What changed in this filing

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Item 1. Business

2025-03-14 compared with 2024-03-29 · 269 added, 634 removed, 551 unchanged (62% of the section changed)

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.

10,583,138 and foreign counterparts).

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.

NRx Pharmaceuticals, Inc.

NRXP) (“NRX” or the “Company”) is a clinical-stage bio-pharmaceutical company which develops and will distribute, through its wholly-owned operating subsidiary, NeuroRx, Inc.

(“NeuroRx”), novel therapeutics for the treatment of central nervous system disorders including suicidal depression, chronic pain, and post-traumatic stress disorder (“PTSD”) and now schizophrenia.

All of our current drug development activities are focused drugs that modulate on the N-methyl-D-aspartate (“NMDA”) receptor in the brain and nervous system, a neurochemical pathway that has been disclosed in detail in our annual filings.

The Company has two lead drug candidates that are expected to be submitted by year end for Food and Drug Administration ("FDA") approval with anticipated FDA decision dates under the Prescription Drug User Fee Act (“PDUFA”) by the end of June 2025:

NRX-101, an oral fixed dose combination of D-cycloserine and lurasidone and NRX-100, a preservative-free formulation of ketamine for intravenous infusion.

In February 2024, NRx incorporated HOPE Therapeutics, Inc.

(“HOPE”), a medical care delivery organization focused on interventional psychiatric treatment of the above conditions with NMDA-targeted and other psychedelic drugs, neuromodulatory devices, such as Transcranial Magnetic Stimulation (“TMS”), digital therapeutics, and medication management.

NeuroRx is organized as a traditional research and development ("R&D") company, whereas HOPE is organized as a medical care delivery company intended to own and/or operate clinics that serve patients with suicidal depression, PTSD, and other serious Central Nervous System (CNS) disorders.

The 2024 fiscal year marked a period of both expansion and change for NRx.

Throughout this time, the Company implemented a restructuring of its leadership to address challenges related to capital formation, clinical trial enrollment, and corporate development.

These efforts led to measurable achievements in 2024 and positioned the Company for growth and the achievement of our development objectives in 2025.

Management’s plan, through the establishment of HOPE is to transform NRx from a pre-revenue biotechnology company to a revenue-generating enterprise that continues to develop life-saving drugs and technologies (through NRx) while also treating patients (through HOPE).

During 2024 and through the date of this Annual Report, the Company has achieved the following:

Recent Developments

We consummated a series of financing agreements with an institutional investor for up to $16.3 million in debt capital, for which we closed on $10.87 million in 2024 and subsequently closed $8.5 million in a combination of convertible debt and an above-market common stock and warrant offering in January 2025.

We were presented with and are currently negotiating a term sheet with a publicly-traded strategic investor to provide additional capital to support the expansion of HOPE clinics.

In addition, management is negotiating with several commercial lenders to provide additional financing to support the acquisition of additional clinics on standard commercial loan terms.

Although no assurances can be given, and assuming we’re able to consummate the proposed financings, management believes that we will have sufficient financing to consummate our previously announced acquisitions, execute our business plan and achieve our projected revenue objectives.

Drug Development

We filed module 3 (manufacturing) of our NDA for NRX-100 (preservative-free sterile ketamine) in a tamper-resistant, diversion resistant packaging presentation.

NRX-100 was previously granted Fast Track Designation by FDA in combination with use of NRX-101.

Ketamine efficacy data is in hand from four clinical trials.

Three manufacturing lots are now completed with filed stability data suitable for shelf life exceeding two years at room temperature.

The anticipated PDUFA date for this settlement is prior to December 30, 2025.

We also anticipate filing an Abbreviated New Drug Application (“ANDA”) for the use of preservative-free ketamine in all currently-indicated clinical applications.

We initiated the filing of a New Drug Application (“NDA”) in the fourth quarter of 2024 for Accelerated Approval under Breakthrough and Priority Review of NRX-101 in treatment of bipolar depression in people at risk of akathisia, based on the Phase 2b/3 and STABIL-B data.

Three manufacturing lots are now completed with more than 24 months of room temperature shelf-stability.

The anticipated PDUFA date for this application is prior to December 31, 2025.

Work is ongoing to prepare the module 3 manufacturing section documenting our transition from manufacturing at WuXi Apptec in Shanghai to manufacturing of NRX-101 in North Carolina with manufacture of three commercial lots.

We accepted a non-binding offer from a commercial pharmaceutical company to license and distribute NRX-100 (preservative-free ketamine) that provides for $325 million in potential milestones plus a sliding scale royalty that ranges from 11% - 16% of sales.

We initiated development of and plan to file a citizen’s petition with the FDA to remove benzethonium chloride, a known neurotoxic substance from presentations of ketamine intended for intravenous use.

Management believes that the preservative-free feature of NRX-100 will be deemed of benefit to patients because of the known toxicity of benzethonium chloride in current generic products.

As a next-generation product, we developed a novel, patentable pH neutral formulation for ketamine (designed as HTX-100) that will be suitable for both intravenous and subcutaneous administration.

Initial laboratory lots demonstrate shelf stability and ongoing stability is being assessed.

Ketamine in its current commercial presentations cannot be administered subcutaneously because of its high acidic (pH 3.5-4.0) properties, an acidity range that is known to cause pain and skin ulcers.

We anticipate long-term patent protection on this novel product.

This product is expected to undergo clinical testing in 2025/2026 and be ready for FDA approval in 2027.

NRX-101 in the treatment of Complicated Urinary Tract Infection (“cUTI”) was granted Qualified Infectious Disease Product (“QIDP”), Fast Track, and Priority Review designations in 2024.

We have now demonstrated that NRX-101 does not damage the microbiome of the gut, in contrast to all other advanced antibiotics and is less likely to cause C.

Difficile infection (a potentially lethal side effect of antibiotic treatment).

NRx is reviewing partnership options.

We executed a Memorandum of Understanding with Foundation FundaMental for rights to develop a potential disease modifying drug for schizophrenia, autism, and acute mania.

If successful, this would represent the first drug to reverse the underlying disease mechanism of these conditions, rather than simply treating symptoms.

HOPE Therapeutics

We partnered with representatives of ketamine clinic operators to construct a care platform that will include ketamine, operational support, and digital therapeutic extensions.

In advance of FDA approval, HOPE anticipates that it will supply ketamine under 503b pharmacy licensure to meet the national ketamine shortage declared by FDA.

We signed non-binding letters of intent to acquire three precision psychiatry centers, the closing of which is subject to execution of definitive agreements.

Although no assurances can be given, we are also currently negotiating the terms for the acquisition of six additional psychiatry centers, which are subject to due diligence review and execution of a letter of intent.

Upon closing, the acquisitions will form the foundation for the development of HOPE to achieve our objective of creating a national network offering interventional psychiatry to treat suicidal depression and PTSD.

We engaged BTIG, a leading investment bank, to support us in identifying and acquiring additional clinic candidates to join the HOPE network sufficient to achieve management’s revenue targets by year-end 2025.

Our potential acquisition targets have contracts with the Veterans Administration for the treatment of depression and, assuming closing of our previously announced acquisitions, we expect to expand to the treatment of PTSD by year-end 2025.

Other Developments

On November 2022, the Company issued a Convertible Promissory Note to Streeterville, LLC, (“Streeterville Notes”) as previously disclosed.

In March 2024, Streeterville deemed a proposed dividend of HOPE shares to constitute a basis of default under the Streeterville Notes.

Subsequent arbitration found that the proposed HOPE dividend was not a basis for default.

In August 2024 the Company signed a settlement agreement with Streeterville to redeem the Streeterville Notes at a discount to the amounts claimed and completed payments of $5.55 million in satisfaction of all claims under the Streeterville Notes in October 2024.

On March 28, 2024, the Company filed with the Secretary of State of the State of Delaware a Certificate of Amendment to the Company’s Second Amended and Restated Certificate of Incorporation (the “Charter Amendment”) to effect a 1-for-10 reverse stock split (the “Reverse Stock Split”) of the Company’s Common Stock, which Reverse Stock Split was effective as of April 1, 2024.

All references in this Annual Report to number of common shares, price per share and weighted average number of shares outstanding have been adjusted to reflect the Reverse Split on a retroactive basis.

Company Overview

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.

Both products have Fast Track designation from the 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.

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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.

The Company has previously announced plans to spin off HOPE as a majority-owned company, with a minority interest held by new shareholders resulting from planned financings.

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.

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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

The COVID lockdown ended in March 2022 and the Company’s Board unanimously voted to return our focus to CNS drug development.

Accordingly, in June 2022 the Company launched a clinical trial of NRX-101 in the treatment of suicidal ideation among patients with bipolar depression (the “003 trial) and in June 2024 announced results indicating that NRX-101 was not superior to standard of care medication for decreasing symptoms of depression (the primary endpoint) but was superior to standard of care for reducing symptoms of suicidal ideation (the declared secondary endpoint).

In late 2023, the Company recognized the need to create a model for integrated care of patients with suicidal depression, PTSD, and related conditions that combines NMDA-targeted medication therapy (such as NRX-100 and NRX-101) with transcranial magnetic stimulation (“TMS”), psychiatric medication management, and digital therapeutics.

Accordingly, in January 2024, management incorporated HOPE as a wholly-owned subsidiary for this purpose.

Management recognized that the complexity of these life-threatening diseases required an integrated care model that is largely unavailable today.

Throughout 2024, the Company developed HOPE’s business plan, attracted initial capital, and identified key pillar acquisitions.

2024 Financings

August 2024 SPA

On August 12, 2024, the Company executed a Securities Purchase Agreement (the “August SPA”) and related agreements, under which the Company agreed to sell and issue, and certain purchasers agreed to purchase, an aggregate of $16.3 million of securities.

The consideration payable by the purchasers under the August SPA was comprised of three equal closings of $5.435 million, each subject to certain closing conditions.

The securities to be issued and sold by the Company include up to $16.3 million of senior secured convertible notes (the “Notes”) and warrants to purchase shares of the Company’s common stock (the “Warrants”).

The proceeds arising from the sale of the Notes and the Warrants were used to settle the Company’s outstanding amounts owed to Streeterville (as defined below) and other working capital needs.

The Company has, as of the date of this Annual Report, consummated the first tranche, second tranche, and third tranche under the August SPA, with gross proceeds to the Company of $16.3 million.

The Notes bear interest at the rate of 6% per annum and mature in 15 months following their date of issuance.

The Notes may be settled in cash or in shares of the Company’s common stock, at the sole discretion of the holder, at the applicable conversion price.

The Notes may not be prepaid by the Company however, the holders of the Notes may elect to convert the Notes, in whole or in part, into shares of the Company’s common stock at any time after the original issuance date.

The conversion price:

(A) for the Notes issued in the first tranche will equal the lower of (i) $2.4168, or (ii) a price equal to 92% of the lowest volume-weighted average price during the seven-trading day period immediately preceding the applicable conversion date (the “Alternative Conversion Price”);

(B) for the Notes issued in the second tranche will equal the lower of (i) $1.766, or (ii) the Alternative Conversion Price;

and (C) for the Notes issued in the third tranche will equal the lower of (i) $3.78, or (ii) the Alternative Conversion Price.

The Notes include certain redemption, protection features and default interest and penalties.

The Notes are secured by all assets of the Company, including its intellectual property.

The Warrants have a term of 5 years, an exercise price of $2.4168 per share for the Warrants issued in the first tranche, $1.766 per share for the Warrants issued in the second tranche, and $3.78 per share for the Warrants issued in the third tranche, each subject to adjustment as more specifically set forth in the Warrants, and are exercisable immediately upon issuance.

April 2024 Offering

On April 18, 2024, the Company entered into an underwriting agreement (the “April Underwriting Agreement”) with EF Hutton LLC (the “Representative”), as the representative of the several underwriters named therein (the “April Underwriters”), relating to an underwritten public offering (the “April 2024 Public Offering”) of 607,000 shares (the “April Shares”) of Common Stock.

The public offering price for each share of Common Stock was $3.30.

On April 19, 2024, the offering closed.

Aggregated proceeds from the offering were approximately $2.4 million (including proceeds from the exercise of the over-allotment option granted to the Representative, as more fully described below), before deducting underwriting discounts and commission and estimated expenses payable by the Company.

Pursuant to the April Underwriting Agreement and the engagement letter dated April 18, 2024, by and between the Company and Representative, the Company agreed to issue to the Representative in connection with the April Offering, a warrant to purchase up to a number of shares of Common Stock representing 5.0% of the Shares and any April Option Shares (as defined below) sold, at an initial exercise price of $3.63 per share, subject to certain adjustments (the “April Underwriter's Warrant”).

On April 19, 2024, the Company issued to the Representative the April Underwriter's Warrant to purchase up to 30,350 shares of Common Stock.

The April Underwriter's Warrants and Over-Allotment Warrants is exercisable nine months following the date of the Underwriting Agreement and terminates on the five-year anniversary of the date of the April Underwriting Agreement.

Pursuant to the April Underwriting Agreement, the Company also granted the Representative a 45-day option to purchase up to an additional 91,050 shares (the “April Option Shares”) of the Common Stock on the same terms as the April Shares sold in the April 2024 Public Offering (the “April Over-Allotment Option”).

In connection with the April Overallotment Exercise, we issued an additional April Underwriter's Warrant to purchase up to 4,553 shares of Common Stock.

The April Overallotment Exercise was exercised in full and closed.

At-The-Market Offering Agreement

On April 15, 2024, the Company increased the maximum aggregate offering amount of the shares of Common Stock issuable under that certain At the Market Offering Agreement, dated August 14, 2023 (the “Offering Agreement”), with H.C.

Wainwright & Co., and filed a prospectus supplement (the “Prospectus Supplement”) under the Offering Agreement for an aggregate of $4.9 million (the “ATM Offering”).

On August 14, 2024, the Company reduced the amount to under the Offering Agreement to $0 and suspended the ATM Offering.

Though December 31, 2024, the Company received aggregate gross cash proceeds to the Company from the ATM Offering of approximately $1.8 million.

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.

On February 27, 2024, we entered into an underwriting agreement (the “February Underwriting Agreement”) with the Representative (as defined above), as the representative of the several underwriters named therein (the “February Underwriters”), relating to an underwritten public offering (the “February 2024 Public Offering”) of 500,000 shares (the “February Shares”) of the Company’s Common Stock.

The public offering price for each share of Common Stock was $3.00, and the February Underwriters purchased the shares of Common Stock pursuant to the February Underwriting Agreement at a price for each share of Common Stock of $2.76.

On February 28, 2024, the February 2024 Public offering closed.

Aggregate gross proceeds from the February 2024 Public Offering were approximately $1.9 million (including proceeds from the exercise of the over-allotment option granted to the Representative, as more fully described below), before deducting underwriting discounts and commissions and estimated expenses payable by the Company.

Pursuant to the February 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 February Option Shares (as defined below) sold, at an initial exercise price of $3.30 per share, subject to certain adjustments (the “February Underwriter’s Warrant”).

On February 28, 2024, the Company issued to the Representative the February Underwriter’s Warrant to purchase up to 25,000 shares of Common Stock.

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

Pursuant to the February Underwriting Agreement, the Company also granted the Representative a 45-day option to purchase up to an additional 75,000 shares (the “February Option Shares”) of the Common Stock on the same terms as the February Shares sold in the February 2024 Public Offering (the “February Over-Allotment Option”).

On March 5, 2024, the February Underwriters exercised the February Over-Allotment Option to purchase the February Option Shares.

In connection with the February Overallotment Exercise, we issued an additional February Underwriter’s Warrant to purchase up to 3,750 shares of Common Stock.

The February 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 270,000 shares of Common Stock and warrants to purchase up to 270,000 shares of Common Stock (the “February Warrants”) at a price of $3.80 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”).

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

2025 Financings

As set forth below, subsequent to December 31, 2024, the Company secured $8.5 million in new financing and anticipates supplementing existing capital with commercial credit and strategic investments sufficient to satisfy our working capital requirements through the end of the fiscal year ending December 31, 2025.

January 2025 Securities Purchase Agreement

On January 27, 2025, the Company entered into a securities purchase agreement (the “RD Purchase Agreement”) with Anson Funds (the “Investors”) for the sale by the Company of 1,215,278 shares (the “RD Shares”) of Common Stock to the Investors, at a purchase price of $2.88 per share, in a registered direct offering (the “Registered Direct Offering”).

Concurrently with the sale of the RD Shares, pursuant to the RD Purchase Agreement the Company also sold to the Investors unregistered Common Stock purchase warrants (the “RD Warrants”) to purchase up to an aggregate of 1,215,278 shares of Common Stock (the “RD Warrant Shares”), in a private placement.

Subject to certain beneficial ownership limitations, the RD Warrants are immediately exercisable upon issuance at an exercise price equal to $2.88 per share of Common Stock, subject to adjustments as provided under the terms of the RD Warrants.

The RD Warrants are exercisable for five years from the RD Closing Date (as defined below).

The closing of the sales of these securities under the RD Purchase Agreement occurred on or about January 29, 2025 (the “RD Closing Date”).

The gross proceeds to the Company from the offerings were approximately $3,500,000, before deducting offering expenses, and excluding the proceeds, if any, from the exercise of the RD Warrants.

The Company intends to use the net proceeds from the transactions for general corporate purposes, including the funding of certain capital expenditures.

The RD Shares were offered and sold by the Company pursuant to an effective shelf registration statement on Form S-3, which was filed with the SEC on June 9, 2022, and subsequently declared effective on June 21, 2022 (File No.

333-265492) (the “Registration Statement”), and the base prospectus dated as of June 21, 2022, contained therein.

The RD Warrants and the RD Warrant Shares were sold and issued without registration under the Securities Act of 1933, as amended (the “Securities Act”), in reliance on the exemptions provided by Section 4(a)(2) of the Securities Act as transactions not involving a public offering and Rule 506 promulgated under the Securities Act as sales to accredited investors, and in reliance on similar exemptions under applicable state laws.

On January 27, 2025, the Company and the Investors entered into a Consent and Waiver Agreement (the “CWA”), relating to certain rights and prohibitions arising under the August SPA and the Notes.

In the CWA, each of the Investors provided its consent under certain restrictive provisions, and waived certain rights, including, among other things, a right to participate in certain Qualified Financings (as defined in the CWA) made by us under the August SPA and the Notes, the prohibition on issuance of certain equity securities, and waiver of any potential liquidated damages arising under that certain Registration Rights Agreement by and between the Company and the Investors dated August 14, 2024, until March 31, 2025.

As consideration for entering into the CWA, in the event that the VWAP of the Common Stock is less than the per share purchase price of the Common Stock sold to the Investors in the Registered Direct Offering on the Trading Day (as defined in the RD Purchase Agreement) immediately prior to the date that the Investors submit their first conversion notice to convert any portion of the Notes issued or to be issued in the Second Closing (as defined in the August SPA) or the Third Closing (as defined in the August SPA), respectively, into shares of Common Stock, the Company agreed to issue to the Investors:

(i) that number of shares of Common Stock equal to (a) the quotient of (I) aggregate purchase price to be paid for all securities in the Registered Direct Offering, divided by (II) the price per share of Common Stock after giving effect to the VWAP-Based Adjustment (as defined below), minus (b) the number of shares of Common Stock issued, or to be issued, to the Investors at or upon the consummation of the Registered Direct Offering (the “Consideration Shares”), and (ii) Common Stock purchase warrants to purchase shares of Common Stock equal to 100% of the aggregate number of Consideration Shares to be issued, with an exercise price equal to the dollar value of the VWAP-Based Adjustment (the “Consideration Warrants”).

For purposes of the CWA, the “VWAP Based-Adjustment” means that amount, in dollars, equal to the greater of either (a) the VWAP of the Common Stock on the Trading Day immediately prior to the date that the Investors submit their first conversion notice to convert any portion of the Notes issued and to be issued in the Second Closing or Third Closing into shares of the Company’s Common Stock, or (b) 80% of the closing price of the Common Stock on the Trading Day immediately prior to the closing of the Registered Direct Offering.

Proposed Strategic Investment and Commercial Funding

The Company was presented with and is currently negotiating a term sheet with a publicly-traded entity engaged in the manufacture of FDA-cleared devices for Transcranial Magnetic Stimulation to provide acquisition capital to support the expansion of HOPE, and is also currently in negotiations with several commercial banks to provide additional acquisition financing for HOPE.

Although no assurances can be given, assuming consummation of the financings on terms currently contemplated by management, we will achieve our objective of financing less than 50% of the proposed acquisition costs, thereby enabling the Company to optimize its cost of acquisition capital as it expands the HOPE clinic network.

Terminated January 2025 Financing

The Company was a party to definitive stock purchase agreements with an Arizona-based investment firm, Smith and Sauer, through their affiliate, JGS Holdings, LLC (“JGS Holdings”) whereby JGS Holdings committed to invest $2.0 million in NRx’s common stock, with an additional commitment of $25.0 million to be invested directly in HOPE.

JGS Holdings defaulted under the terms of the agreements, despite several extensions of the closing date.

The Company formally terminated the stock purchase agreement on March 13, 2025.

Although no assurances can be given, assuming management is able to consummate the financing referenced above with an alternative strategic investor to replace the investment contemplated with JGS Holdings, together with alternative sources of equity and debt capital, management believes it will able to fund its previously announced acquisitions on terms more favorable to our shareholders.

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.

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 clinical use and by the year 2000, DCS was rarely used in the United States.

Previously, the critical doses of DCS required to achieve a clinical effect in treatment of these conditions was not understood.

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.

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 management anticipates we can replicate that stability at commercial scale.

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

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Javitt discovered and patented the finding that when serotonin-targeted drugs are added to NMDA-targeted drugs, the hallucinogenic side effects of NMDA-targeted drugs are blocked and, at the same time, the NMDA component blocks the akathisia that is a known side effect of serotonin-targeted drugs – a side effect associated with suicidal ideation and behavior.

D-cycloserine, the NMDA-targeting component of NRX-101, is a mixed NMDA agonist/antagonist that has been demonstrated in nonclinical studies to have no potential for neurotoxicity 10 or addiction.

DCS, the NMDA-targeting component of NRX-101, is a mixed NMDA agonist/antagonist that has been demonstrated in nonclinical studies to have no potential for neurotoxicity or addiction.

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.

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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 2b/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 second quarter of 2024.

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

In 2024, the Company announced completion of a clinical trial to compare NRX-101 to lurasidone alone in patients with bipolar depression and subacute suicidal ideation (NCT03395392).

In previous studies (the STABIL-B trial), NRX-101 administered after the use of ketamine in acutely suicidal patients was superior to lurasidone alone in maintaining remission from depression and suicidality.

(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

In this trial, NRX-101 was found to be equivalent to lurasidone in achieving remission from depression (i.e.

both drugs were effective), but was superior to lurasidone (P=.05) in achieving remission from suicidality.

Additionally, NRX-101 was seen to achieve a 76% superiority to lurasidone alone in achieving remission from akathisia (P=.026) a symptom of all known serotonin-targeted antidepressants that is closely-linked to suicidality.

Superiority of NRX-101 vs.

lurasidone alone in reducing symptoms of Akathisia.

Presented at the 2004 American Society of Clinical Psychopharmacology

In this trial, conducted under a Special Protocol Agreement with the FDA, there was no placebo group because suicidal patients were compared to the standard of care and it would not have been ethical to randomize actively suicidal patients to placebo.

The Company believes that based on these data, New Drug Approval for NRX-101 can be achieved by conducting a properly-powered phase III trial comparing NRX-101 to placebo in patients with bipolar depression who do not have active suicidal ideation.

The Company is in discussion with commercial partners to conduct such a trial.

In the interim, the Company believes that accelerated approval for NRX-101 can be obtained for treatment of patients with active suicidal ideation and akathisia despite treatment with currently approved medicines.

NRX-100 and other Ketamine Products in Development

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

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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 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.

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.

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.

In addition, Relief has agreed to use commercially reasonable efforts to continue the existing Right to Try Program for Aviptadil in the U.S.

for at least two years.

The company has initiated the filing of a New Drug Application for NRX-100 and anticipates filing the full NDA package by June 2025, aiming for a 2025 PDUFA date.

The basis of the NDA filing consists of efficacy data gathered from several large clinical trials, representing the experience of more than 1000 patients together with real-world data gathered from more than 20,000 patients that consistently demonstrate the effectiveness of ketamine in treating symptoms of both depression and suicidality.

The illustration below has been presented by the Company in public conferences as illustrative of some of the data to be presented as part of the NDA.

New Drug Approval of intravenous ketamine HCl is not anticipated to yield long-term patent protection because ketamine is an old, well-known compound, although the preservative-free presentation of ketamine, together with the proprietary Risk Evaluation Management Strategy (REMS) that will likely be required for FDA approval will confer some degree of market protection.

However, ketamine – in any form – is not currently approved for use in psychiatry, although a form of S-ketamine is approved and commands a substantial price in the marketplace.

FDA regulations do provide for a three-year period of data exclusivity (“Paragraph 4 protection”) for sponsors who obtain a new FDA approval for an already-approved medication.

NRx anticipates benefiting from this exclusivity in the case of NRX-100.

In recent months, there has been increased support voiced by at senior levels of the U.S.

Government for the approval of ketamine and other psychedelic drugs for the treatment of depression and related conditions.

Although the use of ketamine is widespread and not currently subject to US patent, all known prior art and commercial presentations of ketamine have included the use of Benzethonium Chloride, a toxic preservative as part of the intravenous administration of ketamine.

Benzethonium Chloride is widely used in antibacterial cleaning solutions and cosmetics for topical use.

The manufacturer of benzethonium chloride classifies it as toxic if swallowed, capable of causing severe skin burns and eye damage, and corrosive, although those effects are not seen at the levels used in intravenous preparations.

However, it has never been shown to be safe for intravenous use in humans and has been demonstrated to be neurotoxic to the cornea when used in eyedrops (Invest Ophthalmol Vis Sci 2012 Apr 18;53(4):1792–1802).

For this reason, benzethonium chloride and related preservatives have increasingly been removed from various eyedrops.

The inclusion of benzethonium chloride is a remnant from a time when sterile product manufacturing techniques required toxic preservatives to maintain stability and sterility.

NRx has demonstrated the ability to maintain stability and sterility for more than two years of room temperature shelf life with its preservative-free presentation of NRX-100.

While the use of a preservative in ketamine may be safe when ketamine is used for single doses of anesthesia, the repeated use of benzethonium chloride-preserved ketamine has never been shown to be safe in either animals or patients.

FDA has published warnings about potential neurotoxicity associated with the repeated use of ketamine, which may be related both to the preservative and to potential excitatory neurotoxicity caused by repeated use of ketamine itself.

The Company intends to file a citizens petition with the FDA seeking to have benzethonium chloride removed from ketamine intended for intravenous use.

The US Food Drug and Cosmetics Act requires that all ingredients in US drugs have demonstrated safety.

The recently confirmed Secretary of Health and Human Services has emphasized in various public comments the importance of removing toxic substances from the US food and drug supply chain.

Should the Company be successful in effecting the removal of benzethonium chloride from current preparations of ketamine, the Company may gain additional exclusivity rights with regard to NRX-100.

NRX-100 and NRX-101 Commercial Licensing

In early March 2024, the Company entered into a non-binding term sheet from a private equity-owned commercial stage pharmaceutical company for the licensing and distribution rights to NRX-100 in the U.S., subject to final regulatory due diligence.

The proposed license agreement provides for an immediate milestone payment with proposed milestones and a sliding scale royalty based on sales volume.

Under the terms of the proposed license, the Company retains all rights ex-US and future rights to HTX-100 (pH neutral ketamine) should that development path succeed.

The Company is in additional discussions with the prospective commercial partner around the licensing of NRX-101.

HTX-100 (pH neutral ketamine)

One path through which the Company has potential to achieve longer term exclusivity around the use of ketamine is through the development of a novel composition of matter that confers benefits not achievable via NRX-100.

Although ketamine has demonstrated clear benefit in treating patients with depression and suicidality, ketamine HCl, the generic form of ketamine, is acidic (pH 3.5-4.0) and therefore suitable for dilute intravenous administration, but not for subcutaneous administration.

Compounds at this level of acidity are known to cause skin ulceration and cannot be approved for subcutaneous use.

Accordingly, ketamine for psychiatric purposes can be administered in clinic settings with trained perfusion nurses and staff, but is unsuitable for office use.

Some have attempted to address this problem through oral administration of ketamine or buccal (i.e.

allowing ketamine to dissolve against the inside of the mouth) administration.

However, these modalities have unpredictable pharmacokinetics and, in the Company’s view are unlikely to result in approvable drugs.

Experience with insulin compounds has yielded a large array of approved medical devices that would be capable of delivering a pH neutral form of ketamine in the office or home setting.

In 2024, the Company developed a pH neutral form of ketamine (HTX-100) that is expected to be patentable through 2040 and is expected to be suitable for subcutaneous use.

In 2025, the company expects to achieve formulation of this product under Good Manufacturing Practices (GMP) and to initiate a clinical trial of HTX-100 for subcutaneous use.

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.

The discovery was made in the context of attempting to determine the molecular mechanism by which phencyclidine (angel dust:

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 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.

About 10 years after the original discovery, it was learned that NMDA inhibition is the mechanism by which ketamine, dextromethorphan, and other NMDA antagonists exert their antidepressant effects.

Javitt subsequently made the seminal observation that when an NMDA antagonist, specifically D-cycloserine (“DCS”), is combined with a traditional (serotonin-targeted) antidepressant or antipsychotic, the two drugs have a synergistic effect wherein antidepressant activity is enhanced, and side effects are decreased.

The mechanism of this synergy has been demonstrated in multiple non-clinical models.

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.

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 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 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.

Basis for US Patent 10583138.

NeuroRx, Inc.

These patented discoveries support NRX-101, the first investigational oral antidepressant to be granted Fast Track designation, Breakthrough Therapy designation and a Special Protocol Agreement by the FDA for severe bipolar depression in patients with ASIB.

NRx is engaged in the research, development and future commercialization of this and other products for the treatment of patients suffering from suicidal ideation in the setting of bipolar depression and major depressive disorder (“MDD”) as well as PTSD and potentially chronic pain.

Drugs that inhibit the brain’s NMDA receptor without ketamine’s limitations, have generated substantial interest, and have been explored for the treatment of the above conditions since the finding that ketamine has potent effects in reducing depression and suicidal ideation.

It is our view that NRX-101 and our intellectual property to combine different molecules may yield a competitive advantage to use NMDA-inhibiting drugs for this purpose, as other compounds may be limited by adverse elements such as neurotoxicity (with prolonged use), hallucinations, potential habituation (i.e., addictive properties), blood pressure elevations, and/or lack of oral bioavailability.

This synergy is a key discovery underlying the patent portfolio described below.

The scientific findings showed that some of the side effects of an NMDA drug can be blocked by the 5-HT2A drug and, in turn, the NMDA component can block akathisia, a known side effect of 5-HT2A-blocking drugs which is known to predispose to suicide.

This dual-targeted approach is a primary basis of our worldwide patent portfolio, which currently encompasses 38 pending applications, and 48 granted patents in multiple jurisdictions covering compositions of matter and methods of use (See “NRx Patent Portfolio”).

The relevant patents and patent applications in this portfolio are either owned by NeuroRx, exclusively licensed to NeuroRx by Glytech, LLC (“Glytech”), a Delaware limited liability company solely owned by Dr.

Daniel Javitt (the “Glytech License”), or exclusively licensed to NeuroRx by Sarah Herzog Memorial Hospital Ezrat Nashim (“SHMH”), a non-profit organization organized under the laws of the State of Israel (the “SHMH License”).

NeuroRx owns a U.S.

composition of matter patent that covers NRX-101.

Patents under the Glytech License, which cover compositions of matter (including NRX-101 and pipeline therapeutic candidates) and methods of use (including methods of using NRX-101 in the treatment of bipolar depression with suicidal ideation and in treating PTSD), have been granted in the U.S., Europe (including validation by 18 members of the European Patent Convention), Japan, Australia and China.

Additional patent applications under the Glytech License cover compositions of matter and methods of use of pipeline therapeutic candidates other than NRX-101 together with methods of use of NRX-101 in treating additional CNS disorders.

These patents are pending in various locations including the U.S., Canada, Israel, Europe, Japan, Australia and China.

Assuming all maintenance fees are timely paid in each jurisdiction and that the patents are not held invalid or unenforceable by a court or patent office, the patents licensed to NeuroRx by Glytech will expire in each jurisdiction in which they have been granted in 2033 (for the base NRX-101 patents) and 2038 (for the PTSD treatment patents).

See “Summary of NRx Material In-licensing Obligations — NRX-100/101 — Glytech Development and License Agreement” for more information.

We intend to seek patent extensions as allowed by law.

Patents under the SHMH License, which cover methods of use of DCS, alone or in combination with an antidepressant agent or an antipsychotic agent (including but not limited to lurasidone) in the treatment of depression, have been granted in the U.S.

and Europe with additional patent applications covering similar subject matter pending in these countries and in Israel and Canada.

Assuming all maintenance fees are timely paid in each jurisdiction and that the patents are not held invalid or unenforceable by a court or patent office, the patents licensed to NeuroRx by SHMH will expire in each jurisdiction in which they have been granted in 2032.

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

Bipolar disorder, formerly known as manic depressive disorder, is a well-established psychiatric diagnosis.

According to the NIH, an estimated 2.8% of the US adult population had bipolar disorder in the past 12 months, and the lifetime prevalence is 4.4% of adults in the U.S.

The risk of ASIB is uniquely high in patients during bipolar depressive episodes, compared to those with MDD, thought disorders, and personality disorders.

Lifetime suicide behavior occurs in 25% to 56% of people with bipolar depression.

It is possible that a significant portion of the approximately 48,000 deaths in 2021 from suicide in the U.S.

were associated with bipolar depression.

Substance abuse is high in this population and death due to drug overdoses are generally not counted as suicides.

Furthermore, according to the CDC, the COVID-19 pandemic increased many of the risk factors for suicide.

Patients with bipolar depression are 20-30 times more likely to attempt suicide than the general population.

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 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.

Thus, ASIB in bipolar depression has uniquely lethal clinical characteristics.

Current Treatment Options for ASIB in Bipolar Depression

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

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.

While these medications are effective at reducing overall symptoms of depression, they do not specifically reduce suicidal ideation, and may potentially increase the risk of suicide.

In the two bipolar depression registration studies of lurasidone 14,15 , individuals with active suicidal ideation were specifically excluded because of concerns regarding the possibility of exacerbating suicidality.

Similarly, acutely suicidal patients are routinely excluded from clinical trials of other experimental anti-depressive agents.

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

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).

DCS has been used in millions of patients and has a well-known safety profile.

Its antidepressant effects were first noted as a serendipitous observation in individuals with co-morbid tuberculosis and depression receiving high-dose DCS treatment for anti-tuberculosis therapy and subsequently confirmed in a prospective investigation.

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.

A slow DCS titration was used, with 250 mg/dX3 days, followed by 500 mg/d for 18 days (i.e., until end of week 3);

followed by 750 mg/day for 1 week (i.e., until end of week 4), followed by 1000 mg/day (i.e., until end of study).

In the study (Figure 2), significant beneficial effects were observed in 13 subjects vs.

placebo control with SSRI-nonresponsive depressive symptoms.

The improvements were manifest within two weeks and persisted throughout the six-week treatment period.

These data suggest a >0.9 effect size.

Statistical separation between groups was observed by end of week 4, i.e., within 1 week of initiation of a dose >500 mg/day.

An unexpected finding of the study was that psychotomimetic effects of combined DCS and antidepressants were minimal, suggesting unexpected synergy between the two components of the treatment.

Lurasidone is an atypical antipsychotic with approval for the treatment of depressive episodes associated with bipolar I depression in adults and pediatric patients (10-17 years old) as a monotherapy and as an adjunctive therapy with lithium or valproate in adults.

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

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

A major concern with use of agents that block the channel site of the NMDAR is their propensity to induce neurotoxicity within frontal brain regions (“Olney lesions”) with extended or higher levels of exposure.

This propensity for neurotoxicity has been observed with direct channel-blocking NMDAR agents, but has not been observed with any glycine-site modulator, such as NRX-101.

The concern regarding neurotoxicity has caused the FDA to issue new guidance for the development of NMDAR-targeted antidepressants, requiring neurotoxicity studies, according to FDA-agreed protocols.

This element of NMDAR-targeted antidepressant use may become increasingly relevant in coming years, because drugs containing ketamine and dextromethorphan, two molecules with known neurotoxic potential in humans have been proposed for repeated administration in the treatment of depression.

We took advice from the FDA in 2016 and conducted a rodent neurotoxicity study according to a protocol agreed in advance between the FDA and NRx Pharmaceuticals.

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.

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.

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

Both ketamine and S-ketamine are known to have significant abuse liability and support self-administration in rodents.

Substantial abuse liability is also known in association with dextromethorphan.

We conducted a rodent abuse liability study in which the relative abilities of ketamine, S-ketamine and DCS to support self-administration were investigated in animals trained to self-administer ketamine (Figure 4).

As expected, both ketamine (gray bar) and S-ketamine (yellow bar) significantly replaced ketamine, consistent with high clinical abuse potential.

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

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

An initial study was conducted to confirm the selected dosing levels for DCS and lurasidone and evaluate the NRx Pharmaceuticals Sequential Therapy approach.

The study enrolled patients with severe bipolar depression and acute suicidal ideation and behavior.

Severe depressive symptoms are defined as a score of 30 or higher on the Bipolar Inventory of Symptoms Scale (“BISS”) derived MADRS score (“BDM”).

Active suicidal intent with or without plan, but requiring hospitalization, was defined as a score of 4 or 5 using the Columbia Suicide Severity Rating Scale (“C-SSRS”).

In Stage 1, all subjects received treatment with a blinded infusion of ketamine (0.5 mg/kg) or saline.

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.

lurasidone alone.

The objective of the study was to demonstrate significant superiority of NRX-101 vs.

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

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

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

Flexible dosing was permitted to allow dose reduction for side effects, or dose increases for agitation.

The primary endpoint consisted of relative change in BDM score between NRX-101 and lurasidone.

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

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 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).

Sequential treatment with ketamine/NRX-101 significantly reduced depression symptoms compared to sequential treatment with ketamine/lurasidone alone (P=0.032) in a last-observation carried forward (“LOCF”) analysis.

6 In a parallel MMRM analysis, a statistical difference of P=0.09 was observed between groups.

In addition, there were no relapses during NRX-101 treatment (0/12, 0%) vs.

2 relapses in the lurasidone alone group (2/5, 40%).

The between-group significance level of P=0.0735 was not significant but showed feasibility of detecting a difference with larger samples given a similar response pattern.

In LOCF analyses of secondary endpoints, a significant between-group difference was also observed both for C-SSRS (P=0.02) and for CGI-SS (P=0.019).

These findings suggest clinically noticeable between-group differences in liability for return of suicidality following initial ketamine treatment.

Both effects were non-significant (P=0.11;

P=0.15) on MMRM analysis.

(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.

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).

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.

ICH requirements should be 1500 patients in the short term, 300-600 patients for 6 months and at least 100 patients for 12 months.

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.

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.

Otherwise, the study methodology remains similar.

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 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

In response to a request for Type C guidance on the chemistry, manufacturing and controls (CMC) aspects of the NRX-101 program, FDA provided Written Responses on January 10, 2023.

As previously announced in October 2022, an updated NRX-101 module 3 was submitted to add the intended commercial manufacturer to the IND.

With FDA’s written response, it appears that NRx Pharmaceuticals has reached alignment with the FDA regarding its proposed registration manufacturing and stability monitoring plan.

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

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 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.

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.

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.

Although there are several serotonin-targeted medicines that are indicated for use in PTSD, no serotonin-targeted antidepressant has demonstrated an effect in extinction of fear memory in patients.

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

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 (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.

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.

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.

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.

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

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

5 unchanged sentences

A meta-analysis of 7 studies representing 94 participants demonstrated a consistent improvement in pain score but a consistent finding of nausea and psychomimetic effects associated with ketamine administration.

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.

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

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

2 unchanged sentences

However, post-hoc analysis demonstrates a significant difference between baseline and six weeks (P<0.01), which is the point in time that the 400mg DCS dose was reached.

(see figure 8)

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

(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.

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.

In 2024 the Company may initiate a pilot study in the treatment of chronic pain using NRX-101 at daily dosages that exceed 500mg/day of DCS.

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.

Based on the above data, the Company licensed a method patent for the use of DCS in Chronic Pain from Prof.

Apkar Apkarian.

A 400 person efficacy trial was funded by the US Department of Defense, sponsored by Northwestern University, and achieved primary completion in February 2024.

The investigators have not yet released findings from this clinical trial.

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).

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

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

11 unchanged sentences

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.

Based on these results, the FDA 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 ( μ g/mL)

DCS + Lurasidone ( μ g/mL)

9 unchanged sentences

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.

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.

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.

A statistically significant and clinically meaningful improvement in suicidal ideation was seen on the Beck’s Scale for Suicidal Ideation within 24 hours of infusion with ketamine, compared to midazolam an active comparator.

Suicidal ideation severity during a randomized trial of sub-anesthetic intravenous ketamine or midazolam control infusion in bipolar depressed participants with clinically significant suicidal thoughts.

The figure depicts change in severity measured using the Beck Scale for Suicidal Ideation (SSI) from baseline to 24 hours after infusion.

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

Source Grunebaum 2017 9

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

8 Participants with acute suicidal ideation associated with bipolar depression, major depressive disorder, and other disorders were randomized to receive either ketamine or placebo infusion.

Overall, the study demonstrated that 63% of ketamine-infused participants vs.

31% of placebo-infused participants achieved remission from suicidal ideation at day 3 (P<.01).

However, the finding was most pronounced for the subset of participants with bipolar depression (85% vs.

P<.001) with an Odds Ratio of 14 for ketamine vs.

Summary of results from multicenter trial of ketamine vs.

placebo in hospitalized patients with suicidal depression.

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).

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.

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.

Int J Toxicol.

2023;42(5):379-385.

10.1177/10915818231176971

Sapko MT, Hanania T, Chang Q, Javitt JC.

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

Pharmacol Biochem Behav.

2023;227-228:173586.

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.

2024:2024.2001.

Javitt J, Sapko M.

D-Cycloserine for the Treatment of Chronic Pain.

Authorea Preprints.

10.22541/au.169175897.70619502/v2

Korczykowski M, Sapko M, Colesare C, Sharpe I, Lavin P, Javitt J.

Real Time Quality Assurance of Depression Ratings in Psychiatric Clinical Trials.

Available at SSRN 4537055.

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

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

lurasidone for the maintenance of initial stabilization after ketamine in patients with severe bipolar depression with acute suicidal ideation and behavior:

a randomized prospective phase 2 trial.

Int J Bipolar Disord.

2023;11(1):28.

10.1186/s40345-023-00308-5

Chen MH, Cheng CM, Gueorguieva R, et al.

Maintenance of antidepressant and antisuicidal effects by D-cycloserine among patients with treatment-resistant depression who responded to low-dose ketamine infusion:

a double-blind randomized placebo-control study.

Neuropsychopharmacology.

2019;44(12):2112-2118.

10.1038/s41386-019-0480-y

Abbar M, Demattei C, El-Hage W, et al.

Ketamine for the acute treatment of severe suicidal ideation:

double blind, randomised placebo controlled trial.

2022;376:e067194.

10.1136/bmj-2021-067194

Grunebaum MF, Ellis SP, Keilp JG, et al.

Ketamine versus midazolam in bipolar depression with suicidal thoughts:

A pilot midazolam-controlled randomized clinical trial.

Bipolar Disord.

2017;19(3):176-183.

10.1111/bdi.12487

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.

International Journal of Toxicology.

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Youssef JG, Lavin P, Schoenfeld DA, et al.

The Use of IV Vasoactive Intestinal Peptide (Aviptadil) in Patients With Critical COVID-19 Respiratory Failure:

Results of a 60-Day Randomized Controlled Trial.

Crit Care Med.

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Loebel A, Cucchiaro J, Silva R, et al.

Lurasidone monotherapy in the treatment of bipolar I depression:

a randomized, double-blind, placebo-controlled study.

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2014;171(2):160-168.

10.1176/appi.ajp.2013.13070984

Loebel A, Cucchiaro J, Silva R, et al.

Lurasidone as adjunctive therapy with lithium or valproate for the treatment of bipolar I depression:

a randomized, double-blind, placebo-controlled study.

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Heresco-Levy U, Gelfin G, Bloch B, et al.

A randomized add-on trial of high-dose D-cycloserine for treatment-resistant depression.

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Kantrowitz JT, Halberstam B, Gangwisch J.

Single-dose ketamine followed by daily D-Cycloserine in treatment-resistant bipolar depression.

J Clin Psychiatry.

2015;76(6):737-738.

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Muller MJ, Szegedi A.

Effects of interrater reliability of psychopathologic assessment on power and sample size calculations in clinical trials.

J Clin Psychopharmacol.

2002;22(3):318-325.

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Kobak KA, Brown B, Sharp I, et al.

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Kobak KA, Kane JM, Thase ME, Nierenberg AA.

Why do clinical trials fail?

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time to test new paradigms?

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National Center for PTSD;

Department of Veterans Affairs.

How Common Is PTSD in Adults?

https://www.ptsd.va.gov/understand/common/common_adults.asp#:~:text=About%205%20out%20of%20every,some%20point%20in%20their%20life.

Accessed March 17, 2024.

Sala N, Paoli C, Bonifacino T, et al.

Acute Ketamine Facilitates Fear Memory Extinction in a Rat Model of PTSD Along With Restoring Glutamatergic Alterations and Dendritic Atrophy in the Prefrontal Cortex.

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de Kleine RA, Hendriks GJ, Kusters WJ, Broekman TG, van Minnen A.

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Biol Psychiatry.

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Enhancing prolonged exposure therapy for posttraumatic stress disorder with D-cycloserine:

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Summary of NRx Material In-licensing Obligations

Development of HOPE Therapeutics

Psychiatric care for depression, PTSD, and related CNS disorders is experiencing a period of rapid change, based on the discovery of NMDA-targeted and other psychedelic drugs (see above) and Transcranial Magnetic Stimulation (“TMS”).

Both are therapies that have been shown to induce new synapse (i.e.

nerve connection) within the brain, a process known as “neuroplasticity” or “synaptic plasticity,” Recent science sponsored in part by NRx shows that these disease states are associated with atrophy of the electrical connections between brain cells, rumination on negative – frequently suicidal – thoughts, and ultimately suicidal behavior.

NMDA-targeted and other psychedelic drugs are demonstrated to create bursts of glutamine and glutamate in the brain with resulting sprouting of the dendrites that create new synapses and corresponding decreases in depressive and suicidal ideation.

TMS is believed to achieve a similar benefit through the application of strong magnetic fields to brain cells and has been demonstrated to relieve symptoms of depression.

Accordingly, TMS has been approved for this purpose in the US.

In Europe, TMS has been approved for a far broader set of indications including PTSD, treatment of alcohol and drug abuse, stroke, Parkinsons, and brain injury.

For the first time in human history, responsible scientists are discussing treatments that induce neuroplasticity as potentially curative for depression, PTSD, and related conditions, in contrast to 70 years of serotonin-targeted drugs that were thought to treat the symptoms of these diseases.

However, it is increasingly believed that no individual medication, device, or other therapy will be sufficient to achieve comprehensive benefit for patients.

Unfortunately, few centers have mastered the art of combining these treatments into a comprehensive approach for treating serious and lethal psychiatry disorders.

In January 2024, the Company incorporated HOPE Therapeutics as a wholly-owned subsidiary of NRx Pharmaceuticals for the purpose of developing a new clinical paradigm for the treatment of depression, PTSD, obsessive-compulsive disorder, and related CNS conditions.

Based on clinical observations with the Company’s drugs, the Company came to the realization that the rapidly-emerging class of NMDA-targeted and other psychedelic drugs have the potential to be paradigm-changing for patients with life-threatening CNS disorders but may not be sufficient to achieve the full clinical benefit that patients require to achieve and maintain a complete, long-term recovery.

We estimate that ketamine and TMS individually have reported remission rates of approximately 50% in patients with severe depression.

However, anecdotal observation and the emerging body of evidence suggests that when patients are offered the full array of currently available treatments in an integrated manner, a far greater proportion of patients may achieve long-term remission from conditions that only a few years ago were treated with hospitalization and electroshock therapy.

Company executives recently traveled to Israel, where these treatments – together with hyperbaric oxygen therapy – are being used to significant effect in the treatment of soldiers with PTSD from recent combat, with dramatic efficacy results in university-based clinical trials.

During the second half of 2024, the Company began outlining the plan for HOPE as a national and ultimately international network of interventional psychiatry centers that would combine neuroplastic treatments in an integrated and reproducible manner.

HOPE Acquisition Targets

In 2024, the Company announced a non-binding term sheet to acquire Kadima, LLC, a pioneering interventional psychiatry clinic in La Jolla, CA.

Kadima’s founder, Dr.

David Feifel agreed to serve as HOPE’s Chief Medical Innovation Officer post-acquisition.

He is one of the first academic psychiatrists to move ketamine and TMS therapy to the community care model and was recently featured on Dr.

Sanjay Gupta’s feature entitled “The Wild West of Ketamine Treatment” as an advocate for how ketamine therapy can be delivered reliably and responsibly.

Additionally, the Company has entered into a non-binding term sheet to acquire two additional clinics in Florida.

The Company is in the process of finalizing definitive purchase agreements with both entities.

In addition to these acquisitions, the Company is negotiating to acquire an additional six clinics in Florida with the objective of acquiring 15-20 facilities in Florida by year-end 2025, as depicted in the following graphic:

Representative potential targeted 2025 acquisition opportunities in Florida.

HOPE Financing/Acquisition Model

The clinical centers that are being incorporated in the 2025 acquisition program are currently operating and are profitable centers that the Company believes can experience substantial revenue growth through the addition of a broader array of comprehensive services.

Management estimates that the acquisition of 20 clinic networks, each with current revenue of approximately $5.0 million will be required to meet our 2025 growth objectives.

Based on the financing proposals received to date and existing capital, the Company is targeting a blended financing cost of acquisition of under 10%.

Future Medical Indications for HOPE

The founding of HOPE began with the Company’s commitment to the treatment of suicidal depression with a plan to utilize (i) current FDA approval for S-ketamine, (ii) TMS, and (iii) if approved by the FDA, NRX-100.

Over time, the vision for HOPE has significantly expanded.

European approvals are already in place for the use of TMS to treat PTSD, Traumatic Brain Injury, Alzheimer’s, Parkinson’s disease, and alcohol and tobacco addiction.

Moreover, Kadima has been a leading research organization in the development of psychedelic drugs and HOPE expects to merge Kadima’s research capabilities with those of NRx Pharmaceuticals.

As an example of that expertise, NRx recently published a report in a leading peer-reviewed journal documenting its ability to achieve >95% reliability in the measurement of depression scores across research sites, a reliability factor considerably above industry standards (J Clin Psychopharmacol.

2025 Jan-Feb;45(1):28-31).

Hence, HOPE Therapeutics expects to be involved in the treatment of a broad array of CNS diseases that – until now – have offered little in the way of new hope to patients.

Unlike the process of drug development, where FDA approval is a protracted process, the use of approved devices for new uses is generally regarded as within the practice of medicine, although insurance reimbursement is frequently tied to FDA-labeled indications.

Summary of NRx Material In-licensing Obligations (NRx-100/101)

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 Company was founded based upon a development agreement with Glytech, a Company founded by Daniel Javitt (“DLA”).

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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The milestone payments due above may be reduced by 25% in certain circumstances, and by the application of certain sub-license fees.

During the years ended December 31, 2024 and 2023, no payments were made.

A royalty in an amount equal to:

3 unchanged sentences

Royalties shall also apply to any revenues generated by sub-licensees from sale of Licensed Products subject to a cap of 8.5% of the payments received by us from sub-licensees in connection with such sales.

During the years ended December 31, 2024 and 2023, no royalties were made.

Annual Maintenance Fee

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Manufacturing Agreements

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

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

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

3 unchanged sentences

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.

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

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

6 unchanged sentences

Government Regulation

In the U.S., the FDA regulates drugs under the FFDCA and its implementing regulations.

In the U.S., the FDA regulates drugs under the Federal Food, Drug, and Cosmetic Act (“FFDCA”) and its implementing regulations.

The process of obtaining marketing approvals and the subsequent compliance with appropriate Federal, state, local and foreign statutes and regulations requires the expenditure of substantial time and financial resources.

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Clinical Trials

Clinical trials involve the administration of the IND to human subjects under the supervision of qualified investigators in accordance with cGCP requirements, which include the requirement that all research subjects provide their informed consent in writing for their participation in any clinical trial, and review and approval by an Institutional Review Board (IRB).

Clinical trials involve the administration of the IND to human subjects under the supervision of qualified investigators in accordance with Current Good Clinical Practices (“cGCP”) requirements, which include the requirement that all research subjects provide their informed consent in writing for their participation in any clinical trial, and review and approval by an Institutional Review Board (“IRB”).

Clinical trials are conducted under protocols detailing, among other things, the objectives of the trial, the trial procedures, the parameters to be used in monitoring safety and the effectiveness criteria to be evaluated, and a statistical analysis plan.

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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.

The manufacture of investigational drugs for the conduct of human clinical trials is subject to cGMP requirements.

The manufacture of investigational drugs for the conduct of human clinical trials is subject to current Good Manufacturing Practices (“cGMP”) requirements.

Investigational drugs and active pharmaceutical ingredients imported into the U.S.

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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 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.

In addition to the defined requirements in the SPA, FDA may require additional clinical safety data, especially if the use of the drug could be intermittent or chronic/intermittent as deemed by the FDA.

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 FDA 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 FDA 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.

In addition to the defined requirements in the FDA SPA, the FDA may require additional clinical safety data, especially if the use of the drug could be intermittent or chronic/intermittent as deemed by the FDA.

As mentioned before, we recently received written guidance from the FDA that the Company is evaluating.

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Implications for NRX-101

Subsequent to the issuance of the SPA, in November 2018, the FDA also issued a Breakthrough Therapy designation to NRX-101.

Subsequent to the issuance of the FDA SPA, in November 2018, the FDA also issued a Breakthrough Therapy designation to NRX-101.

Breakthrough Therapy designation is awarded to drugs that have demonstrated preliminary evidence of efficacy for the treatment of a serious medical condition for which there is an unmet medical need.

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

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.

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.

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

27 unchanged sentences

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.

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

A 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.

27 unchanged sentences

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.

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.

48 unchanged sentences

Activities that violate the FCPA, even if they occur wholly outside the U.S., can result in criminal and civil fines, imprisonment, disgorgement, oversight, and debarment from government contracts.

The FCPA is currently under a temporary pause in enforcement.

This pause was initiated by an executive order from President Trump on February 10, 2025 for a 180-day period.

The order aims to reassess the guidelines and policies surrounding FCPA investigations and enforcement actions with a focus on promoting U.S.

economic competitiveness and national security.

Exclusivity and Approval of Competing Products

52 unchanged sentences

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.

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

The 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