

The Company previously announced completion of a Type C meeting in which FDA agreed to the Company’s Chemical Manufacturing Control and stability program for drug manufacture.

The FDA further advised the Company that as a chronic, or chronic-intermittent treatment, the safety database requirement under ICH guidelines for NRX-101 should be 1,500 patients short term, 300-600 patients at 6 months and with at least 100 treated for 1 year.

The Company is evaluating the timing and cost of this requirement to expand clinical access to this larger population.

In addition to its ongoing clinical trials, the Company is planning to augment its safety database via an expanded access program, which could be supported by the availability of its new manufacturing capabilities for NRX-101 and is expected under federal law governing Breakthrough Therapy Designation.

The Company will seek cost reimbursement for operating this Expanded Access Program as permitted under current FDA regulations.

In related comments, the FDA accepted the Company’s rationale for deferring pediatric and adolescent studies with NRX-101 until after drug approval and advised the Company to include this rationale in its regulatory filings.

The FDA will consider the Company’s submission of an Advice Request to evaluate waiving or deferring chronic carcinogenicity testing as a post-approval commitment.

Finally, the FDA’s Controlled Substances Staff advised the Company to closely monitor abuse-related adverse events and possible cases of abuse during clinical trials.

Data Safety Monitoring Board (DSMB) Review of NRX-101 for the Treatment of Severe Bipolar Depression and Subacute Suicidal Ideation or Behavior

In February 2023, the Company reported the recommendations of an independent Data Safety Monitoring Board (DSMB) which reviewed the safety findings of the first fifty enrolled participants in the Company’s phase II clinical trial of NRX-101 for the treatment of severe bipolar depression and subacute suicidal ideation or behavior ( www.clinicaltrials.gov NCT NCT03395392).

Data Safety Monitoring Board (DSMB) Review of Phase 2b/3 Clinical Trial NRX-101 for the Treatment of Severe Bipolar Depression and Subacute Suicidal Ideation or Behavior

In February 2023, the Company reported the recommendations of an independent Data Safety Monitoring Board (DSMB) which reviewed the safety findings of the first fifty enrolled participants in the Company’s Phase 2 clinical trial of NRX-101 for the treatment of severe bipolar depression and subacute suicidal ideation or behavior (www.clinicaltrials.gov NCT NCT03395392).

Based on a safety analysis of the first 50 enrolled patients, the DSMB recommended that enrollment in the trial continue as planned and identified no drug-related Serious Adverse Events or other safety issues of concern.

In March 2023, the Company reported the recommendations of the DSMB which reviewed the initial efficacy findings for the enrolled participants in the Company’s phase II clinical trial of NRX-101 for the treatment of severe bipolar depression and subacute suicidal ideation or behavior.

In March 2023, the Company reported the recommendations of the DSMB which reviewed the initial efficacy findings for the enrolled participants in the Company’s Phase 2 clinical trial of NRX-101 for the treatment of severe bipolar depression and subacute suicidal ideation or behavior.

The DSMB found no futility signal at this stage of the trial and the DSMB recommended that enrollment in the trial continue as planned.

According to the study's statistical analysis plan, the

failure to identify futility requires that a numerical advantage of the investigational drug relative to the comparator treatment must be observed by the DSMB.

The DSMB will continue to monitor safety and efficacy in the trial.

Clinical Objectives

Our clinical objective is to offer patients the clinical benefit of rapid reduction in symptoms of depression and suicidal ideation that has been observed with intravenous ketamine, while maintaining that benefit with a daily oral agent that does not have ketamine’s potential for abuse and psychosis, and/or required supervised administration.

NRX-101 is designed to offer an oral, rapid-onset and sustained home-use therapy that can significantly extend ketamine’s proven anti-suicidal and antidepressant benefits without the drawbacks of ketamine.

We believe that NRX-101 possesses potential development advantages over competing solutions.

These include:

• Initial focus on bipolar depression with suicidal ideation and behavior.

Competitors’ pipeline products are focused on MDD and exclude bipolar patients from clinical trials.

Patients with active suicidal ideation were routinely excluded from the clinical trials of those medicines currently approved for the treatment of bipolar depression.

• Lack of habituation and addiction.

Ketamine and esketamine are DEA schedule III controlled substances and known to be potentially highly addictive.

Preclinical habituation studies show no addiction potential for DCS (the NMDA component of NRX-101) and there is no reported history of abuse of DCS in more than 60 years of human use.

• Hallucinations and vomiting have not been a concern in our clinical studies with NRX-101.

Ketamine and some of its derivatives have been associated with hallucinations and other dissociative side effects in numerous clinical studies.

Ketamine and esketamine must be administered under medical supervision.

For intranasal esketamine (an approved intranasal ketamine derivative for psychiatric use) blood pressure spikes, nausea and vomiting are frequent adverse events.

Its label requires the drug to be administered under medical supervision and monitoring of blood pressure.

• Our preclinical studies showed no neurotoxicity:

Ketamine and other NMDA blocking drugs have the potential to cause brain cell death when abused / used over extended periods of time and recent FDA guidance requires that proposed NMDA-targeted antidepressants prove the lack of neurotoxicity in histological studies.

Additional indications for NRX-101

Depression and other symptoms of Post-traumatic Stress Disorder

Data Integrity Monitoring in Psychiatric Clinical Trials

Psychiatric clinical trials commonly include psychometric instruments as endpoints.

Interrater reliability (IRR), which is the concordance between two or more raters on the same instrument in the same patient, must be satisfactorily high or signal detection and statistical power will be diminished, potentially leading to failed trials.

18 Poor IRR in clinician-administered rating scales has many sources including a lack of adherence to structured and semi-structured interviews, rater scoring differences, inconsistent interview duration, poor interview quality, and rater bias.

19,20 NRx pursued a unique approach to ensure IRR.

Our novel patient rating system is an a priori-defined, protocol-specific, data-driven method to optimize psychometric training, data validity and reliability across each site rating.

In this system, the Sponsor employs expert raters with extensive experience in training, conducting, and analyzing the clinician-rated scale of interest.

In this patient rating system, these Rater Program Managers (RPMs) work closely with the clinical operations team to select suitable clinical trial sites, document site rater qualifications and training, and confirm that all data management conforms to the Study Protocol and GDP & GCP guidelines.

Most importantly, RPMs review the site raters’ psychometric assessments within 24 to 48 hours to identify discordance and provide corrective feedback according to defined adjudication processes, as needed.

This unique approach was highly successful in the Phase 2b/3 clinical trial “NRX101 for Suicidal Treatment Resistant Bipolar Depression” (ClinicalTrials.gov Identifier:

NCT03395392).

While it has been proposed that a spread of one standard deviation (6 points) on the Montgomery-Åsberg Depression Rating Scale (MADRS) is acceptable, we chose a more stringent 3-point concordance.

In a sample of 236 ratings (58 patients), IRR between site ratings and blinded independent RPM ratings was 94.49% (223/236) using this 3-point cutoff.

The absolute mean difference in MADRS rating pairs was 1.77 points (95% CI:

The intraclass correlation was 0.984 and an eta2 = 0.992 (F = 124.35, p < 0.0001).

This exceptionally high concordance rate demonstrates the feasibility and value of in-house expert rater monitoring of site rater assessments.

NRX-101 for the Treatment of Depression and Other Symptoms of Post-Traumatic Stress Disorder

Post-traumatic stress disorder (PTSD) affects 13 million Americans and 5 of every 100 adults in the US has PTSD in any given year.

vii PTSD is frequently accompanied by Depression.

21 PTSD is frequently accompanied by Depression.

However, the hallmark of PTSD is recurrent memories of the traumatic event, often called “flashbacks,” that may lead to avoidance behavior, negative thoughts, hyperarousal, and suicidal ideation.

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Recently, Sala and coworkers demonstrated the extinction of fear memory in a rodent model of PTSD.

viii The same rodent model was implemented by NRx to study the effects of NRX-101 on fear memory extinction.

22 The same rodent model was implemented by NRx to study the effects of NRX-101 on fear memory extinction.

Effect of DCS (dark blue) and NRX-101 (light blue) in extinction of Fear Memory in the WKY rodent model.

Data on File, NRx Pharmaceuticals, Inc.

A small clinical trial was conducted by de Kleine and coworkers in which a low dose of DCS (50 mg/day) demonstrated an augmentation of response to psychotherapy for PTSD.

ix In a related editorial, Krystal suggested, “some provocative findings suggest that when fear extinction takes place during D-cycloserine administration, usual forms of neuroplasticity are enhanced and additional forms of neuroplasticity are recruited that may enhance extinction and protect against reinstatement.

A small clinical trial was conducted by de Kleine and coworkers in which a low dose of DCS (50 mg/day) demonstrated an augmentation of response to psychotherapy for PTSD (Figure 7).

23 In a related editorial, Krystal suggested, “some provocative findings suggest that when fear extinction takes place during D-cycloserine administration, usual forms of neuroplasticity are enhanced and additional forms of neuroplasticity are recruited that may enhance extinction and protect against reinstatement.

24 Authors of a 2017 meta-analysis of 7 clinical trials of DCS for PTSD, 2 trials comparing DCS with placebo as add-on treatment to ongoing stable pharmacotherapy and 5 trials that compared DCS with placebo given prior to exposure therapy, stated that “D-cycloserine might have a role in augmentation of exposure therapy.” 25

Figure 7 Estimated model means for self-reported posttraumatic stress disorder symptom scores (Posttraumatic Stress Symptom Scale—Self Report;

PSS-SR) per completed session for the completer subgroups, with errors bars indicating standard errors.

DCS, D-cycloserine (source:

deKleine, et.

DCS, D-cycloserine.

de Kleine, et.

Javitt demonstrated in animal models that for DCS to maximize its effect on fear memory, plasma dosages in excess of 25µg/mL, must be achieved, which represents an oral dose in excess of 500mg/day.

As noted in US patent 10881665B2,

low dose DCS did not demonstrate a beneficial effect on fear memory (freezing behavior), while a dose of DCS sufficient to reach this plasma threshold did produce a significant reduction in freezing behavior.

As noted in US patent 10881665B2, low dose DCS did not demonstrate a beneficial effect on fear memory (freezing behavior), while a dose of DCS sufficient to reach this plasma threshold did produce a significant reduction in freezing behavior.

The Company’s 2022 completion of phase 3/commercial-scale NRX-101 manufacturing enables clinical trials of NRX-101 for the treatment of PTSD under FDA Good Clinical Practices.

Potential application to treatment of Chronic Pain

NRX-101 for the Treatment of Chronic Pain

Chronic pain is commonly defined as pain that lasts beyond 3 months and extends past normal tissue healing time.

Between 18% and 34% of Americans are believed to suffer from chronic pain.

xi The use of opiates to treat chronic pain has led to a national crisis resulting in widespread addiction and death.

26 The use of opiates to treat chronic pain has led to a national crisis resulting in widespread addiction and death.

Few alternatives to opiates have emerged that both treat chronic pain and potentially decrease craving for opiates among chronic pain sufferers.

4 unchanged sentences

A pilot study of D-cycloserine in the treatment of chronic pain was undertaken by Schnitzer and coworkers in patients with chronic low back pain.

xiv The study randomized 41 participants to a placebo-controlled dose-escalation study of 100mg, 200mg, and 400mg (each dose for two weeks) vs.

29 The study randomized 41 participants to a placebo-controlled dose-escalation study of 100mg, 200mg, and 400mg (each dose for two weeks) vs.

The primary outcome measure was back pain intensity on a 1-10 numeric rating scale.

3 unchanged sentences

Back pain intensity ratings over a six- week, dose escalating, placebo or DCS treatment in CBP.

(a) Across subject averageback pain, assessed on the primary outcome measure of 0–10 numeric rating scale.

(a) Across subject average back pain, assessed on the primary outcome measure of 0–10 numeric rating scale.

(b) Within subject change in pain, relative to baseline, using the 0–10 numeric rating scale.

Error bars are SEMs.

(Source Schnitzer 2016 xiv .)

Source Schnitzer 2016.

Although the authors expressed the post-hoc clinical effect in terms of time from baseline, the observation that DCS did not demonstrate an NMDA-antagonist effect until the critical threshold documented in the NRx patent portfolio was reached is consistent with our understanding of the DCS mechanism of action.

1 unchanged sentence

The Company’s 2022 completion of phase 3/commercial-scale NRX-101 manufacturing enables clinical trials of NRX-101 for the treatment of chronic pain under FDA Good Clinical Practices.

NRX-100 (ketamine)

The Company has not initiated large-scale research involving the use of ketamine for rapid induction and has taken advice from FDA regarding the more straightforward development path that can be achieved if the Company pursues the labeling of NRX-101 in “recently suicidal patients following stabilization.” However, the demonstration that ketamine can achieve

stabilization of those with acute suicidal ideation in bipolar depression provides potentially important insight into the potential value of oral NMDA antagonists in the treatment of this condition.

NRX-101 for the Treatment of Complicated Urinary Tract Infection and Acute Pyelonephritis

D-Cycloserine (DCS) is a broad-spectrum antibiotic that is currently FDA-approved to treat pulmonary or extrapulmonary tuberculosis disease and urinary tract infection (UTI).

30 The drug inhibits two sequential enzymes in the bacterial cell wall peptidoglycan biosynthetic pathway, alanine racemase and D-Ala-D-Ala ligase.

31 DCS also antagonizes a third bacterial enzyme, D-amino acid dehydrogenase.

32 DCS is bactericidal or bacteriostatic depending on the concentration or microorganism of interest.

Since DCS is mostly excreted unchanged by the kidney, the drug reaches substantial levels in the urine.

Indeed, DCS was used to treat various types of infections in the 1950s and 60s, including UTI, with numerous reports showing its clinical efficacy.

33-36 The use of DCS as an antibiotic for the treatment of UTI fell out of favor in the 1970s, however, due to its potential to cause CNS side effects.

The incidence of multi-drug-resistant urinary tract pathogens is outpacing the development of new antimicrobial agents.

Only 17 new systemic antibiotics and 1 related biologic have been approved by the FDA between 2010 and 2022, and very few antibiotics are in clinical development.

37 This has forced a renewed interest in older antimicrobial drugs.

The addition of lurasidone should permit DCS to be administered at dosages that would permit bactericidal action in the urinary tract with dose-limiting side-effects.

NRx tested DCS and NRX-101 (DCS + lurasidone) against various urinary tract pathogens including several multidrug resistant strains.

DCS showed activity against all bacterial isolates tested (Table 1) with minimal inhibitory concentrations (MICs) below levels that can be achieved in the urine.

As expected, lurasidone alone had no antibacterial activity, nor did it interfere with the antibacterial activity of DCS.

Based on these results, the US Food and Drug Administration has awarded Qualified Infectious Disease Product and Fast Track Designation to NRX-101 for the treatment of complicated UTI including acute pyelonephritis.

Minimum Inhibitory Concentrations of DCS and Lurasidone in Cation-Adjusted Mueller Hinton Broth

Antibiotic (μg/mL)

Lurasidone (μg/mL)

DCS + Lurasidone (μg/mL)

aeruginosa PA01

aeruginosa 27853

aeruginosa Xen 41

aeruginosa BAA 3105

pneumoniae 1705

baumannii 19606

baumannii 1605

a, Gentamicin;

c, Tobramycin;

d, Ciprofloxacin

NRX-100 (ketamine) – Development under HOPE Therapeutics

Ketamine HCl is a dissociative, rapid-acting general anesthetic for intravenous or intramuscular injection, approved for surgical anesthesia.

Ketamine has shown in multiple randomized clinical trials the potential to rapidly reduce depressive symptoms and suicidal ideation.

However, the clinical effect has been demonstrated to diminish three to seven days post-dose when used intravenously and two days post-dose when the S-enantiomer is delivered intranasally.

Ketamine is classified as a schedule III substance under the Controlled Substances Act, due to its potential for addiction.

This effect is apparently unrelated to its properties as an anti-infective.

Ketamine HCl, infused at 0.5 mg/kg IV over 40 minutes has been shown to induce acute reductions in suicidality and depression in patients with bipolar depression, relative to control.

The Company has undertaken to assemble a New Drug Application for use of Ketamine in suicidal depression, based on existing clinical trials conducted under government auspices that the Company and its regulatory counsel believe constitute evidence of safety and efficacy in “adequately-controlled studies” required for drug approval.

The Company has executed licenses to use the underlying data from those trials with Columbia University and with a consortium of 8 French Government-owned psychiatric hospitals.

A randomized controlled trial of ketamine in the treatment of suicidal ideation among patients with bipolar depression was conducted at Columbia University under NIH funding.

3 unchanged sentences

Error bars represent ± one standard error of the mean (SEM).

Source Grunebaum 2017 iv .

Source Grunebaum 2017 9

A randomized, controlled multicenter trial was conducted at 8 French hospitals by Abbar and coworkers.

7 unchanged sentences

The overall odds ratio of 3.7 (P<0.001) was largely driven by the 14 fold increased odds of remission from suicidal ideation seen among the subgroup with bipolar depression (P<.001).

Source Abbar 2022.

A randomized prospective open-label trial was conducted to determine the efficacy of ketamine versus that of electroconvulsive (electroshock) therapy for suicidal ideation in bipolar depression.

In addition to providing a basis for developing ketamine as an induction drug for treatment of suicidal ideation in bipolar depression, the above clinical findings provide important clinical support for the use of NMDA-antagonist drugs in the treatment of this condition.

Additional Potential Psychiatry Products

Our intellectual property estate enables us to pursue additional combinations of known molecules, including dextromethorphan, d-methadone, and other named NMDA antagonists.

The majority of patients with depression have MDD.

Additionally, PTSD is an area of high unmet need for which there are very few pharmacological treatment options.

PTSD can also be associated with suicidality and depression, in particular severe PTSD.

Whereas episodes of depression in bipolar disorder are episodic and tend to resolve in two to three months, depression is a chronic feature of MDD, and it can also be associated with PTSD.

NRX-102, is a potential new product in which we expect to pair a fixed dose combination of DCS with Mirtazapine, a currently approved antidepressant.

In the 2013 Phase II study, clinical data demonstrate the potential efficacy of DCS in combination with an SSRI antidepressant versus an SSRI antidepressant alone in treating patients with treatment resistant MDD.

We expect to resume the exploratory preclinical development of NRX-102.

Further, we have identified additional 5-HT2A antagonists that may be appropriately paired with DCS.

We are also further guided by preclinical data disclosed in our patents and publications which demonstrates that DCS may inhibit the akathisia induced by SSRI antidepressants.

Existing clinical data have shown DCS to be a useful initial therapeutic agent with which to target the glycine site on the NMDA receptor.

However, DCS has mixed agonist/antagonist effects and its antagonist properties are only manifest at high doses of DCS.

We have identified other small molecule NMDA antagonists that are effective at lower doses and may be paired with 5-HT2A antagonists in order to yield a dual-targeted pro-drug.

Accordingly, we plan to explore design initiatives to develop candidate prodrugs that will expand on the dual-targeted properties of NRX-101 and NRX-102.

Our patent portfolio includes issued and pending claims for many such dual- targeted combinations.

Nierenberg A, Lavin, Javitt DC, et.

Jordan W, Sapko MT, Siegel R, Javitt J.

NRX-101, a Rapid-Acting Anti-Depressant, Does Not Cause Neurotoxicity Following Ketamine Administration in Preclinical Models.

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D-cycloserine is not susceptible to self-administration using an intravenous self-administration model in male ketamine-habituated Sprague-Dawley rats.

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10.1016/j.pbb.2023.173586

Sapko MT, Manyak M, Panicucci R, Javitt JC.

NRX-101 (D-Cycloserine+ Lurasidone), a Qualified Infectious Disease Product, is Active Against Drug-Resistant Urinary Pathogens In Vitro.

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D-Cycloserine for the Treatment of Chronic Pain.

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Available at SSRN 4537055.

Nierenberg A, Lavin P, Javitt DC, et al.

NRX-101 (D-cycloserine plus lurasidone) vs.

1 unchanged sentence

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Schnitzer TJ, Torby S, Herrmann K, Kaushal G, Yeasted R, Apkarian AV.

A Systematic Review and Meta-analysis of Randomized Controlled Trials.

Anesth Analg.

2019;129(1):241-254.

10.1213/ANE.0000000000004185

Schnitzer TJ, Torbey S, Herrmann K, Kaushal G, Yeasted R, Vania Apkarian A.

A randomized placebo-controlled pilot study of the efficacy and safety of D-cycloserine in people with chronic back pain.

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Summary of NRx Material In-licensing Obligations

Glytech Development and License Agreement (“Glytech DLA”)

Development and License Agreement (“Glytech DLA”)

The Company was founded based upon a development agreement with Glytech, a Company founded by Daniel Javitt.

The initial Glytech development agreement was signed on August 6, 2015, and subsequently amended on May 2, 2016, October 19, 2016, June 13, 2018, April 16, 2019, December 31, 2020, August 6, 2022, November 6, 2022 and January 31, 2023.

The initial Glytech development agreement was signed on August 6, 2015, and subsequently amended on May 2, 2016,

October 19, 2016, June 13, 2018, April 16, 2019, December 31, 2020, August 6, 2022, November 6, 2022 and January 31, 2023.

Pursuant to the Glytech DLA, Glytech granted to NeuroRx an irrevocable, perpetual, exclusive (even as to Glytech) royalty-free license, with the right to sublicense, to use the Licensed Technology (as defined below) to develop, manufacture and offer for sale drug products for the treatment of depression and suicide associated with bipolar disorder in humans, including all products containing (a) DCS (including metabolites and structural variants thereof) combined with an antidepressant agent or an antipsychotic agent (including but not limited to lurasidone), or (b) DCS (including metabolites and structural variants thereof) for treatment of all types of bipolar, depressive and/or anxiety disorders and/or symptoms thereof.

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“Excluded Technology” means any other patent right and knowhow owned by Glytech that does not relate specifically to compositions containing either DCS or lurasidone.

Regardless of the option, NRx has the intellectual property necessary to perform it’s business as currently anticipated.

NRx Obligations

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AU 2018203371

US 11,576,911

European Patent Convention

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BR 11 2019 026449 3

CN 201880051813.X

GE AP201815254

MX/a/2019/015120

KR 10-2609676

ZA 2019/08616

JP 2019-564867

AU 2018274767

BR 11 2019 024802-1

CN 201880048653.3

GE AP201815247

MX/a/2019/014113

KR 10-2019-7038209

ZA 2019/08617

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Manufacturing Agreements

As part of our agreement with Relief Therapeutics we have transferred all manufacturing rights and know-how that we acquired for ZYESAMI (aviptadil) to Relief, including our collaborations with Nephron Pharmaceuticals and Alcami as contract manufacturers, and with the Polypeptide Group as a supplier of active pharmaceutical ingredient (“API”).

The ZYESAMI manufacturing contract with Alcami does not affect our ability to contract with Alcami for other purposes.

The Company has established a manufacturing agreement with Alcami for the manufacturing of NRX-101.

In 2022, the Company has entered into a manufacturing agreement with Alcami for the manufacturing of NRX-101.

This enabled the technology transfer of manufacturing processes previously done in China to the U.S.

In October of 2022 the Company submitted a Module 3 IND amendment to the FDA, allowing it to manufacture clinical supplies in the U.S.

Cardinal Health Distribution Agreement

We have entered into an Exclusive Distribution Agreement with Cardinal Health 105, Inc.

(“Cardinal Health”), with an effective date of September 25, 2020 (the “CHDA”).

Under the CHDA, we appointed Cardinal Health as the exclusive third-party logistics distribution agent, and as an authorized distributor, of certain NRx’s products (the “Products”) in the U.S.

and its territories, possessions, and commonwealths.

Although this contract was initially signed in connection with the distribution of ZYESAMI, this agreement remains in place, as it could enable our distribution for NRX-101.

Under the CHDA, Cardinal Health will provide services to us including, without limitation, storage, distribution, returns, customer support, financial support, EDI and system access support (the “CHDA Services”).

The CHDA Services are to be provided by Cardinal Health as set forth in one of two operating model guidelines:

the Traditional Third-Party Logistics (“3PL”) Operating Guidelines (“OPG”), or the Title Model Operating Guidelines (“TMOPG”).

Both the OPG and the TMOPG are attached to and incorporated by reference into the CHDA.

NRx and Cardinal Health have not yet decided which of these two operating model guidelines will govern the delivery of the CHDA Services;

that decision will be made closer to approval by the FDA of our first commercial product.

• Identify written policies and procedures to be followed in delivering the CHDA Services;

• Identify the deliverables from each Party required under the CHDA;

• Define the roles and responsibilities of each Party and key personnel;

• Define the reports and data required;

• Set the baseline for the OPG program for delivery of the CHDA Services, and manage future changes to the operating model.

Under the OPG, Cardinal Health will accept the Products from us on consignment, with the Products being transported by us or its shipping agent to Cardinal Health’s secured access 3PL warehousing facilities.

Cardinal Health has established standard operating procedures for managing all activities at its warehousing facilities, which are approved and controlled by Cardinal Health’s centralized distribution management system.

All Cardinal Health warehouse personnel are trained under documented programs that are compliant with applicable federal and state laws and regulations and with cGMP.

Our Products are warehoused by Cardinal Health under controlled temperature conditions, with any temperature excursions lasting more than one hour being reported within two business days from the discovery of the excursion.

The Products are picked from inventory in Cardinal Health’s warehouse on a “First-to-Expire, First-Out” basis.

Pricing and conditions of sale are set by us.

Cardinal Health publishes price lists for the Products to be sold to its customers.

Cardinal Health sends invoices via email to customers on the day of shipment, or by mail on the morning following shipment, of the Products.

Customers then remit payment to our bank lockbox via EFT, ACH or wire transfer,

and NRx’s bank then forwards information regarding payments to Cardinal Health which then reconciles and applies cash receipts to the accounts receivable.

Most of the logistical provisions in the TMOPG are identical to those of the OPG.

The primary material difference between the TMOPG and the OPG is that under the TMOPG, title to and ownership of the Products pass from NRx to Cardinal Health upon purchase of the Products by Cardinal Health from NRx or its manufacturing agent.

Cardinal Health handles all sales, shipment/distribution, customer service and AR activities in the same way as outlined for the OPG model, except that Cardinal Health maintains a bank lockbox for receipt of payments of invoices by customers, rather than that lockbox being maintained by NRx.

Pricing and Payment;

Forecast and Price List

As compensation for the CHDA Services delivered by Cardinal Health, we are responsible for paying the fees set forth in the CHDA.

The fees schedule is confidential to Cardinal Health and cannot be disclosed without permission from Cardinal Health.

Fees are subject to adjustment not more than once per contract year (after the first contract year) by 3%, or if Cardinal Health can reasonably demonstrate a material increase in the cost of providing the CHDA Services.

Under the CHDA, we are responsible for providing a forecast of volume of the Products to be handled by Cardinal Health.

Any variances from the forecast, and any adjustments that may therefore be needed to the forecast going forward, are handled through good-faith negotiation by the parties.

We are also responsible for providing to Cardinal Health a Product price list, setting prices to be charged to customers for the Products sold by or distributed by Cardinal Health.

Any change to be implemented in pricing for the Products must be communicated by us to Cardinal Health at least 72 hours prior to the effective date of such price change.

Term and Termination

The CHDA has an initial term of three (3) years following first shipment of an FDA-approved Product to a commercial customer (the “Initial Term”), and automatically renews for additional terms of one (1) year (each, a “Renewal Term”), unless the CHDA is earlier terminated during either the Initial Term or any Renewal Term by a written notice of termination given by either party to the other at least 90 days prior to the end of the Initial Term or any Renewal Term.

The CHDA also can be immediately terminated by either party if:

(1) the other party files for bankruptcy protection or enters into receivership or trusteeship, and if a bankruptcy or insolvency order is entered such order is not discharged within 30 days;

or (2) the other party materially breaches any provision of the CHDA and such breach is not cured within 30 days of receiving notice of breach from the non-breaching party, except that Cardinal Health may terminate the CHDA if NRx fails to timely pay invoices from Cardinal Health within 15 days of having received written notice of non-payment from Cardinal Health.

Following termination for any reason, each party’s rights and obligations that accrued prior to the date of termination shall survive the termination, and all Products warehoused at Cardinal Health’s 3PL facilities will be returned to NRx or its designee.

In December 2022, as part of our agreement with Relief Therapeutics we transferred all manufacturing rights and know-how that we acquired for ZYESAMI (aviptadil) to Relief, including our collaborations with Nephron Pharmaceuticals and Alcami as contract manufacturers, and with the Polypeptide Group as a supplier of active pharmaceutical ingredient (“API”).

This technology transfer does not affect our ability to contract with Alcami and Nephron for other purposes.

In 2023, the Company entered into a development and manufacturing agreement with Nephron Pharmaceuticals, Inc.

for the manufacture of ketamine HCl (NRX-100, HTX-100) that the Company intends to distribute via its HOPE Therapeutics franchise.

Manufacture will initially consist of the generic formulation of ketamine in a novel diversion-resistant presentation.

Under the development portion of the agreement the Company intends to develop a pH-balanced new formulation of ketamine that will be suitable for subcutaneous use and that may be suitable for oral administration with predictable systemic absorption.

Government Regulation and Product Approval

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Failure to comply with the applicable U.S.

requirements at any time during the product development process, approval process or after approval, may subject an

applicant to a variety of administrative or judicial sanctions or other actions, such as the FDA’s delay in review of or refusal to approve a pending NDA, withdrawal of an approval, imposition of a clinical hold or study termination, issuance of Warning Letters or Untitled Letters, mandated modifications to promotional materials or issuance of corrective information, requests for product recalls, consent decrees, corporate integrity agreements, deferred prosecution agreements, product seizures or detentions, refusal to allow product import or export, total or partial suspension of or restriction of or imposition of other requirements relating to production or distribution, injunctions, fines, debarment from government contracts and refusal of future orders under existing contracts, exclusion from participation in federal and state healthcare programs, FDA debarment, restitution, disgorgement or civil or criminal penalties, including fines and imprisonment.

requirements at any time during the product development process, approval process or after approval, may subject an applicant to a variety of administrative or judicial sanctions or other actions, such as the FDA’s delay in review of or refusal to approve a pending NDA, withdrawal of an approval, imposition of a clinical hold or study termination, issuance of Warning Letters or Untitled Letters, mandated modifications to promotional materials or issuance of corrective information, requests for product recalls, consent decrees, corporate integrity agreements, deferred prosecution agreements, product seizures or detentions, refusal to allow product import or export, total or partial suspension of or restriction of or imposition of other requirements relating to production or distribution, injunctions, fines, debarment from government contracts and refusal of future orders under existing contracts, exclusion from participation in federal and state healthcare programs, FDA debarment, restitution, disgorgement or civil or criminal penalties, including fines and imprisonment.

The process required by the FDA before a new drug may be marketed in the U.S.

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The FDA has advised us that no further preclinical studies are needed for submission of an NDA for NRX-100.

The FDA has advised us and we have agreed that a genotoxicity study and a non-clinical maternal/fetal study for potential fetal effects

are required prior to filing of an NDA for NRX-101.

The FDA has advised us and we have agreed that a genotoxicity study and a non-clinical maternal/fetal study for potential fetal effects are required prior to filing of an NDA for NRX-101.

Furthermore, drugs that are potentially used chronic or chronic/intermittently do need to show preclinical carcinogenicity studies.

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In Phase 1, the drug is initially introduced into healthy human subjects or subjects with the target disease or condition and tested for safety, dosage tolerance, absorption, metabolism, distribution, excretion and, if possible, to gain an early indication of its effectiveness.

In Phase II, the drug typically is administered through well-controlled studies to a limited subject population with the target disease or condition to identify possible adverse effects and safety risks, to preliminarily evaluate the efficacy of the product for specific targeted diseases and to determine dosage tolerance and optimal dosage.

In Phase III, the drug is administered to an expanded subject population, generally at geographically dispersed clinical trial sites, in two adequate and well-controlled clinical trials to generate enough data to statistically evaluate the efficacy and safety of the product for approval, to establish the overall risk-benefit profile of the product and to provide adequate information for the labeling of the product.

In Phase 2, the drug typically is administered through well-controlled studies to a limited subject population with the target disease or condition to identify possible adverse effects and safety risks, to preliminarily evaluate the efficacy of the product for specific targeted diseases and to determine dosage tolerance and optimal dosage.

In Phase 3, the drug is administered to an expanded subject population, generally at geographically dispersed clinical trial sites, in two adequate and well-controlled clinical trials to generate enough data to statistically evaluate the efficacy and safety of the product for approval, to establish the overall risk-benefit profile of the product and to provide adequate information for the labeling of the product.

Furthermore, depending on the expected use of a drug (e.g., acute, intermittent, chronic), regulatory requirements may include a safety database that goes beyond the number of subjects in the efficacy studies.

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Progress reports and other summary information detailing the results of the clinical trials must be submitted at least annually to the FDA and more frequently if certain unexpected Serious Adverse Events occur or other significant safety information is found.

Phase I, Phase II and Phase III clinical trials may not be completed successfully within any specified period, or at all.

Phase I, Phase 2 and Phase 3 clinical trials may not be completed successfully within any specified period, or at all.

Furthermore, the FDA or the sponsor may suspend or terminate a clinical trial at any time on various grounds, including a finding that the research subjects are being exposed to an unacceptable health risk or the trial is not being conducted in accordance with the applicable regulatory requirements or the protocol.

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In the case of NRX-100/101, the FDA has agreed with us in writing that the investigational product meets the standards for a 505.b.2 (commonly called drug-repurposing) pathway, whereby the extensive safety literature regarding the individual components of NRX-101 may be cited in lieu of repeating various preclinical and Phase I clinical studies.

Because of examples in recent years where sponsors have received Complete Response Letters based on lack of agreement with the FDA regarding the research path required for NDA submission, we worked collaboratively with the FDA for one year in order to negotiate a Special Protocol Agreement (“SPA”) that would govern the development of NRX-101 and would define the Phase III trial required for the target indication., should the clinical trial be successful.

Because of examples in recent years where sponsors have received Complete Response Letters based on lack of agreement with the FDA regarding the research path required for NDA submission, we worked collaboratively with the FDA for one year in order to negotiate a Special Protocol Agreement (“SPA”) that would govern the development of NRX-101 and would define the Phase 2I trial required for the target indication., should the clinical trial be successful.

This SPA was issued to us in April 2018 and defines the single clinical trial required for submission of NRX-101 for treatment of bipolar depression with acute suicidal ideation or behavior.

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The FDA reviews an NDA to determine, among other things, whether the drug is safe and effective and whether the facility in which it is manufactured, processed, packaged or held meets standards designed to assure the product’s continued safety, quality and purity.

Under the FFDCA, before approving a drug for which no active ingredient (including any ester or salt of active ingredients) has previously been approved by the FDA, the FDA must either refer that drug to an external advisory committee or provide in an action letter, a summary of the reasons why the FDA did not refer the drug to an advisory

The external advisory committee review may also be required for other drugs because of certain other issues, including clinical trial design, safety and effectiveness, and public health questions.

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Moreover, the recently enacted Drug Quality and Security Act, imposes new obligations on manufacturers of pharmaceutical products related to product tracking and tracing.

Among the requirements of this new legislation,

manufacturers will be required to provide certain information regarding drug products to individuals and entities to which product ownership is transferred, label drug products with a product identifier, and keep certain records regarding drug products.

Among the requirements of this new legislation, manufacturers will be required to provide certain information regarding drug products to individuals and entities to which product ownership is transferred, label drug products with a product identifier, and keep certain records regarding drug products.

The transfer of information to subsequent product owners by manufacturers will eventually be required to be done electronically.

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The DEA regulates the handling of controlled substances through a closed chain of distribution.

This control extends to the equipment and raw materials used in their manufacture and packaging in order to prevent loss and diversion into illicit channels of commerce.

extends to the equipment and raw materials used in their manufacture and packaging in order to prevent loss and diversion into illicit channels of commerce.

Annual registration is required for any facility that manufactures, distributes, dispenses, imports or exports any controlled substance.

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In addition to FDA restrictions on marketing of pharmaceutical products, federal and state fraud and abuse, and other laws regulations, and requirements restrict business practices in the biopharmaceutical industry.

These laws include anti-kickback and false claims laws and regulations, state and federal transparency laws regarding payments or other items of

value provided to health care professionals, as well as data privacy and security laws and regulations and other requirements applicable to the healthcare industry, including pharmaceutical manufacturers.

These laws include anti-kickback and false claims laws and regulations, state and federal transparency laws regarding payments or other items of value provided to health care professionals, as well as data privacy and security laws and regulations and other requirements applicable to the healthcare industry, including pharmaceutical manufacturers.

There are also laws, regulations, and requirements applicable to the award and performance of federal contracts and grants.

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Government or knowingly making, using, or causing to be made or used a false record or statement material to a false or fraudulent claim to the federal government, including payments under a federal grant.

A claim includes “any request or demand” for money or property presented to the U.S.

claim includes “any request or demand” for money or property presented to the U.S.

The False Claims Act also applies to false submissions that cause the government to be paid less than the amount to which it is entitled, such as a rebate.

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Government contracts and grants.

HIPAA also created Federal criminal statutes that prohibit, among other actions, knowingly and willfully executing, or attempting to execute, a scheme to defraud any healthcare benefit program, including private third-party payers, knowingly and willfully embezzling or stealing from a healthcare benefit program, willfully obstructing a criminal investigation of a healthcare offense, and knowingly and willfully falsifying, concealing or covering up a material fact or making any materially false, fictitious or fraudulent statement in connection with the delivery of or payment for healthcare benefits,

items or services.

As discussed above, the Affordable Care Act amended the intent standard for certain of HIPAA’s healthcare fraud provisions such that a person or entity no longer needs to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation.

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Penalties for violating HIPAA include civil penalties, criminal penalties and imprisonment.

Among other things, HITECH, through its implementing regulations, makes HIPAA’s privacy and security standards directly applicable to “business associates,” defined as a person or organization, other than a member of a covered entity’s workforce, that creates, receives, maintains or transmits protected health information on behalf of a covered entity for a function or activity regulated by HIPAA.

or transmits protected health information on behalf of a covered entity for a function or activity regulated by HIPAA.

HITECH also increased the civil and criminal penalties that may be imposed against covered entities, business associates and possibly other persons, and gave state attorneys general new authority to file civil actions for damages or injunctions in Federal courts to enforce the Federal HIPAA laws and seek attorneys’ fees and costs associated with pursuing Federal civil actions.

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The commercial success of our product candidates and our ability to commercialize any approved product candidates successfully will depend in part on the extent to which governmental authorities, private health insurers and other third-party payers provide coverage for and establish adequate reimbursement levels for our therapeutic product candidates.

In the U.S., the European Union and other potentially significant markets for our product candidates, government authorities and third-party payers are increasingly imposing additional requirements and restrictions on coverage, attempting to limit reimbursement levels or regulate the price of drugs and other medical products and services, particularly for new and

innovative products and therapies, which often has resulted in average selling prices lower than they would otherwise be.

For example, in the U.S., Federal and state governments reimburse covered prescription drugs at varying rates generally below average wholesale price.

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Among policy makers and payers in the U.S.

and elsewhere, there is significant interest in promoting changes in healthcare

systems with the stated goals of containing healthcare costs, improving quality and expanding access.

and elsewhere, there is significant interest in promoting changes in healthcare systems with the stated goals of containing healthcare costs, improving quality and expanding access.

In the U.S., the pharmaceutical industry has been a particular focus of these efforts and has been significantly affected by major legislative initiatives, including, most recently, the Affordable Care Act, which became law in March 2010 and substantially changes the way healthcare is financed by both governmental and private insurers.

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Generally, the ANDA or 505(b)(2) NDA cannot be approved until all listed patents have expired, except when the ANDA or 505(b)(2) NDA applicant challenges a listed patent or if the listed patent is a patented method of use for which approval is not being sought.

A certification that the proposed product will not infringe the already approved product’s listed

patents or that such patents are invalid or unenforceable is called a Paragraph IV certification.

A certification that the proposed product will not infringe the already approved product’s listed patents or that such patents are invalid or unenforceable is called a Paragraph IV certification.

We may seek Paragraph IV Certification for our product candidates.

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Orphan Drug Designation and Exclusivity

The Orphan Drug Act provides incentives for the development of drugs intended to treat rare diseases or conditions, which generally are diseases or conditions affecting less than 200,000 individuals annually in the U.S., or affecting more

than 200,000 in the U.S.

and for which there is no reasonable expectation that the cost of developing and making the drug available in the U.S.

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Whether or not we obtain FDA approval for a product, we would need to obtain the necessary approvals by the comparable regulatory authorities of foreign countries before we can commence clinical trials or marketing of the product in those countries.

The approval process varies from country to country and can involve additional product testing and additional administrative review periods.

approval process varies from country to country and can involve additional product testing and additional administrative review periods.

The time required to obtain approval in other countries might differ from and be longer than that required to obtain FDA approval.

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Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business