NRx is a clinical stage pharmaceutical company, through its wholly-owned operating subsidiaries NeuroRx, Inc. (Delaware company) and NeuroRx 2015 LTD (Israel company) to develop new therapies for the treatment of central nervous system diseases and life-threatening lungs Department of disease. We are developing four drug products as follows: NRX-100 and NRX-101, which have received the FDA’s breakthrough therapy designation for the treatment of suicidal bipolar depression and PTSD; ZYESAMITM (avitazidil ​​acetate), An FDA Fast Track-designated, investigational, pre-commercial pre-drug for COVID-19-related respiratory failure; and BriLife™, a live virus vaccine against SARS-CoV-2 wild-type and mutant infections to prevent COVID -19.

NRX-101 demonstrated a statistically significant reduction in depression and suicide rates in a randomized trial for the active control drug (lurasidone), and has obtained FDA breakthrough treatment designation, special agreement agreement and biomarker support letter.

As a sterile liquid for intravenous use, ZYESAMI uses a statistical method agreed with the FDA in advance. Compared with placebo, there is a statistically significant reduction in mortality in patients with severe COVID-19 and respiratory failure. The method controls for differences in baseline disease severity (if you do not control for baseline severity, you will see a numerical but not statistically significant advantage). ZYESAMI ™ has been approved for emergency use by the state of Georgia, pending applications in the surrounding Caucasus countries, and has been submitted to the FDA's EUA, and is currently awaiting a regulatory decision. Applications are being submitted to other regulatory agencies around the world. Other Phase III trials of ZYESAMI™ are now being conducted by the National Institutes of Health (NIH) and entities funded by BARDA.

In the Phase 2a trial conducted in Israel, the BriLife vaccine has demonstrated a statistically significant increase in COVID neutralizing antibodies compared to placebo, which is a sign of immunity to SARS-CoV-2. The Phase 2b dose is currently being completed in Israel Range trials and Georgia.

Our history of developing NRX-100/101 to treat suicidal depression and post-traumatic stress disorder

NRx was founded by Drs in 2015. Based on Daniel Javitt, Jonathan and Daniel Javitt found that when NMDA antagonists are used in combination with brain 5-HT2A receptor inhibitors (for example, SSRI antidepressants and atypical antipsychotics), they have a synergistic effect, thereby developing drugs for the treatment of mental illness. . This synergy has now been confirmed in laboratory rodent behavior experiments and multiple phase 2 clinical trials.

Dr. Daniel Javitt observed that when depression patients were treated with DCS (an NMDA antagonist), they showed enhanced antidepressant effects, but did not exhibit hallucinations and other NMDA effects previously reported with DCS. He further observed that DCS seems to be able to attenuate the common antidepressant side effects (akathisia) of all known antidepressants that target serotonin.

These findings support NRX-101, the first investigational oral antidepressant to be granted a breakthrough treatment designation and a special agreement agreement by the FDA for severe bipolar depression in patients with acute suicidal ideation and behavior. We focus on the research, development and commercialization of this product and other products for the treatment of suicidal ideation patients suffering from bipolar depression and major depression ('MDD') as well as PTSD and obsessive-compulsive disorder. Since the discovery that ketamine has an effective effect in reducing depression and suicidal ideation, drugs that inhibit the brain's NMDA receptors have been explored to treat these diseases. However, attempts by other drug manufacturers to use NMDA inhibitors for this purpose have been limited by neurotoxicity, hallucinations, habituation (ie addiction), elevated blood pressure, and lack of oral bioavailability.

This synergy is the key finding behind the patent portfolio described below. The side effects of NMDA drugs are blocked by 5-HT2A drugs. In turn, NMDA components block akathisia, which is a known side effect of 5-HT2A blocking drugs, which is known to cause suicide. As far as we know, this dual-purpose approach is the foundation of our global patent portfolio, which currently includes more than 40 patent applications and more than 30 patents issued in multiple jurisdictions, covering substance composition and methods of use. Related patents and patent applications in this portfolio are owned by NRx, and are exclusively licensed to NRx ("Glytech License") by Glytech, a Delaware LLC wholly-owned by Dr. Daniel Javitt, or licensed to NRx Ezrat by Sarah Herzog Memorial Nashim Hospital ("SHMH") is a non-profit organization established under the laws of the State of Israel ("SHMH License").

The patents licensed by Glytech, covering substance components (including NRX-101 and pipeline therapy candidates) and methods of use (including the use of NRX-101 to treat bipolar depression with suicidal ideation and methods to treat PTSD) have been in the United States and Europe (Including the verification of the 18 member states of the European Patent Convention), Japan, Australia and China. Other patent applications under the Glytech license (covering the use of substance components and pipeline therapy candidate drugs, and the use of NRX-101 in the treatment of other depression) are pending review in each of these countries and Canada. Assuming that all maintenance fees are paid in time in each jurisdiction, and the patent is not deemed invalid or unenforceable by the court or patent office, the patent granted to NRx by Glytech will expire in each jurisdiction in 2033 (for the basic NRX- 101 patent) and 2038 (for PTSD treatment patent). For more information, see "Summary of NRx Material Licensing Obligations-NRX-100/101-Glytech Development and License Agreement".

The patents under the SHMH license, covering material compositions that may represent NRx pipeline therapeutic candidates, and the use of such compositions in the treatment of certain depression, have been authorized in the United States and Europe, and other patent applications cover similar The subject is currently under application in these countries as well as Israel and Canada. Assuming that all maintenance fees are paid in time in each jurisdiction, and the patent is not deemed invalid or unenforceable by the court or patent office, the patent granted by SHMH to NRx will expire in each jurisdiction in 2032. See'Summary of NRx Material License Obligations-NRX-100/101-Sarah Herzog Memorial Hospital License Agreement' for more information.

We have completed the Phase 3 clinical trial of ZYESAMI and submitted an EUA to the FDA on May 31, 2021 to treat COVID-19 (a life-threatening respiratory disease), and we are in the phase 3 clinical development phase of the drug product. Treatment of life-threatening central nervous system diseases. Nervous system condition. The listed respiratory products are based on the neuropeptide VIP, which is secreted by neuroendocrine cells throughout the body and concentrated in the human lung and brain. VIP showed promise in the treatment of acute respiratory distress syndrome ('ARDS') in 2005, and became uniquely important when it was proven to have the potential to treat COVID-19 in 2020.

Aviptadil is the general name of synthetically manufactured VIP, which is different from natural peptides. Our first VIP derivative product-ZYESAMI (a reformulation of RLF-100), our COVID-19 drug-was awarded Fast Track

It was designated by the FDA in June 2020 and was included in the Coronavirus Treatment Acceleration Plan. The term "VIP" should be interpreted as referring to the natural peptides produced in the human body, while the terms "aviptadil" and "ZYESAMI" refer to our APIs (active pharmaceutical ingredients) and medicines, respectively. We have completed the Phase IIb/III randomized controlled trial of ZYESAMI and placebo (NCT 04311697), which is conducted under the FDA Fast Track designation. The Phase IIb/III trial enrolled 196 patients, and the last patient completed 60 days of observation on February 24, 2021. In all patients and locations, ZYESAMI reached the primary preset end point of "survival without respiratory failure" on day 60 (P = .02) When adjusting the ventilation status and treatment site, and proved the probability of survival on day 60 A statistically significant increase, regardless of whether the participant has fully recovered (P = <.01). The statistical analysis plan assigned to the fda before the start of the study specifies that regression will be used for such adjustments. The adjustment is based on the agreed baseline severity, but no In the treatment area, compared with placebo, the survival rate of patients receiving zyesami within a few days doubled>

It is generally believed that the morbidity and mortality of COVID-19 are related to the release of inflammatory cytokines, especially interleukin 6 (IL-6). Among all the patients and care locations in our study, the blood IL-6 levels of patients treated with placebo increased 10 times within 7 days after treatment, while patients treated with ZYESAMI increased 2 times (P<.02 il- This increase of 6 is statistically related to the improved survival rate of patients treated with zyesami>

As far as we know, ZYESAMI is the first COVID-19 treatment drug to achieve these results in a randomized, double-blind multicenter trial. Although these results do not guarantee that ZYESAMI will be considered safe or effective for the treatment of COVID-19, and extensive clinical testing and regulatory approvals are required before ZYESAMI is commonly used to treat COVID-19, based on these findings, we will On May 31, it applied to the FDA for EUA, and plans to apply for breakthrough therapy designation and submit an NDA application. Other trials are being conducted through the ACTIV3 program and I-SPY program sponsored by NIH.

ZYESAMI is named after Professor Sami Said, a distinguished professor at the State University of New York at Stony Brook, who discovered VIP in 1970 and published more than 370 peer-reviewed studies on its impact. Its potential effectiveness in COVID-19 is based on the principle that the coronavirus specifically invades the alveolar type II cells of the lung (lung) epithelium, where it prevents the production of surfactants, replicates into millions of virus particles, and releases inflammation. Sex cytokines cause cell death types and shut down the production of surfactants, which are fluids that line the lungs and allow oxygen to pass from the air to the blood. ZYESAMI has shown in preclinical laboratory experiments at the Oswaldo Cruz Institute (Rio de Janeiro, Brazil) that it can increase the production of surfactants, prevent the replication of SARS-CoV-2 coronavirus in human lung cells, prevent the production of cytokines, and prevent Lung cell death (cytopathic). VIP has been shown to have an important potential role in the treatment of other lung diseases, including chronic obstructive pulmonary disease ('COPD'), sarcoidosis, asthma/allergies, and chronic airway inflammation syndrome. We intend to study the use of VIP under these and other conditions in the future. As we all know, VIP is also very active in the brain. If an appropriate central nervous system transmission mechanism can be developed, we plan to explore its potential use in the treatment of Huntington's disease, multiple sclerosis and other central nervous system diseases.

Our collaboration with avidtadil began on March 4, 2021, when Relief Therapeutics approached our CEO Jonathan Javitt and asked him to develop aaviptadil formulations based on file data, including an FDA IND license (52,088). In the 1970s, Professor Said discovered aviptadil (synthetic VIP) to treat lung diseases, and it was proven in VIP phase I clinical trials. The Relief Therapeutics board nominated Jonathan Javitt as the vice chairman of Relief Therapeutics and voted to grant Jonathan Javitt a 10% stake in Relief Therapeutics. The FDA refused to use 52,088 on the grounds that the IND was an IND sponsored by researchers owned by Stony Brook University and was cancelled by the FDA in 2014 after the death of the IND lead researcher, Professor Said). No other IND against avidtadil is effective in any jurisdiction. It is reported that the predecessor of Relief Therapeutics has applied for many times but has not obtained an IND for human use of avidtadil.

With the consent of Relief Therapeutics, NeuroRx submitted IND 149,152 to the FDA on March 24, 2020, and received the FDA's "Study May Proceed" letter on March 28, 2020. The two companies agree

Under the initial framework of cooperation, Relief Therapeutics will fund all development costs related to aviptadil and NeuroRx, and will receive an additional 20% stake in Relief Therapeutics. The proposal was submitted to us by the chairman of Relief Therapeutics in various clause lists. In addition, NeuroRx and Relief Therapeutics agreed to distribute the profits from the sales of avidtadil to different departments, provided that Relief Therapeutics provides funding for the development. In the following months, NeuroRx learned that the management of Relief Therapeutics did not have the corporate power to issue the shares of Relief Therapeutics offered. Subsequently, Relief Therapeutics proposed various business mergers under which NRx would have a majority stake in the surviving company. Although the board of Relief Therapeutics and NeuroRx approved a merger of this type, granting 55% of NeuroRx's surviving companies, the board of Relief Therapeutics never submitted an agreement to the shareholders of Relief Therapeutics for consideration. Jonathan Javitt also asked Relief Therapeutics to update its disclosure of intellectual property rights related to avidtadil, but Relief Therapeutics refused. At that time, Jonathan Javitt told Relief Therapeutics that he would not join the board of Relief Therapeutics or serve as the vice chairman of Relief Therapeutics.

In addition, in September 2021, NeuroRx and Relief Therapeutics agreed to cooperate as independent companies under a structure under which Relief Therapeutics has the right to fund all development costs related to aviptadil in exchange for a predetermined profit distribution. NeuroRx If Relief Therapeutics does not provide funds, it has the right to continue its development plan with other investor funds. The agreement recognizes that NRx owns all intellectual property rights developed or licensed by NRx. Relief Therapeutics recommended in various annual reports released in 2020 and earlier that its investors should formulate aviptadil as a human drug, and have "1 million doses" available for use Treat patiently. During the development process, NeuroRx learned that there was no stable formulation of avitadil, and began to develop an intravenous formulation, and submitted the production record to the FDA for review.

We reported to Relief Therapeutics in December 2020 that the formula data provided by Relief Therapeutics cannot be replicated, and new formulas and manufacturing methods are needed. In addition, we received a warning from the former Relief Therapeutics that it refused to fund the development of a stable formulation of aviptadil, and NRx continued to use the funds of other investors named ZYESAMI, named after Professor Sami Said. In May 2021, Relief Therapeutics informed its shareholders that Relief Therapeutics was aware of the stability problems of its formulations when it signed the cooperation agreement in September 2020.

ZYESAMI is currently not protected by any US or international patents. U.S. Patent 8178489B2 and foreign patents are not applicable to ZYESAMI, because it only covers avitamin preparations formulated in buffer. Laboratory evidence indicates that VIP (aviptadil) aggregates and may be inactivated by known buffers. We are in the process of discovery to expand the stability of ZYESAMI, and have made certain discoveries that may lead to future patent applications, and may or may not lead to allowable patent claims. If patent protection covering the ZYESAMI formulation is not granted, and if the drug is approved by the FDA, it is expected to receive FDA data exclusivity protection for at least five (5) years under what is commonly referred to as “paragraph 4”. If no patent is granted at the end of this data exclusivity period, competitors may sell a generic version of ZYESAMI.

In addition to the licensed patent portfolio, we also have five trademark applications pending before the U.S. Trademark Office, aiming to register the following trademarks:

In addition, NRx Pharmaceuticals has an exclusive worldwide license to use the BriLife™ logo.

The registration application of CYCLURAD was submitted on December 26, 2017, and belongs to the international category 5, a pharmaceutical preparation used for the treatment of depression (such as NRX-101). It was licensed by the U.S. Trademark Office on July 10, 2018, and is currently in the fifth extension of its declaration of use.

The SAMIVIP registration application was submitted on April 17, 2020, and belongs to the international category 5 for pharmaceutical preparations (such as avitadil) used to treat viruses and other diseases and disorders. Obtained permission from the U.S. Trademark Office on October 13, 2020. As of April 13, 2020, no statement of use was submitted on this matter, and the application was resubmitted to the US Trademark Office on May 6, 2021, and it has been restored to the pending status.

The registration application for SAMIVIR was submitted on August 2, 2020, and belongs to the international category 5 for pharmaceutical preparations (such as avitadil) used to treat viruses and other diseases and disorders. It was approved by the US Trademark Office on February 23, 2021, and the use statement should be submitted to the US Trademark Office before August 23, 2021.

The registration application for SAMIAIR was submitted on September 14, 2020. It belongs to the international category 5 and is used for the treatment of viruses and other diseases and disorders of pharmaceutical preparations (such as avitidine). It was approved by the US Trademark Office on February 23, 2021, and the use statement should be submitted to the US Trademark Office before August 23, 2021.

The registration application for ZYESAMI was submitted on November 10, 2020, and belongs to the international category 5 for pharmaceutical preparations (such as avitidine) used to treat viruses and other diseases and disorders. It is currently under review by the US Trademark Office.

We believe that our products are urgently needed by patients, because currently no antidepressants (such as SSRI drugs) or atypical antipsychotics (such as D2/5HT2A drugs) that target serotonin have been shown to reduce bipolar depression, MDD or post-traumatic stress disorder. In addition, all drugs in these categories carry an FDA-authorized warning about the increased risk of suicide in susceptible patients. Due to its NMDA blocking properties, ketamine has been shown to reduce suicidal ideation, but it is known to be hallucinogenic, addictive, and potentially neurotoxic, and cannot be administered orally. The management does not know that any commercial sponsor in the United States is developing ketamine to treat bipolar depression. Therefore, the only FDA-approved therapy for suicidal bipolar depression is still electroconvulsive therapy, which is a known effective treatment. , But the number of serious side effects.

According to the FDA special agreement agreement for our main product candidate NRX-101, we have started a key phase IIb/III clinical trial. The analysis of our first phase II study STABIL-B trial showed that using statistical methods approved by the FDA, within 42 days, depression (P=0.03) and suicidal ideation (P=0.02) A statistically significant reduction according to our special protocol agreement.

ZYESAMI's way to obtain regulatory approval

During the eleven (11) months beginning March 24, 2020, NRx, with the support of Lavin Statistical Consultants, Chesapeake Regulatory Team, Covance Laboratory Services, Target Health, LLC, and Hyman Phelps McNamara:

In the event of a public health emergency declared by the Secretary of Health and Human Services, the FDA has the authority to grant EUAs to drugs and vaccines that may help respond to the emergency. exist

In September 2020, we opened a Pre-EUA document to the FDA and required the narrow EUA to be used only for treatments that have been permitted under the extended access agreement granted by the FDA in July 2020 but the hospital cannot implement the extended access plan. The FDA notified us in December 2020 that EUA can only be granted after the submission of randomized, placebo-controlled data, and stated that it will review such data "in a timely manner" after submission. In a follow-up communication in January 2021, the FDA suggested that the determination of the EUA requires a review of complete effectiveness and safety data.

One month after the "last visit", we reported that it had reached the pre-specified primary endpoint and informed the public that it planned to apply for an EUA. We also shared this information with the FDA under the open Pre-EUA file.

Within 8 weeks after the “last visit”, the joint research team reviewed approximately 53,909 individual case report forms electronically and manually, and the research supervisors conducted a review of them based on the source data (ie, electronic medical records and doctor reports). verify. An analysis of 1185 treatment emergency adverse event ('TEAE') reports was conducted, and 180 serious adverse events were investigated in detail by medical supervisors, and each report required a detailed description. 5988 concurrent medication reports were evaluated to detect possible serious adverse events. In the next two weeks, all investigation results were reviewed with the chief investigator at each site, and everyone signed the case report for accuracy. The database was officially locked on May 7, 2021.

On May 31, 2021, we submitted an EUA application for ZYESAMI to the FDA to provide a regulatory document describing the safety and efficacy data of the study drug within 3 months after the last visit in the clinical trial. Although there is no guarantee that the FDA will conclude that ZYESAMI meets or exceeds the EUA standard for the treatment of COVID-19, we hope that the FDA will grant an EUA to ZYESAMI.

NRX-101 Phase IIb/III clinical trial

In the second half of 2017, we initiated the Phase IIb/III clinical research program of NRX-101 in accordance with the FDA IND application. The application was granted Fast Track designation by the FDA in August 2017 and a breakthrough therapy by the FDA in November 2018. Specify. In April 2018, the FDA granted a special agreement agreement. We successfully completed the phase II clinical trial of NRX-101 in patients with severe bipolar depression and acute suicidal ideation after a single dose of ketamine was stabilized, and we saw statistics on depression (P=0.04) and suicidal ideation (P=0.02) (Significantly lower chemistry) compared to lurasidone alone during 42 days of treatment. No serious adverse events or dose-limiting adverse events were observed in the NRX-101 group. If this statistically significant advantage is replicated in phase III clinical trials, according to the terms we agreed with the FDA in the special agreement agreement, our goal is to submit an NDA to the FDA for regulatory approval of NRX-101 in the United States By the end of 2021, MAA until 2022.

The following table summarizes the clinical trials and status, and the following sections discuss each item in more detail.

ZYESAMI's Phase IIb/III clinical trial for the treatment of critically ill COVID-19 (COVID-AIV) respiratory failure

We have completed a phase IIb/III intravenous ZYESAMI clinical trial in 196 people for the treatment of respiratory failure in critically ill patients with COVID-19 ("intravenous trial"). The Secretary of the United States Department of Health and Human Services has declared the COVID-19 pandemic as a public health emergency under the terms of the 2013 Pandemic and All Hazard Readiness Reauthorization Act. Therefore, ZYESAMI can be authorized to use the safety and "potentially effective" standards widely in the United States under the following clauses, instead of the more stringent "proven in fully controlled trials" required for the approval of traditional medicines under FFDCA section 505.b.1 It is a safe and effective" standard.

In the intravenous trial, in all patients and sites, ZYESAMI reached the primary endpoint of successful recovery from respiratory failure on day 28 (P = .014) and day 60 (P = .013), and it also showed the possibility of survival The statistically significant advantage of sex to the 60th day (P = <.001, as discussed below when adjusting the baseline ventilation status and the pre-specified covariates of the treatment site. If these pre-specified covariates are not statistically adjusted , The study did not demonstrate a statistically significant difference in the primary endpoint.>

Participants were registered in 10 hospitals in the United States from May to December 2020 and were followed up to the 60th day. Six of these hospitals have intensive care units ("ICU") with intensive care physicians, researchers, and respiratory therapists present 24 hours a day, and are classified as tertiary hospitals. The primary endpoint was pre-designated by the FDA as "survival without respiratory failure" on day 60. Secondary endpoints include the survival time and length of hospitalization of recovered patients.

In all patients, the median hospital stay of patients treated with ZYESAMI was shortened by 10 days (P = .025), and the median length of hospital stay in patients treated with ZYESAMI was reduced by 10 days (P = .025) without controlling the ventilation status or the treatment site compared with patients treated with placebo. A non-statistically significant advantage was seen in favor of ZYESAMI on the primary endpoint at day 60.

When controlling the ventilation status and the treatment site, a significant advantage in favor of ZYESAMI was observed (P=.018). Compared with the subgroup of patients treated with high-flow nasal cannula ('HFNC') (n=98), the effect was The largest number of patients receiving mechanical or non-invasive ventilation in a tertiary hospital. In this group, patients with ZYESAMI had a 71% chance of recovering successfully on day 28, 48% in the placebo group (P=0.017), a 75% successful recovery rate on day 60, and 55% in the placebo group (P= .036). 84% of HFNC patients treated with ZYESAMI in tertiary medical centers survived to day 60, compared with 60% of placebo patients (P=.007). Compared with regional hospitals, patients in tertiary care centers performed significantly better than regional hospitals. The findings may be affected by the intensity of the public health crisis of the regional hospitals participating in the intravenous trial, the degree of overcapacity in ICUs is higher, the implementation of temporary ICU beds, and intensive care Staff shortage.

We applied for the EUA for ZYESAMI on May 31, 2021. The EUA will provide us with one year to complete the CMC, factory inspection and advisory committee requirements related to the approval of traditional medicines.

ZYESAMI is included in the NIH ACTIV3b/TESICO clinical trial of severe COVID-19 and respiratory failure (ACTIV3b/TESICO)

ZYESAMI has been selected by the National Institutes of Health ('NIH') by the Steering Committee of the COVID-19 Severe Inpatient Treatment ("TESICO") program funded by the National Heart, Lung, and Blood Institute and the National Institute of Allergy and Infectious Diseases. The agreement is part of the NIH Accelerating COVID-19 Therapeutic Interventions and Vaccines ('ACTIV') public-private consortium. The clinical trial is expected to recruit 800 patients at study sites in the United States, the European Union, and the United Kingdom for a factorial design, and use ZYESAMI with placebo and Veklury (Redsivir) alone or in combination with ZYESAMI for the treatment of critically ill COVID-19 breathing Exhaustion. The TESICO trial was approved by the FDA and Advarra IRB in the first quarter of 2021, and the first patient was recruited in April 2021.

ZYESAMI is included in the I-SPY clinical trial for the treatment of severe and critical COVID-19 (I-SPY) with early or impending respiratory failure

We have signed a contract with Quantum Leap Healthcare Corporation to include ZYESAMI in the I-SPY clinical trial platform, and the inhaled ZYESAMI will be part of the four-drug group tested as part of I-SPY COVID-19 Trial, one for An adaptive platform test for critically ill patients.

Phase IIb/III clinical trial of inhalation of ZYESAMI in early COVID-19 (AVICOVID-2)

Although our initial focus is on using ZYESAMI in patients with severe COVID-19 and respiratory failure (ie, requiring ventilation, extracorporeal oxygenation, or high-flow nasal oxygen to survive), we have obtained FDA approval for testing in patients with early disease Inhale ZYESAMI. We believe that as long as the patient can still inhale normally and there are no inflammatory debris blocking the alveoli, the inhaled medicine will reach the ATII cells in the lung better than the intravenous medicine. We have signed a contract with COVANCE, Inc. to provide contract research organization support for this clinical trial. The clinical trial will start recruiting in January 2021 and is expected to end by the end of the year.

Clinical trials of Aviptadil in other lung diseases

Clinical trials of aviptadil in non-NRx or Relief Therapeutics preparations have been conducted and reported by others and recorded in the aviptadil investigational drug product file (appendix). We are optimistic that inhaled forms of drugs may also be beneficial for other lung diseases. A phase II study conducted within the 2008 time frame demonstrated statistical and clinically significant benefits in the treatment of sarcoidosis and pulmonary hypertension.​​​ Although the initial trials for the treatment of pulmonary fibrosis have failed, we intend to further explore the treatment of pulmonary fibrosis and cystic fibrosis. In addition, we intend to solve acute lung injury caused by involuntary smoke inhalation, as well as chronic lung injury caused by smoking.

Market opportunities for our products

ZYESAMI provides potential business opportunities for multiple disease areas, including critical COVID-19, general ARDS (all intravenous forms), moderate COVID-19, COPD, sarcoidosis (all inhaled forms) and other lung injuries /disease. In the United States, as of June 11, 2021, approximately 33,246,578 people have been infected with COVID-19, and 600,000 people have died since March 2020. Assuming a mortality rate of 30%-40%, this means that approximately 1,300,000 people have been treated in the ICU so far. The COVID-19 global pandemic has led to the rapid adoption of any approved (for example, under the EUA) and affordable treatments. Positive clinical data supporting emerging compounds have led to very rapid changes in use without the need for extensive promotion efforts. During the pandemic, sales of this rapid adoption therapy can reach $0.5B-$1B per year. Even with the recent emergence of highly effective vaccines, the background level of severe COVID-19 infection is likely to prevail, just as more than 500,000 people are hospitalized and 25,000 die from seasonal flu every year despite widespread vaccination.

In addition to the current COVID-19 pandemic, approximately 200,000 patients are admitted to the ICU due to ARDS each year in the United States, and 75,000 people die from ARDS each year in the United States. ZYESAMI can provide additional treatment options for these patients. The incidence of moderate COVID-19 cases is estimated to be 4 times

Critical COVID-19. If inhaled ZYESAMI shows effectiveness in moderate COVID-19, inhaled ZYESAMI may become an early hospitalization and ambulatory COVID-19 therapeutic agent.

In the United States, it is reported that approximately 6% of people over the age of 40 are diagnosed with COPD. Expansion to a wider non-COVID-19 or intensive care/ICU market, such as COPD will depend on the establishment of ZYESAMI (aviptadil) clinical projects compared with existing drugs, some of which have annual sales of approximately US$100-200 million The United States, although many are now universal. However, a large number of unmet needs still exist and have always resulted in a product mix to better serve specific groups of people. Targeting a narrow, highly unmet demand subgroup may provide ZYESAMI (aviptadil) with attractive opportunities in this market.

In the United States, approximately 30 million people suffer from some form of depression, and another 12 million suffer from post-traumatic stress disorder. Although depression is associated with an increased risk of death from cancer, heart disease, and other comorbidities, the most common cause of death associated with depression is suicide. Suicide is the 10th most common cause of death in the United States and the third most common cause of death in children and adolescents.

Approximately 10% of people with depression have a variant of this disease, called bipolar depression, which represents approximately 3.5 million Americans. Compared with patients with MDD, thinking disorders, and personality disorders, patients with bipolar depression have a particularly high risk of acute suicidal ideation/suicidal behavior. It is estimated that one in two people with bipolar depression will attempt suicide. Unfortunately, one in five people with bipolar depression will die by suicide. Therefore, severe bipolar depression ('SBD/ASI') with acute suicidal ideation has unique and fatal clinical features, which are comparable to the clinical features of many cancers. Given that current treatment of SBD/ASI includes psychiatric hospitalization and possible ECT, this situation represents a clearly unmet medical need. This has been verified by the fast track and breakthrough therapy titles granted by the FDA.

Breakthrough therapy designation is only granted by the FDA for a few drugs that have shown preliminary evidence of efficacy for unmet medical needs under severe medical conditions. According to published research, compared with other drugs, the development time of breakthrough therapy designation and regulatory approval is reduced by 50% (4.1 years and 8 years), and the regulatory success rate at the time of first submission is significantly increased (91% and 75%). .

Most people with depression have MDD. According to a 2003 report entitled "Investing in Mental Health" by the World Health Organization, more than 150 million adults worldwide suffer from MDD at any given time. Bipolar depression is sporadic and often resolves within two to three months, while MDD is characterized by chronic depression. According to the United States National Comorbidity Survey Rehearsal ("NCS-R") released in 2007, there are more than 16 million adults in the United States, accounting for approximately 6.8% of the entire adult population, who will suffer from MDD episodes within 12 years. Month period. In addition, according to NCS-R, about 45% of these cases can be classified as serious, and suicide is usually a serious complication associated with depression.

ZYESAMI (Aviptadil) mechanism of action

VIP was discovered in 1970 by Professors Sami Said and Victor Mutt of Karolinska Institutet, and has become the subject of nearly 1,000 peer-reviewed publications. We hold a non-exclusive license for science and intellectual property developed by Professor Said through a license granted by the State University of New York Research Foundation. Although the license is non-exclusive, the foundation has agreed not to grant any other licenses to the subject of the foundation to allow any third party to manufacture or provide sales of products or services for the treatment of COVID-19 during this period. SUNY License Agreement (definition as follows).

Understanding the mechanism of VIP involves a basic understanding of how the lungs transport oxygen from air to blood and how carbon dioxide transports from blood back to air. The large airways (bronchial tubes) of the lungs branch into smaller units (bronchioles), and finally end in tiny sacs (alveoli) where oxygenation occurs. The alveoli can remain open because they are lined with a detergent-like liquid called a surfactant. It is the surface tension of this liquid that keeps the alveoli open, just like the detergent in soap bubbles allows trace amounts. The water droplets maintain their structure. Without surfactants, the lungs cannot be oxygenated, leading to a fatal disease called "respiratory distress."

Surfactants are produced by a small group of cells that make up only 5% of the inner wall of the lung, called "alveolar type II" ("ATII") cells. These ATII cells nourish 95% of lung cells, and the function of these lung cells is largely passive. ATII cells are specific targets for coronaviruses because they have a specific receptor ("ACE2") on their surface that can bind to the spikes of the virus. Once the virus binds to ACE2, it enters the cell, takes over the nucleus and makes millions of copies of itself. The virus causes cells to produce inflammatory cytokines, which have a fatal effect on the whole body. The virus eventually causes the cell to rupture (cytopathic), releasing millions of virus particles, which continue to infect more ATII cells and other cells in other parts of the body.

VIP is specifically used to protect ATII units. Every mammal produces the same form of VIP, which shows that it is essential for protecting the lungs throughout the evolutionary process. In animal models, VIP protects the lungs from smoke damage, acids and other corrosive chemicals, and various infections. It does this by binding to specific receptors on ATII cells ('VPAC1'). In the context of the coronavirus, as demonstrated by the preclinical studies of Jonathan Javitt and Jihad G. Youssef, VIP prevents C replication and cytokine production in ATII cells, prevents cell death and increases cell production of surfactants.

Figure 1: The anatomical structure of the alveoli and its surfactant layer.

As life evolves from the aquatic environment to the terrestrial environment, the respiratory epithelium, which is responsible for the exchange of oxygen and carbon dioxide, needs to adapt from exposure to a non-toxic water environment to continuous exposure to atmospheric gases that are rapidly toxic to epithelial cells. This is achieved through the development of a surfactant layer, which is arranged in the air sacs of the lungs, which not only protects the lung epithelium from direct exposure to air, but also by generating a bioequivalent of soap bubbles in each alveolar To keep the airbag unobstructed. The surfactant layer is completely maintained by ATII cells (Figure 1), and the dysfunction or death of this cell population can quickly lead to alveolar collapse. In fact, the first lung manifestation of COVID-19

It is characterized by a ground-glass appearance on the chest X-ray, indicating that alveolar collapse is accompanied by a decrease in blood oxygen saturation, long before the lungs begin to fill with inflammatory exudate and debris.

COVID-19 pneumonia and respiratory failure are caused by the SARS-CoV-2 virus selectively attacking ATII cells through ACE2 surface receptors that are not present in alveolar type I cells (Figure 2). ATII cells account for only 5% of the lung lining, but they produce all the surfactants needed to maintain surface tension and achieve oxygenation (Figure 1). Virus replication triggers cytokine production and cytopathic (cell rupture), which triggers a fatal "cytokine storm." Traditional anti-cytokine (especially anti-IL6 monoclonal antibody "mab") drugs have been shown to be insufficient to absorb this cytokine load once produced.

The role of VIP in protecting the pleomorphism of the lungs

Although the "intestinal peptide" is named a historical accident, 70% of VIPs are concentrated in the human lung (Figure 3), just like Jonathan Javitt and Jihad G. Youssef. VIP has been conserved throughout evolution, so all mammals will produce VIP, and there are no known variants. VIP plays a key role in the human response to the inflammatory and corrosive challenges of epithelium (especially lung epithelium). The role of VIP in preventing or alleviating many forms of experimental lung injury has been widely documented. Human trials have shown that VIP is used in the treatment of ARDS related to sepsis, pulmonary sarcoidosis, pulmonary hypertension, and various forms of asthma/allergies. The role of.

VIP binds to ATII cells through VPAC1 surface receptors. Although its pharmacokinetics was short-lived, the only VIP (Phase Bio PB1064) that entered the clinic with extended duration modification was VPAC1 selective and proved to be futile in the first 25 patients and ceased development.

Inhibition of virus replication in human lung cell (Calu-3) model: Recently, it has been shown that VIP can inhibit SARS-CoV-2 replication in infected human Calu-3 cells and monocytes. Calu-3 cells are a suitable model because they retain many of the characteristics of ATII cells, including the ability to make surfactants. Oswaldo Cruz Institute is a recognized biocontainment safety level 3 laboratory that uses primers, probes and cycling conditions recommended by the Centers for Disease Control and Prevention to detect virus replication by quantitative RT-PCR to detect SARS-CoV-2. VIP significantly reduced SARS-CoV-2 RNA synthesis, achieving 33% and 45% inhibition at 5 nM and 10 nM, respectively (Figure 3). VIP of 1 nM completely blocked the cytopathic effect mediated by SARS-CoV-2, as measured by the LDH level in the cell culture supernatant).

Applying conditioned media from VIP-treated infected monocytes to SARS-CoV-2 infected Calu-3 cells reduced virus replication in these cells by 50%. This finding indicates that VIP induces monocytes to release antiviral factors, which may increase the resistance of neighboring cells to the growth of SARS-CoV-2.

Figure 2: SARS-CoV infects human type II cells. Human type II cells are cultured at the air-liquid interface to maintain a differentiated state and be infected with SARS-CoV-1. Virus particles (white arrows) can be found in normal-looking lamellar bodies and vesicles near mitochondria. (Courtesy of R Mason, National Jewish Hospital.)

Figure 3: Inhibition of SARS-CoV-2 replication in human Calu-3 cells incubated with VIP (left) and cytopathic inhibition in these cells measured by the release of LDH into the culture medium (right). Source Temerozo 2020.

Inhibition of cytokine synthesis: There is a large amount of literature on the role of VIP in blocking cytokine synthesis in ATII cells, and VIP has been shown to reduce the production of TNFα in ARDS and sarcoidosis. Compared with uninfected cells, infected monocytes and Calu-3 cells produced large amounts of IL-6, IL-8, TNFα, and MIF (15, 4, 12, and 18 times). VIP treatment resulted in a reduction of these pro-inflammatory cytokines by 66%, 50%, 66%, and 50%, respectively, which means that VIP may provide critical protection for the inflamed lungs infected by the coronavirus. As mentioned above, it is generally believed that the morbidity and mortality of COVID-19 are related to the release of inflammatory cytokines, especially interleukin 6 (IL-6). Among all the patients and care locations in our study, the blood IL-6 levels of patients treated with placebo increased 10 times within 7 days after treatment, while patients treated with ZYESAMI increased 2 times (P<.02 il- This increase of 6 is statistically related to the improved survival rate of patients treated with zyesami>

Preservation of surfactants: If the mechanism of ALI in SARS-CoV-2 infection is only driven by cytokine-induced inflammation, then steroids and other anti-inflammatory drugs may have some beneficial effects. Lung injury in COVID-19 is increasingly considered to be similar to lung injury in premature infants. Despite mechanical ventilation, the loss of surfactant secreted by ATII cells leads to the death of premature infants. VIP increases the combination of methylcholine and phosphatidylcholine (the main component of lung surfactant) by enhancing the activity of choline phosphocytidine transferase.

Inhibition of cytopathy: In addition to the empirical observation of VIP blocking the cytopathy induced by coronavirus, there is a large amount of literature showing that VIP is a proven activation-induced inhibitor of perforin and granzyme B, so it actively contributes Reduce harmful pro-inflammatory and cell death induction processes, especially in the lungs. Caspase-3 has been identified as a key mediator of mammalian cell apoptosis through its role in cleaving a variety of substrate proteins and inducing DNA fragmentation. In the animal model of ALI, the caspase activity was significantly increased compared to the activity in the normal lung, and VIP showed inhibition of caspase activation.

Data supporting biological effects

Phase 1 and Phase 2 clinical data of the use of VIP in lung diseases

A phase 1 study of patients with sepsis-related ARDS (people with a survival probability of less than 50%) showed that 7 out of 8 patients achieved clinical improvement, and 6 patients survived long-term (the 7th died from an unrelated myocardial infarction) ). In addition, when using a ventilator, circulating TNF-α is significantly reduced and blood oxygenation is improved.

After the discovery of this acute care in the first phase, the sponsor at the time (Baijian) chose to focus on chronic lung diseases and initiated the second phase of human studies on sarcoma, pulmonary fibrosis, and pulmonary hypertension. Significant reduction in cough and dyspnea after inhalation of avitadil four times a day was recorded in the sarcoma. Measured TNF-α, a significant reduction in the release of T cells from bronchial washes, and a statistically significant reduction in the CD4/CD8 ratio, which is a widely accepted measure of immune response. The intravenous safety data are detailed in the IMPD and filed with the FDA.

In short, the level of no side effects accepted by the FDA is 200 µg/kg/day. The expected dose of aviptadil in this study is less than 10μg/kg/day, and the expected dose and

The lowest possible toxic dose. IMPD records a large number of safety studies and the efficacy studies of aviptadil in normal volunteers. It is possible to lower blood pressure and cause diarrhea. These two conditions may be dose-limiting side effects in some patients, but they are very difficult in the ICU environment. Easy to handle.

ZYESAMI's human trial in COVID-19 respiratory failure (COVID-AIV)

We have completed the Phase IIb/III randomized controlled trial of ZYESAMI and placebo (NCT 04311697), which is conducted under the FDA Fast Track designation. The intravenous trial was conducted by NRx with support from Target Health, LLC, Covance Clinical Services, and Lavin Statistical Associates. Relief Therapeutics funded the cost of the first 144 patients during the 28-day follow-up period, which accounted for approximately half of the total cost of conducting clinical trials. We funded the balance of research expenses. Intravenous Trial was originally conceived by us and approved by the FDA as a 28-day clinical trial. "Surviving at 60 days without respiratory failure" (ie, recovering from respiratory failure (without recurrence), discharged from the hospital and survived during the observation period) is the pre-designated primary endpoint designated by the FDA. Secondary endpoints include survival at day 60, the average score of the NIAID severity scale, and the median length of hospital stay. After screening and informed consent, participants were randomly assigned to receive 3 consecutive intravenous infusions of ZYESAMI or 3 consecutive infusions of placebo (normal saline) in a 2:1 random allocation.

In December 2020, before unblinding, we recognized that one-third of the patients participating in the trial were still in the ICU at 28 days and notified the FDA that a 60-day endpoint was needed. The FDA revised its guidelines to evaluate the primary endpoint of 196 participants 60 days before the patient level is unblinded. Before removing the blinding method of the overall mortality difference between the tertiary and regional sites, the nursing site was added as a covariate, which was triggered by the large number of COVID-related (ie non-drug-related) fatal and serious adverse event reports received by the regional sites After this confirmation, the statistical analysis plan was revised and the FDA was notified. The FDA's February 2021 guidance includes a task to consider the effects of the treatment site. These data are also confidentially shared with the National Institutes of Health to inform the TESICO researchers who chose the 90-day observation period to determine the primary endpoint.

The statistical significance used here is represented by the P value. P value is the probability that the report result is obtained purely by chance (for example, the statistical significance of P value used in this article is represented by P value. P value is the probability that the report result is obtained purely by chance (for example, P value

As mentioned above, in its revised guidance in February 2021, the FDA requires that the prognosis of patients with severe COVID-19 and respiratory failure be measured at 60 days. Therefore, we modified our primary, pre-specified composite endpoint to "survive at 60 days without respiratory failure", and key secondary endpoints include 60-day survival rate and improvement in the NIAID ordinal scale. The intravenous trial recruited 196 participants, and the last participant completed 60 days of observation on February 24, 2021. In all patients and locations, ZYESAMI reached the primary preset end point of "survival without respiratory failure" on day 60 (P = .02) and proved that regardless of whether the participant fully recovered, the probability of survival on day 60 was statistical The increase in academic significance (P =

In addition to treatment (ie ZYESAMI and placebo), there are two other factors that are statistically significant in predicting success on day 60: whether the patient initially received high-flow nasal oxygen and mechanical or non-invasive ventilation therapy, and whether the patient was in grade three Medical centers and regional hospitals receive treatment.

The form of treatment is closely related to the severity of baseline respiratory failure. The difference between the results of tertiary hospitals and regional hospitals may be affected by the fact that the regional hospitals included in this trial recruited participants from mid-November 2020 to January 2021, and their resources were severely limited, 200% Or more ICU capacity surplus, staff shortage, and delayed admission of critically ill patients. Therefore, if it is widely approved, the differences in care observed in our clinical trials may not reflect the expected results of ZYESAMI treatment in any way. The primary endpoint analysis by subgroup is comparable to the analysis of all patients and research centers in significance. Figure 4 provides an illustrative sub-analysis.

In addition to robust overall significance among all 196 treated patients in all 10 clinical centers, a pre-specified subgroup analysis of survival and no respiratory failure compared with those of 127 patients treated with HFNC It was clinically and statistically significant (P=.02) regardless of the treatment site, mechanical or non-invasive ventilation was used. In this group, patients with ZYESAMI had a 71% chance of recovering successfully on day 28, 48% in the placebo group (P = .017), a 75% successful recovery rate on day 60, and 55% in the placebo group (P = .036). 84% of HFNC patients treated with ZYESAMI in tertiary medical centers survived to day 60, compared with 60% of placebo-treated patients (P = .007).

Recovery from respiratory failure (without recurrence), acute care discharge, and survival during the observation period are the pre-designated primary endpoints designated by the FDA for the study. It was initially planned to be evaluated at 28 days and then extended to 60 days based on recent conditions— -Issued FDA guidelines. The above analysis included all 196 participants who were randomized to receive treatment in a placebo-controlled, double-blind clinical trial (NCT04311697) conducted in 10 hospitals in the United States. ZYESAMI or placebo treatment is a supplement to standard care treatment, including steroids, convalescent plasma, antiviral therapy, anticoagulants, and various anti-cytokine drugs.

The influence of the baseline NIAID score on the follow-up results of the ZYESAMI and placebo groups.

A key result in evaluating recovery is the "NIAID score", which ranges from 8 points (representing patients with no COVID-related symptoms at home) to 1 point (representing patients who have died). A NIAID of 2 or 3 means patients with respiratory failure, 4 or 5 means patients are in hospital but no respiratory failure, 6 means patients are not in emergency care (home or rehabilitation) but need oxygen, 7 means patients are not in emergency care and do not need oxygen . The FDA guidelines believe that the two-step improvement of NIAID has clinical significance.

In addition to the pre-specified analysis of the primary and secondary endpoints, a secondary analysis was performed using the baseline NIAID score as a stratification variable (NIAID 2 and 3) (Figure 4). In the NIAID=2 subgroup (58.6% vs. 0%; LR ²=10.5, p=.001) and NIAID=3 subgroup (83.1% vs. 62.8%; LR ²=5.6, p=.03). When the daily NIAID score was divided by the baseline NIAID score, among subjects with a baseline NIAID score = 2 (F1,106=4.75, p=.036), the significant advantage of ZYESAMI-treated patients proved to be independent of the place of care. Patients on the placebo mainly showed a downward trajectory, while those taking the drug showed an upward trajectory (Figure 5). For subjects with a baseline NIAID score=3, in all care locations, the differences between groups reached a significant trend level over time (F1,34=4.75, p=.1), and both groups showed the average over time improve. This difference becomes significant when considering the subgroup receiving treatment in tertiary hospitals.

Figure 4: 60-day average NIAID score stratified by baseline NIAID score.

The role of ZYESAMI in preventing IL-6 "cytokine storm"

As mentioned above, it is generally believed that the morbidity and mortality of COVID-19 are related to the release of inflammatory cytokines, especially interleukin 6 (IL-6). In all the patients and care locations in our study, the blood IL-6 levels of patients treated with placebo increased by 10 times within 7 days after treatment, while patients treated with ZYESAMI increased by 2 times (P<.02 graph) Preventing the increase of il-6 is statistically correlated with improved survival of patients treated with zyesami> Figure 5A: The percentage change of IL-6 from the baseline before treatment (day 0). There is a significant difference between day 3 and day 7. Significant difference, which is conducive to the independent significance of Avitadil (P=.020) on the 3rd day (P=.003) and the 7th day (p=.048). Figure 5B: Based on binomial regression The correlation between the change in the log ratio of IL6 and the change in the 60-day success prediction. The dashed vertical line illustrates the log ratio IL6 level on day 7 of the treatment period with avitamin and placebo, as shown.

As can be seen from Figure 5A, regardless of the baseline severity, the average increase in IL-6 in the placebo-treated group was compared with the 2-fold increase in the drug-treated group in all patients and sites. There is a clear correlation between IL-6 levels and 60-day primary efficacy (survival without respiratory failure) and 60-day survival rate.

This data shows that the IL-6 cytokine data records the biological effects of all patients and parts, even if the final treatment result depends on the most advanced ICU care, especially on the non-termination of the life support for the saved patients. The purpose of resource allocation.

The following shows the incidence of TEAE> 5% for each system organ category and any preferred term; by day 28 after enrollment, except for gastrointestinal diseases, there was no significant difference between overall treatment or any single system organ category ( Two-sided Fisher Exact test p=0.0002). Two specific system organ categories of interest (diarrhea, hypotension) plus infusion site reactions (redness, swelling) are highlighted below as part of all reported categories. ZYESAMI and SOC (30.5% vs. 1.5%) observed more diarrhea and more hypotension (25.2% vs. 18.5%). Finally, ZYESAMI's infusion site reaction was 7 (5.3%) more than SOC 1 (1.5%). No accidental drug-related serious adverse events (SAE), including mortality, were recorded.

A prospective, administrative control trial of ZYESAMI in patients with high comorbidities of COVID-19 (open label for high comorbidities)

The second open-label study of administrative distribution of 45 patients at Houston Methodist Hospital under the extended access agreement (NCT04453839) showed that ZYESAMI has improved survival and recovery rates for patients with respiratory failure with high comorbidities compared with standard care 9 times (P

In this single-center trial, there was a huge and statistically significant difference in the likelihood of recovery from respiratory failure between patients treated with ZYESAMI and patients treated with standard care. These non-random data strongly support the data obtained in the intravenous trial and provide additional insights for the use of ZYESAMI in patients whose condition is too severe to be included in the intravenous trial.

Figure 5C: Recovery of respiratory failure in intubated patients with high levels of comorbidities treated with ZYESAMI and placebo.

Further research will be conducted on mechanically ventilated patients treated with ZYESAMI and placebo under the I-SPY and ACTIV 3b agreements supported by the federal government, and more than 800 patients are expected to be recruited.

A prospective trial of inhaled avitadil in the treatment of moderate and severe COVID-19 (AVI COVID-2)

The focus of the above research is that ZYESAMI increases the likelihood of recovery and survival for patients with COVID-19 respiratory failure (a highly fatal disease) who have been admitted to the ICU. There is reason to believe that the same mechanism that ZYESAMI uses to achieve potential benefits in critically ill patients may be applicable to patients with a milder form of COVID-19. In this case, the inhaled use of ZYESAMI is preferable because the challenge of maintaining continuous intravenous infusion is well known and 30% of patients are known to develop diarrhea caused by intravenous avitamin. We have been granted IND 151070 by the FDA and have been informed by the FDA that the final approval of the new drug for inhaled ZYESAMI does not require further non-clinical studies. The FDA has issued a "possible" letter regarding the AVI COVID-2 trial of inhaled avitadil, which will be administered via a hand-held nebulizer in a placebo-controlled trial (NCT04360096). Recruitment for the trial started in January 2021 and is expected to end by the end of this year. The trial cost is approximately US$15 million. The primary endpoint of the trial will be the percentage of patients who have progressed to respiratory failure on ZYESAMI versus placebo treatment. Secondary endpoints include blood oxygenation, shortness of breath, and six-minute walk distance (a commonly used measure in trials of respiratory diseases).

Prospective trial of inhaled avitadil in the treatment of critically ill COVID-19 (I-SPY)

Inhalation rather than intravenous injection of avitadil may help treat patients with critically ill COVID-19 and respiratory failure. This potential use of ZYESAMI will be tested as a branch of the clinical trial of the I-SPY platform, supported by BARDA. We have signed a clinical trial participation agreement with Quantum Leap Health Care Collaborative, the sponsor of the I-SPY COVID-19 trial, and agreed to provide $1.5 million for trial costs. Compared with the aforementioned Phase 3 trials, the I-SPY platform aims to produce Phase 2 results. If a positive result is found to indicate that inhaled ZYESAMI is beneficial for critically ill patients with COVID-19, we will need to discuss with the FDA the way to find indications for this label, and a second confirmatory test may be required.

VIP Association and human case-control study of COVID-19 survival

Compared with normal controls, the plasma VIP level of severe COVID-19 patients is increased, and the increase of VIP is related to the severity of COVID-19 inflammation (r2 0.16; P<.01 Figure teremozo conducted a case-control study at oswaldo cruz in Rio de Janeiro Institute, patients with severe covid-19 and respiratory failure. VIP levels are associated with survivors and non-survivors over 17 years old

Receive maximum intensive care due to ventilatory COVID-19 respiratory failure. Significantly higher levels of VIP were recorded among the survivors (P<.05>

Figure 6: A case-control study of VIP levels of key COVID-19 survivors and non-survivors. The plasma VIP levels of survivors were twice as high.

Overview of Aviptadil's Non-clinical Safety Research

We have obtained the right to evaluate Relief Therapeutics' toxicology, clinical pharmacology and pharmacokinetic data for humans and four other species. In written communications, the FDA believes that these non-clinical data are sufficient to support the NDA.

Relief's predecessor company, Mondo Biotech, and Biogen, Inc. developed avidadil in cooperation and accepted joint recommendations from the FDA and EMEA. Between 2006 and 2010, three Class B meetings were held with the FDA, resulting in a complete set of non-clinical studies on four species (mice, rats, dogs, and primates) to support avitamins For intravenous and inhalation use. These studies have been submitted under FDA IND 149,152 and include pharmacokinetics, pharmacodynamics, safety pharmacology (cardiovascular), acute toxicity, repeated dose toxicity, reproductive toxicity, and local tolerability. The FDA has agreed in writing that all NDA-approved non-clinical studies have been conducted, and agreed to roll-out the acceptance of non-clinical data before clinical safety and efficacy data.

Open label dose escalation study

The purpose of this phase I study is to obtain preliminary data on the safety and effectiveness of intravenous avitadil in patients with ARDS complicated by sepsis in an open-label study.

The trial was conducted in patients with ARDS complicated by sepsis syndrome. These patients may or may not have evidence of other organ dysfunction. Although there is usually a 24 to 48-hour time window from the diagnosis of sepsis/septic shock to the appearance of severe lung and other organ damage, organ damage may progress rapidly, and a certain degree may already be present when sepsis is first diagnosed Lung injury. By restricting the study population to patients with advanced or related sepsis/septic shock and excluding patients with other risk factors for ARDS (such as trauma, drug overdose, acid inhalation, and inhaled toxins), the study group is expected to be more unified and clear.

According to the most recent consensus definition, all patients who participated in this trial were diagnosed with ARDS in the case of sepsis syndrome. Patients are observed for 24 hours, during which time all inclusion criteria must be met. If all criteria have been met once (not necessarily at the same time), the patient is included and receives study medication within 12 hours of meeting the entry criteria.

In the lower dose group of 50 pmol/kg/hr (5 patients), the administration of aviptadil was stopped in one (bronchial obstruction due to hypersecretion not considered to be related to aviptadil), and in the other (hypotension) The medium dose is halved. In the third case, stop dosing early to keep some IV solution for analysis.

In the high-dose group (3 patients) at 100 pmol/kg/hr, no one stopped taking avitadil. However, due to hypotension (1 case) or duality (1 case), the dose was temporarily reduced twice.

Critical COVID-19 with extended access to severe comorbidities (high comorbidity open label)

Open label extended access protocol NCT04453839

As of the submission date, 300 patients have participated in this extended visit study for patients with severe COVID-19 respiratory failure and severe comorbidities who are not eligible for NCT04311697. To date, no serious adverse events related to drugs have been reported. This is not a prospective trial because there is no control group. However, the safety information collected will become part of our drug safety database, and based on the above-mentioned randomized controlled trials, the identified efficacy endpoints may be considered supportive in future FDA filings. To date, a 70% survival rate has been observed over 28 days, which is comparable to the drug and placebo survival rates observed in the Phase IIb/III trial. No other data from the extended access protocol has been analyzed. This activity is carried out by NRx. As an extended access agreement, it is an activity recommended by the FDA in Phase II/III. The only endpoints collected were survival at 60 days and no respiratory failure. However, the study did not compare groups. Therefore, these data are expected to contribute to ZYESAMI's safety database, but will not provide primary evidence of effectiveness. To date, an IND safety report has been submitted to the FDA concerning a patient who developed metabolic acidosis related to diarrhea after receiving avitadil treatment. Metabolic acidosis was treated without further sequelae.

Product Picture/Therapy Kit Definition

In the IV form, ZYESAMI will be given three 12-hour intravenous infusions over three consecutive days. Each ZYESAMI treatment kit ("3-pack") will contain three sterile 5ml aviptadil glass vials, 100μg/ml, with a validated crimping sealed container closure system, as part of the risk assessment and management, the system is Serialize and register the strategy we want to implement to a single patient. Each treatment kit will contain a plastic embossed pharmacist weight/dose table. The infusion is delivered to the patient through a standard intravenous infusion pump available in every hospital in the United States.

The dosage table in the NRx pharmacy manual indicates that the dosage that produces 100 pmol/kg/hr is 0.333 µg/hr. This represents the intermediate dose used in the ongoing Phase 2/3 trial. Therefore, a 70 kg patient needs 280 micrograms of API for a 12-hour infusion. We will provide a 5 ml vial, which contains 500 micrograms of avitidine acetate and 5 milliliters of 0.9% NaCl (ie 100 micrograms/ml). The treatment kit may not provide enough medication for all doses of all patient weight categories. However, we will provide a 100% discount on any kits used to provide supplementary medicines to patients who are overweight and cannot get enough drug substance from a single treatment kit.

We cooperated with Nephron Pharmaceuticals and started to expand ZYESAMI 100μg/ml in saline. With current production capacity, we can provide 10,000 patient treatment courses per month. In addition to the APIs we supply from Bachem Americas, we have now signed a contract with Polypeptide Group (Torrance, California) to supply avidadil acetate (the API or active pharmaceutical ingredient used in the production of ZYESAMI) in large quantities. As used below, BOC and FMOC refer to different synthetic chemical pathways in peptide synthesis. Bachem Americas’ BOC manufacturing process is limited to 120 grams of API per month (approximately 60,000 patient treatment sessions). The BOC process is also subject to

The use of hydrofluoric acid, a compound that is harmful to the environment, is restricted by the U.S. Environmental Protection Agency. We developed the FMOC process in cooperation with the Polypeptide Group. The FMOC process does not rely on hydrofluoric acid, and the production volume is between 1KG and 5KG, and the cost is greatly reduced, thereby eliminating the supply of raw materials as a material constraint.

Source and manufacture of API

Bachem Americas has established a drug master file with the FDA, and we have been granted reference rights. We have signed a contract with Bachem Americas to supply 1 KG of aviptadil in the first quarter of 2021. We also signed a contract with Polypeptide Group to supply FMOC processed materials from the second quarter of 2021. Both forms of aviptadil API are the same acetate salt. Polypeptide Group's materials have not yet passed the FDA's human use certification, and it is expected that the certification will be part of our ZYESAMI confidentiality agreement. We have signed a contract with Peptide Group for the first batch of 1 kg of aviptadil, and the first batch of 1 kg has been issued to us.

Basis for formulation and initial stability

Currently, aviptadil is provided to humans in the form of saline, and this form has been shown to have clinical benefits in open-label studies (Figure 7). A lot of time and resources have been invested in improving the formulation of Avitadil. Inventor Dorian Bevec, MD, a former consultant of our company, led the inhalation use trial for sarcoma, asthma/allergies and pulmonary hypertension, and observed the intravenous phase I trial. However, it is believed that freeze-dried formulations containing polysorbate 80, sucrose, and mannitol cause peptide aggregation and were abandoned by Mondo Biotech in 2009. The addition of citrate buffer and EDTA will reduce potency and purity for 28 weeks.

As of July 31, 2021, Relief Therapeutics has not yet invested in ZYESAMI's commercial cGMP formulations required for regulatory approval and commercialization. In addition, Relief Therapeutics did not provide us with any information that could lead to stable cGMP formulations.

Figure 7: Purity and potency of Avitadil in a physiological saline and buffer system over 18 months

Bachem's aviptadil pressure test data show that aviptadil can be stable for at least 77 weeks at 5°C in salt water (Figure 7). NRx did not successfully replicate these data using modern, proven chromatographic techniques from two different cGMP manufacturers. In January 2021, we recommended that Relief Therapeutics abandon the RLF-100 formulation method and cooperate with Nephron Pharmaceuticals and Nextar, Ltd. to develop a new method to develop ZYESAMI's long-term stable liquid formulation. NRx and Nephron Pharmaceuticals believe that the mechanism for the rapid degradation of avastatil in solution has been established, and innovations in formulation, manufacturing and container sealing have been developed to cope with this degradation. As of July 31, 2021, NRx has started the GMP production of ZYESAMI™, and expects a long-term stable formulation that may have a one-year thawing stability. If the FDA considers ZYESAMI™ to be safe and effective, it is possible to store the formulation.

We also signed a feasibility study and material transfer agreement with TFF Pharmaceuticals, Inc. ('TFF') to explore a "film freezing" method to develop long-term stable products that may be directly suitable for inhalation and as a liquid product Reconstituted to provide long-term stability.

Our storage methods may include freezing at -70°C, may include freeze-drying methods that do not cause peptide aggregation, or other more modern carriers that have been developed for short peptides. As part of the development of our manufacturing scale-up plan, extensive stress testing will be performed at various temperatures and concentrations. However, there is no guarantee that this type of technology will succeed, and we may be forced to bring to the market a drug form with a validity period of 90 days or less while developing a long-term stable product display. In this case, the profitability of the product may be impaired by the cost of the supply chain and accepting end users' requirements to return obsolete products.

On August 2, 2021, we announced the establishment of a development relationship with Mannkind, Inc. ('MNKD'). Based on this relationship, we will explore the use of MNKD's Technosphere® platform to develop ZYESAMI. The platform has been successfully implemented to develop the FDA-approved inhaled insulin (Afrezza®) form, which is currently sold in the United States and globally.

CNS Product Portfolio: Acute suicidal ideation and behavior in bipolar disorder

CNS portfolio background

Our CNS product portfolio is based on the basic scientific discoveries of Dr. Daniel Javitt, MD, Columbia University Psychiatry Professor and NeuroRx co-founder. In 1987, Daniel Javitt discovered the role of blocking the brain's NMDA receptors (a molecule on the surface of brain cells) in producing psychosis. This discovery was made in the context of an attempt to determine the molecular mechanism by which phencyclidine (angel dust: a once-popular drug of abuse, often added to marijuana) causes acute psychosis in a high proportion of users. Daniel Javitt discovered that phencyclidine exerts its mental effects by blocking NMDA receptors and uses the rest of his ongoing career to study the brain chemistry of schizophrenia, depression and related diseases. Daniel Javitt is one of the most widely published scientists in the field of molecular psychiatry.

About 10 years after Daniel Javitt's initial discovery, people learned that NMDA inhibition is the mechanism by which ketamine, dextromethorphan and other NMDA antagonists exert their antidepressant effects. Daniel Javitt then made the groundbreaking observation that when NMDA antagonists, especially DCS, are used in combination with traditional (serotonin-targeted) antidepressants or antipsychotics, the two drugs have a synergistic effect. Antidepressant activity is enhanced and side effects are reduced. Daniel Javitt explained the mechanism of this synergy in multiple non-clinical models. This discovery led to the extensive patent portfolio we now have and the development of NRX-101, the first researched human drug for suicidal depression.

NMDAR-based treatment of bipolar depression

NRX-101 is a dual-targeted sequential therapy ("NRx Pharmaceuticals Sequential Therapy") that includes initial treatment with NRX-100 (intravenous ketamine) followed by NRX-101 (combined DCS and lurasidone) 6 weeks of treatment. The treatment aims to stabilize individuals with acute suicide crisis associated with acute exacerbation of depressive symptoms in patients with bipolar disorder, and then stabilize them for a longer period of time to resolve the crisis. The drug is used to treat depression and acute suicidal ideation and behavior ('ASIB') in individuals with acute decompensated bipolar disorder.

Bipolar disorder, formerly known as manic depression, is a mature psychiatric diagnosis, with a lifetime prevalence of 4.4% among American adults. Compared with patients with MDD, thinking disorders, and personality disorders, the risk of ASIB during a bipolar depressive episode is particularly high. Between 25% and 56% of patients with bipolar depression commit suicide throughout their lives. Approximately 40% of the nearly 50,000 suicide deaths in the United States each year are related to bipolar depression. Patients with bipolar depression are 20-30 times more likely to attempt suicide than the general population. In 5 years, one in five people with bipolar depression will attempt suicide. The overall suicide death rate for people with bipolar disorder is 164 per 100,000 person-years, which is approximately 10 times that of the general population. Those who attempted suicide were 2.3 times more likely to die by suicide than by any other method. Therefore, ASIB of bipolar depression has unique and fatal clinical features.

Current treatment options for ASIB in bipolar depression

Despite its fatal characteristics, there are no approved drug treatments for ASIB patients with bipolar depression. Therefore, although the side effects of ECT include memory loss and confusion, and are costly, ECT, usually combined with inpatient psychiatric care, is still the only FDA-approved treatment for ASIB patients with bipolar depression. In recent years, several combined D2/5-HT2a antagonists have been shown to be effective in the treatment of bipolar depression (olanzapine/fluoxetine combination, quetiapine and lurasidone). Treatment guidelines support the treatment of acute bipolar depression. depression. Although these drugs are effective in reducing the overall symptoms of depression, they do not specifically reduce suicidal ideation, as shown in recent lurasidone clinical trials. In addition, in these two studies, individuals with active suicidal ideation were specifically excluded due to concerns that these drugs may increase suicidal tendencies (Montgomery Asperger Depression Scale, MADRS Project 10  4). Similarly, patients with acute suicide are usually excluded from clinical trials of other experimental antidepressants. Therefore, ASIB for bipolar depression represents a major unmet medical need that must be hospitalized frequently or involuntarily under ECT under highly supervised conditions.

Although all approved depression drugs act mainly through monoaminergic mechanisms, it was accidentally discovered that ketamine has a rapid and profound effect on depression and suicidal behavior, leading to the recognition of the glutamate system and N-methyl-D-day The aspartate receptor ('NMDAR') may also play an important role in depression and suicide. In this study, biphasic patients with acute suicide and depression will receive a single low-dose intravenous ketamine to determine clinical response. For patients who respond to acute suicide and improvement of depressive symptoms, the study product will be taken orally twice a day for up to six weeks to determine whether NRX-101 can prolong the time for depressive symptoms to subside and clinical recurrence.

Develop the basic principles of NRX sequential therapy

NRX-100 is an intravenous infusion of ketamine to induce acute reactions. It is taken in combination with NRX-101. NRX-101 is a fixed-dose compound oral capsule composed of DCS and lurasidone, which can maintain bipolar patients with acute depression The acute suicide remission. NRx Pharmaceuticals Sequential Therapy utilizes the unique synergy of three FDA-approved drugs with a long safety history: DCS, Lurasidone, and Ketamine.

DCS is a broad-spectrum antibiotic approved for the treatment of tuberculosis (silomycin or cycloserine). DCS has been used by millions of people, but no major safety issues have been reported. Its antidepressant effect was first observed incidentally in patients with comorbidity of tuberculosis and depression who received high-dose DCS anti-tuberculosis treatment, and was subsequently confirmed in prospective studies. However, since DCS is prone to cause significant psychiatric side effects when administered at high doses, no further studies were conducted at that time. The interaction between DCS and NMDA receptors was first demonstrated in 1989, leading to some interest in NMDAR blockers as potential antidepressant treatments. For example, the use of forced swimming to test depression has shown that DCS and the related compound ACPC are active in mice.

Figure 8: When DCS is added to existing antidepressants, the effect of DCS on persistent depressive symptoms in MDD.

Despite adequate treatment with approved antidepressants, it was subsequently shown that high doses (> 500 mg) of DCS can reduce persistent depressive symptoms in patients with MDD. Use a slow DCS titration, 250 mg/day X 3 days, then 500 mg/day for 18 days (ie until the end of week 3); then 750 mg/day for 1 week (ie, until the fourth Week end), then 1000 mg/day (ie, until the end of the study). In this study (Figure 8), significant beneficial effects were observed in 13 subjects compared with placebo, and these subjects had depressive symptoms that did not respond to SSRI. this

The improvement appeared within two weeks and persisted throughout the six-week treatment period. These data indicate an effect size >0.9. At the end of the 4th week, a statistical separation between the groups was observed within 1 week of the starting dose> 500 mg/d. An unexpected finding of the study was that the combination of DCS and antidepressants had little psychotropic effects, which indicated an unexpected synergy between the two components of the treatment.

Figure 9: The effect of continuous ketamine and DCS treatment on patients with continuous treatment of acute bipolar depression who received an atypical antipsychotic approved for the treatment of bipolar depression. Top: The effect of using the Hamilton Rating Scale for Depression (HDRS, HAM-D) on depression ratings. Bottom: The impact on suicide as assessed by the HAM-D suicide program.

Lurasidone is an atypical antipsychotic that has been approved for the treatment of depressive episodes associated with bipolar depression in adults as a monotherapy and adjunctive therapy to lithium or valproate. Among similar drugs, lurasidone requires the lowest therapeutic dose and the least side effects.

Ketamine hydrochloride is a dissociative, fast-acting general anesthetic, used for intravenous or intramuscular injection, and approved for surgical anesthesia. Ketamine has a wide safety margin. Its application in more than 12,000 surgical and diagnostic procedures has been studied in more than 10,000 subjects participating in 105 independent clinical studies. A number of randomized clinical trials have shown that ketamine can relieve symptoms of depression and suicidal ideation almost immediately. However, it has been shown that when used intravenously, 3 days after administration and when the S-enantiomer is delivered intranasally, the clinical effect is reduced.

Ketamine is a direct NMDA channel blocker that binds to the binding site of phencyclidine, and high-dose DCS has an NMDA antagonist effect mediated by the interaction with the glycine binding site. This effect obviously has nothing to do with its properties as an anti-infective agent. By combining the potential of DCS to prolong the antidepressant effects of ketamine with the antipsychotic properties of lurasidone, NRx Pharmaceuticals' sequential therapy has the potential to stabilize patients with bipolar depression and address serious medical needs during acute crises.

NRX-100 (ketamine hydrochloride, 0.5 mg/kg intravenously within 40 minutes) has been shown to induce a sharp reduction in suicide and depression in patients with bipolar depression compared to the control group. Many reports have proven that in patients with suicidal ideation and depression, after a single infusion of ketamine, MADRS is reduced by 50%, and the suicide rate is reduced by 75%. Although repeated use of ketamine is not supported and may be banned in the literature, DCS is used in combination with selective serotonin reuptake inhibitor (SSRI) antidepressants to treat patients with resistant depression, as well as with atypical antipsychotics, Especially when lurasidone is used in combination, it has been shown to be separated from the control and the ability to maintain suicide and depression remission within 6 weeks of oral use (Figure 9).

Figure 10: Inhibition of NMDAR activity by DCS in the presence of glycine.

The cross-species transition of DCS effects is based on plasma levels, so NMDAR antagonist effects are consistently observed at plasma levels >25 µg/ml (~250 µM) (Figure 10). This plasma level is reached at doses >30 mg/kg in rodents and >10 mg/kg in humans. Evidence for the involvement of functional targets at these doses comes from 1) rodent behavior studies, 2) clinical studies of DCS in schizophrenia, and 3) clinical studies of DCS in depression.

In 1990, Hood et al. evaluated the effect of DCS on NMDAR activation for the first time. In 1989, they noticed that the inhibitory effect of DCS on NMDAR activation was similar to our proposed active dose. These effects were subsequently confirmed by Watson et al. in 1990, and the high-dose antagonist effect of DCS was also widely discussed by Lanthorn et al. in 1994.

Figure 11: The effect of NMDAR antagonists AP7 (top panel) and DCS (bottom two panels) on fear-induced startle, showing similar effects of the two drugs, and an effective dose of DCS >30 mg/kg.

Most rodent behavior studies conducted with DCS used a DCS dose of 30 mg/kg to produce a significant dose-dependent anxiolytic effect in the fear-enhanced startle test (Figure 11 middle and bottom), which is in contrast to the known NMDAR glycine production Similar site antagonist 7-chlorokynurate. The author declares as follows: "...The results of this study show that D-cycloserine exhibits anti-anxiety activity at higher doses, which is consistent with antagonist activity," and also demonstrated the effectiveness of DCS in the treatment of anxiety and fear Potential effectiveness-related diseases, including generalized anxiety disorder or PTSD.

Figure 12. The PK of DCS during the treatment of TB. From Hung et al. Year 2014.

The PK of DCS in humans is well known because it has long been used to treat drug-resistant tuberculosis. For example, Hung et al. evaluated plasma levels during treatment with different TB doses in 2014 (Figure 12). As shown in the figure, a clinical dose of 10 mg/kg (ie ~500-1000 mg, depending on body weight) produces ~25

µg/mL, this is the target dose in our development plan. It is also known that DCS easily crosses the blood-brain barrier, and the concentration found in cerebrospinal fluid (CSF) is similar to that observed in plasma.

Based on animal data, we predict that DCS will have a significant anti-NMDAR effect on humans at doses> 500 mg, which corresponds to a dose that produces plasma levels> 25 µg/mL.

Figure 13: Rodent neurotoxicity study showing "Ollney lesion" induced by NMDAR channel blocker MK-801 (light green area). No significant neurotoxicity was observed with DCS.

A major problem with the use of agents that block NMDAR channel sites is that they tend to induce neurotoxicity in the frontal brain area ("Olney's disease"). This neurotoxic tendency has been observed in direct channel blocking NMDAR drugs, but it has not been observed in any glycine site modulators (such as NRX-101). According to the agreement agreed by the FDA, concerns about neurotoxicity led the FDA to issue new guidelines for the development of NMDAR-targeted antidepressants, requiring neurotoxicity studies. This element of NMDAR-targeted antidepressant use may become more and more important in the next few years, because drugs containing ketamine and dextromethorphan, two molecules known to be neurotoxic to humans, have been proposed for repeated use It is given to treat depression.

In 2016, we listened to the FDA’s recommendations and conducted a rodent neurotoxicity study based on a pre-agreed agreement between the FDA and NRx Pharmaceuticals. The drug combination (DCS, lurasidone, and ketamine) used for the sequential treatment of NRx Pharmaceuticals was tested according to this protocol, and there was no evidence of neurotoxicity (Figure 13), and the safety factors were 4 times, 16 times and 7.4, respectively Multiples of ketamine, DCS and lurasidone. Each of the proposed drugs has a long history of safe use in humans, and their adverse event characteristics are well characterized.

Figure 14. The relative effects of DCS and ketamine on self-administration in rodents, showing a significant difference between ketamine and DCS, but no significant difference between DCS and saline. Source: Psychogenics, Inc.

NMDAR-targeted antidepressants that directly block the channel have shown serious addiction and abuse tendency, which is not seen in glycine site modulators. This tendency may be related to theories that have been proposed, which suggest that these drugs also bind to opioid receptors. DCS has also been studied in the analysis of drug abuse tendency using intravenous self-administration. Both ketamine and S-ketamine are known to have a significant tendency to abuse and support self-administration by rodents. There is also a large amount of abuse liability associated with dextromethorphan. We conducted a rodent abuse tendency study in which the relative ability of ketamine, S-ketamine, and DCS to support self-administration was studied in animals trained in self-administration (Figure 14). As expected, both ketamine (grey bar) and S-ketamine (yellow bar) have significantly replaced ketamine, which is consistent with clinical abuse potential. DCS did not significantly replace ketamine in this assay, which is consistent with the lack of clinical use reports despite more than 50 years of clinical use.

NRx Pharmaceuticals sequential therapy (NRX-100 followed by NRX-101) for the treatment of acute suicidal ideation and behavior in bipolar depression: STABIL-B study

A preliminary study was conducted to confirm the selected dose levels of DCS and Lurasidone, and to evaluate NRx Pharmaceuticals' sequential treatment approach. The study recruited patients with severe bipolar depression and acute suicidal ideation and behavior. Major depressive symptoms are defined as a bipolar symptom scale (BISS) derived MADRS score (BDM) score of 30 or higher. Use the Columbia Suicide Severity Rating Scale (C-SSRS) to define active suicide intention with or without plan as 4 or 5. In stage 1, all subjects received blind infusion of ketamine (0.5 mg/kg) or normal saline. The response to stage 1 is defined as a 25% improvement in BDM and C-SSRS ☐3. A 6-week double-blind comparative study of NRX-101 and lurasidone alone was performed on the responders of Phase 1. The purpose of this study is to prove that NRX-101 has significant advantages over lurasidone alone in maintaining the improvement after the initial successful IV ketamine treatment and preventing recurrence.

Dose: The target dose for DCS is 950 mg, and the target dose for lurasidone is 66 mg. During the first 5 days of treatment, both compounds were titrated upwards. Allows flexible dosing to allow the dose to be reduced due to side effects, or to increase the dose due to excitement.

Endpoints: The primary end point includes the relative change in depression (BDM) scores between NRX-101. Secondary endpoints include suicide, as reflected by the C-SSRS score and the overall suicide impression score (CGI-SS) assessed by the clinician and relapse.

Phase 1: 22 subjects entered Phase 1. Seventeen were assigned to intravenous ketamine (NRX-100) and five were assigned to saline. All subjects showed a significant response to the treatment and entered the second stage.

Phase 2: Data from 17 subjects who responded to intravenous ketamine during Phase 1 were analyzed. These subjects were randomly assigned to NRX-101 (n=12) or Lurasidone (n=5). In the last observation carried forward (LOCF) analysis, the sequential treatment with ketamine/NRX-101 significantly reduced the symptoms of depression compared with the sequential treatment with ketamine/lurasidone alone (p=.032). In the parallel MMRM analysis, a statistical difference of p=.09 was observed between the groups. In addition, there was no relapse during NRX-101 treatment (0/12, 0%), while the lurasidone group alone had 2 relapses (2/5, 40%). The significance level of p=.0735 between groups is not significant, but it shows the feasibility of detecting large sample differences under similar response patterns.

In the LOCF analysis of the secondary endpoint, significant differences between the suicide score (C-SSRS) (p=.02) and the clinically assessed overall suicide impression (CGI-SS) (p=.019) were also observed) . These findings indicate that after initial ketamine treatment, there is a clinically significant difference in the responsibility for the recovery of suicidal tendencies. These two effects were not significant for MMRM analysis (p = .11; p = .15).

Figure 15: Changes in depression (BDM) scores during phase 1 and phase 2 of the STABIL-B study. All subjects showed significant improvement in stage 1. In Phase 2, subjects assigned to NRX-101 did not show a significant deterioration in depression or return to baseline before Study 1. In contrast, significant deterioration was observed in the lurasidone alone group. By day 42, the average difference in BDM score was 7.7 points (p=.032 between groups), which was considered statistically significant (d=1.60). Source: NRx Pharmaceuticals, undisclosed data.

No major safety issues related to treatment were observed in the two groups, and no deaths were reported in the study. The plasma DCS levels reached during the study were within the expected range based on previous human PK studies.

Overall, these results support the continued development of NRX-101 for maintaining the clinical benefits of depression and suicidal tendencies after the initial successful treatment of intravenous ketamine. Significant differences between depressive symptoms (pre-designated primary endpoint) and suicide (pre-designated key secondary endpoint) were observed in the LOCF analysis. For suicide, not only a significant difference in LOCF was observed in the official suicide rating, but also a significant difference in LOCF was observed in the clinical impression, indicating a clinically significant effect.

Although the difference was not significant in the MMRM analysis, the magnitude of the difference between the groups indicated that the sample size of 72 subjects was sufficient to achieve clinical significance, but the effect was similar. In addition, the study supports the feasibility of sequential NRX-100/NRX-101 treatments and supports the continued use of DCS/lurasidone combination preparations.

Ongoing Phase III clinical trials

An ongoing study is investigating the effect of NRx Pharmaceuticals sequential treatment and intravenous ketamine (NRX-100) combined with DCS lurasidone (NRX-101) and ketamine-lurasidone alone. This study uses a faster titration schedule for DCS than that used in STABIL-B, which allows for faster access to recommended therapeutic dose levels. Otherwise, the research methods are still similar. The purpose of this study is to replicate the results of the 2015 study by Kantrowitz et al. and the STABIL-B trial, which showed that symptoms quickly relieved after initial ketamine treatment, and then maintained improvement throughout the 6-week NRX-101 treatment period. The main hypothesis is that after the initial successful ketamine treatment, NRX-101 will be better than lurasidone alone in maintaining remission, which is reflected in the significant separation between depression and suicide scores as assessed by the MADRS and C-SSRS scales. And to prevent recurrence assessed by clinicians.

The study was conducted under a special agreement agreement (SPA) with the FDA, and the treatment has achieved breakthrough status. The study will recruit 72 18-65-year-old subjects who will be randomly assigned to NRX-101 and lurasidone at a 2:1 ratio. It is currently implemented in 4 treatment points. Due to COVID-19 concerns, recruitment was stopped in February 2020. We expect to resume enrollment in the second half of 2021.

Our clinical goal is to provide patients with the clinical benefit of rapidly reducing the symptoms of depression and suicidal ideation observed with intravenous ketamine, while maintaining this benefit through daily oral medication, which does not have the possibility of ketamine abuse and psychosis. NRX-101 is designed to provide an oral, fast-acting and continuous home-use therapy that can significantly extend the proven anti-suicide effect of ketamine and reduce the side effects of ketamine.

We believe that NRX-101 has potential development advantages over competing solutions, including:

Most people with depression have MDD and PTSD, not bipolar depression. Depressive episodes in patients with bipolar disorder are sporadic and often subside within two to three months. Depression is a chronic feature of MDD and PTSD. NRX-102, involves a fixed-dose combination of DCS and mirtazapine, which is currently an approved antidepressant. In the Phase 2 study in 2013, clinical data demonstrated the potential efficacy of DCS in combination with SSRI antidepressants compared with SSRI antidepressants alone in the treatment of patients with refractory MDD.

As a follow-up to NRX-101, we plan to pair DCS with mirtazapine (one of the SSRI antidepressants evaluated in the Phase 2 study) or its isomer in a fixed-dose combination. We expect to continue the exploratory preclinical development of NRX-102 in the second half of 2021. In addition, we have identified additional 5-HT2A antagonists, which may be properly paired with DCS to develop NRX-102. Our patents and publications indicate that DCS can inhibit akathisia induced by SSRI antidepressants.

Available clinical data indicate that DCS is a useful initial therapeutic agent that can be used to target the glycine site on the NMDA receptor. However, DCS has a mixed agonist/antagonist effect, and its antagonist properties are only shown at high doses of DCS. We have identified other small molecule NMDA antagonists that are effective at lower doses and can be paired with 5-HT2A antagonists in a 1:1 molar ratio to produce dual-targeted prodrugs. Therefore, we are committed to launching a medicinal chemistry and fundamental design program to develop candidate prodrugs that will expand the dual targeting properties of NRX-101 and 102.

NRX-201/202 will target bipolar depression and MDD/PTSD, respectively, and is expected to replace the DCS component of NRX-101/102 with molecules that target the same glycine site more specifically than DCS. Our patent portfolio includes issued and pending claims for many such dual target combinations.

We are cooperating with Nephron Pharmaceuticals in the United States and Nextar, LTD in Israel to produce our drugs. Both are qualified cGMP manufacturers, inspected by the US FDA, and in the case of Nextar, by EMEA and the Israeli Ministry of Health). We also signed a contract with Cardinal Health (defined below) to distribute our products nationwide.

The Israel Institute of Biology ('IIBR') was established in 1952. It is a government research institution founded by scientists from the Israel Defense Forces Science Corps and academic organizations affiliated with the Israeli Prime Minister's Office. The IIBR is located in the city of Ness Ziona, Israel. In 2020, under the order of the Prime Minister of Israel, IIBR developed the BriLife™ vaccine against COVID-19.

On July 12, 2021, the Israeli Minister of Health announced the signing of a binding memorandum of understanding with NRx, granting NRx an exclusive global license to develop and sell vaccines.

The Brilife (IIBR-100) vaccine contains recombinant Vesicular Stomatitis Virus (VSV), which is an animal virus that does not cause human disease. The spike protein is replaced by SARS-CoV-2, "resulting in the rapid and effective induction of neutralizing antibodies against SARS-CoV-2 coronavirus."

Brilife (VSV ΔG) is a vaccine based on live virus vectors, built on an FDA-approved platform, which has been successfully used to combat Ebola virus. BriLife genetically modified VSV-ΔG to express the spike protein of SARS-CoV-2 coronavirus on its envelope. The human body recognizes the spike protein expressed on the envelope and begins to produce an immune response. Since the entire spike protein is expressed, it will bind to the human angiotensin converting enzyme 2 (ACE2) receptor present in the lung and skin. These are the same receptors that the SARS-CoV-2 virus binds to. The in vivo golden Syrian hamster model using COVID-19 proved the non-clinical efficacy of the vaccine. The results showed that the use of rVSV-ΔG-SARS-CoV-2-S vaccine for single-dose vaccination can quickly and effectively induce SARS-CoV- 2 Neutralizing antibodies. In addition, vaccination protects hamsters from SARS-CoV-2 attack, as evidenced by the weight loss of vaccinated hamsters, as well as the extensive tissue damage and reduction in viral load in the lungs and turbinates compared with unvaccinated hamsters .

In cooperation with NRx, IIBR announced on July 12, 2021 that it will provide technical assistance while collecting the usual royalties and milestone payments for its intellectual property.

On June 19, 2020, a non-peer-reviewed study concluded that the vaccine “produced rVSV-ΔG-spike, which is a VSV vaccine candidate based on the ability of recombinant replication to express SARS-CoV-2 Spike protein." rVSV-ΔG-spike is similar to SARS-CoV-2 in terms of spike expression characteristics, antigenicity, and ability to induce neutralizing antibody production (Figure 8). In addition, single-dose vaccination of hamsters with rVSV-ΔG-spike can trigger a safe, effective and sufficient neutralizing antibody response against SARS-CoV-2 challenge.

IIBR-100 vaccination protects SARS-CoV-2 vaccination, which is manifested in lung protection and rapid virus clearance and rapid restoration of normal physiological parameters. These results paved the way for further examination of rVSV-ΔGspike as a SARS-CoV-2 vaccine in clinical trials.

A phase 1/2 trial was conducted in Israel. The inoculation concentration of 107 BriLife showed that the average level of neutralizing antibodies was comparable to the level observed in individuals in the recovery period (Figure 9). This level of immunity exceeds that of current non-mRNA vaccines. On November 27, 2020, the “Jerusalem Post” reported that Professor Yossi Karko, Director of the Hadassah Clinical Research Department, said: “We are pleased to announce that the first phase of the clinical trial of the coronavirus vaccine has been successful.”

Figure 8: Neutralizing antibody levels after 107 Prime/Boost immunizations compared with individuals in recovery period.

If the 108 primary immunization/boost regimen reaches twice the level of neutralizing antibodies, it is expected that immunization will be comparable to mRNA vaccines. Figure 9 is inferred from the work of Khoury et al. al., to show the percentage of efficacy seen with other vaccines in the clinic.

Figure 9: Protection efficiency of COVID vaccine as a function of neutralizing antibody titer.

Compared with mRNA vaccines, BriLife vaccines may provide significant benefits to variants of SARS-CoV-2. Because it presents the entire spike protein complex to the immune system, mutations in the spike complex may be unlikely to bypass the immunity generated by the vaccine. In addition, new variants of the spike complex can be quickly introduced into self-reproducing vaccines in order to continue to evolve the vaccine as the variants appear.

Summary of NRx Material Licensing Obligations

Glytech Development and License Agreement

We have signed the Glytech DLA dated May 2, 2016, which amends and restates the earlier agreement dated August 6, 2015, and the date of adoption is October 19, 2016 and June 13, 2018 , The April written agreement was further revised four times on 16 16, 2019 and December 31, 2020.

According to the Glytech DLA, Glytech grants NRx an irrevocable, permanent, exclusive (even for Glytech) royalty-free license, and the right to sublicense, use the licensed technology (defined below) to develop, manufacture, and sell for the treatment of human biphasic Drug products for depression and suicide related to mood disorders, including all products containing (a) DCS (including its metabolites and structural variants) in combination with antidepressants or antipsychotics (including but not limited to lurasidone) , Or (b) DCS (including its metabolites and structural variants) for the treatment of all types of bipolar, depression and/or anxiety disorders and/or their symptoms. The key substance component patent supporting NRx (US Patent No. 10,583,138) was transferred to us by Glytech in January 2021, and is no longer the subject of the Glytech DLA license; (2) Glytech agrees to receive NRX-101 at any time The remaining part of the licensed technology and exclusion technology (see below for definition) that are not necessary for the manufacture or sale of NRX-101 is transferred and transferred to NRx without additional consideration. If on or before August 6, 2022, (i) Glytech holds If the total liquidity value of some NRx equity ("Glytech Equity") is at least US$50 million, we will issue a written notice for twenty (20) consecutive trading days immediately before any given date, and (ii ) There are no legal or contractual restrictions on the sale of all securities represented by Glytech's equity, which was applicable to Glytech at that time (or reasonably foreseeable to be applicable to Glytech in the next twenty (20) years). NRx Pharmaceuticals believes that these standards have been met before Glytech's stock registration.

Glytech also agrees to transfer and transfer the licensed technology and excluded technology to us at the same time as the merger, acquisition, or other transaction involving NRx is completed, without additional consideration. Among them, as a result of such transactions, Glytech received its deeds upon completion of the transaction. The status of NRx shareholders, at least 50 million US dollars in cash proceeds.

In this section of the Glytech DLA, the term "total liquidity value" on any given date refers to the sum of the daily liquidity value for each trading day during the qualifying measurement period applicable to that date, and the "total liquidity value" on any given date The sum of "daily liquidity value" trading day refers to the total income that Glytech will receive if the number of Glytech Equity shares sold on that trading day is equal to 5% of the total number of common stocks or successor shares sold on that trading day. "Licensed technology" refers to the patent rights and patents related to the combined use of DCS controlled by Glytech or its affiliates with one or more antidepressants or one or more atypical antipsychotics (such as lurasidone) The subject of the disclosure, description or claim of proprietary technology. "Excluded technology" refers to any other patents and know-how owned by Glytech, and has nothing to do with the composition containing DCS or lurasidone.

The Glytech DLA imposes certain obligations on NRx related to the maintenance of Glytech licenses, including:

The term of Glytech DLA lasts indefinitely, unless one or both parties terminate in accordance with its terms. Glytech has the independent right to terminate Glytech DLA under the following circumstances: (a) NRx seriously violates Glytech DLA, including serious breaches of the above obligations, and fails to correct such violation notice within thirty (30) days (except for such violations) It cannot be corrected within thirty (30) days, and NRx diligently corrects such violations in a commercially reasonable manner) or (b) if NRx is insolvent or has filed voluntary or involuntary bankruptcy proceedings against it.

If Glytech terminates the Glytech DLA, the Glytech license will be revoked and NRx needs to transfer and transfer all its assets to Glytech, including but not limited to any inventions, patents and know-how developed by NRx from the licensed technology, as well as all data and research. Any form, related to licensed technology and products.

NRx currently complies with its obligations under the Glytech DLA.

Sarah Herzog Memorial Hospital License Agreement

NRx and SHMH signed an exclusive license agreement ("SHMH License Agreement") dated April 16, 2019.

The SHMH license agreement grants NRx exclusive, global, royalty-free U.S. Patent No. 9,789,093, certain patent applications pending at the time, and subsequent patent applications filed in the same priority family and patents issued therefrom, including corresponding foreign countries Patents and patent applications (collectively referred to as "licensed patents") are used to develop, manufacture, offer, sell, and otherwise commercialize pharmaceutical products for the treatment of depression and suicide related to bipolar disorder in humans, including all drug products that contain ( a) DCS (including metabolites and structural variants) and antidepressants or antipsychotics (including but not limited to lurasidone) or (b) DCS (including metabolites and structural variants) in combination Treatment of all types of bipolar disorder, depression and/or anxiety disorders and/or their symptoms. We have the right to grant sub-licenses in accordance with the agreed sub-licensing procedures, but are responsible to SHMH for any violations of sub-licensors by the sub-licensors.

We need to pay certain fees to maintain the license, including:

In some cases, and through the application of certain sublicense fees, the milestone payment payable described above may be reduced by 25%.

The amount of royalties is equal to: (a) When at least one licensed patent is still valid, if such products are not within the scope of the valid claim (as defined below), then 1% of the revenue from the sale of any product containing the licensed patent is in The country or region where the sale takes place, or (b) 2.5% of the revenue from any product containing a licensed patent that contains at least one valid statement in the country or region where the product is manufactured or sold. "Effective claims" refers to any claims in the licensed patent that have been issued, are still valid and have not yet been finally invalidated or are determined to be unenforceable. If we raise legal questions about the validity, enforceability or scope of any licensed patent and do not have an advantage in such procedures, the aforementioned royalty rate may be doubled.

Royalties also apply to any income generated by the sublicensee from the sale of licensed products, but the upper limit is 8.5% of the payments we receive from the sublicensee in connection with such sales.

The fixed amount of USD 100,000 was paid on April 16, 2021, after which the fixed amount of USD 150,000 will expire on the anniversary of that date within the term of the SHMH license agreement.

We must compensate SHMH for any costs incurred in filing and prosecuting licensed patents within the term of the SHMH agreement. We are also responsible for directly paying any ongoing costs associated with maintaining the licensed patents.

The SHMH license agreement imposes certain other obligations on us, including:

If we fail to fulfill its payment and other obligations under the SHMH license agreement, including the above obligations, the licensed patent will be at risk. We are currently fulfilling its obligations under the SHMH license agreement.

The SHMH license agreement lasts until the last licensed patent expires or the last licensed patent is invalid or unenforceable.

If NRx (a) has a serious breach of contract and fails to correct such breach within sixty (60) days after receiving written notice of such breach or (b) is insolvent, or has undergone voluntary or involuntary bankruptcy proceedings, and such The procedure was not shelved within sixty (60) days. If we file an application or claim that challenges the validity, enforceability or scope of any licensed patent, SHMH also reserves the right to terminate the SHMH license agreement related to the licensed patent contained in such procedures.

After the SHMH license agreement is terminated, the license to use the licensed patent will be terminated, and all the rights contained therein shall belong to SHMH.

As of the date of this agreement, we have not received any notice from SHMH, accusing NRx of serious violations of the SHMH license agreement.

State University of New York Licensing and Option Agreement

We have signed the following written license and option agreement with the foundation, dated September 1, 2020 ("The State University of New York License Agreement").

According to the license agreement of the State University of New York, the foundation has granted us a revocable, non-exclusive, global license, without the right to sublicense, and two (2) years of royalties are required to use the foundation subject matter ( See below for definitions) in order to develop, manufacture and sell products and/or services for the treatment of human COVID-19 and/or COVID-19-related respiratory failure. Although the license is non-exclusive, the foundation has agreed in writing that it will not grant any other licenses to the subject matter of the foundation to allow any third party to manufacture or provide products or services for the treatment of COVID-19. The duration of the SUNY license agreement.

"Foundation theme" refers to the technical information and materials owned by the Foundation, as well as all other intellectual property rights, including scientific and clinical information and data related to (a) therapeutic use, agreements, trademarks and trade secrets for the treatment of human COVID- 19 and/or COVID-19 related respiratory failure ("main field use") Foundation themes, and (b) Foundation themes for the treatment or prevention of other human lung diseases, including adult respiratory distress syndrome ( "ARDS") and sepsis ("Alternative Field Use"). Such technical information and materials include know-how, formulations, knowledge, compositions, methods, processes and procedures related to the separation, preparation, formulation and/or administration of VIPs for the treatment of human diseases, including IND application questions For "Vsoactive Intestinal Peptide (VIP) in Adult Respiratory Distress Syndrome", Hussein Foda, MD, researcher; State University of New York, Stony Brook, sponsor.

The term of the State University of New York Licensing Agreement is two (2) years (the "term") from the date of signing of the agreement, during which time the parties are expected to negotiate alternative royalties for primary on-site use. The royalties and other terms and conditions contained in any such alternative licenses will be negotiated by both parties in consideration of current conditions and compliance with industry standards. If the parties cannot agree on the terms and conditions of the replacement license, unless otherwise agreed, the current license will terminate at the end of the term.

The State University of New York Licensing Agreement also grants NRx the exclusive right to negotiate a global license for commercial royalties and the right to sublicense, manufacture and provide sales of products and/or services that cover alternative areas of use The theme of the foundation. Within the time limit, the foundation has agreed not to provide any third party with any commercial rights to use the theme of the foundation in alternative areas. However, if NRx exercises its option and the two parties cannot agree to the terms and conditions of the commercial license to collect royalties within 60 days, the option will automatically terminate and NRx will not have the right to obtain foundation targets in alternative areas. Things.

The SUNY license agreement imposes certain obligations on NRx to maintain the license, including the following:

We are currently fulfilling its obligations under the State University of New York licensing agreement.

If we seriously violate the licensee agreement of the State University of New York, the foundation has the right to issue a notice of breach. If NRx is unable to correct such breach and provide adequate guarantees for future performance within thirty (30) days of receiving the notice, the Foundation may terminate the State University of New York licensing agreement. If NRx: (i) ceases to attempt to conduct business related to the rights granted in such agreements, the State University of New York license agreement will automatically terminate; (ii) insolvency; (iii) transfer for the benefit of creditors; (iv) ) Challenge the validity or enforceability of such agreements to any court, arbitrator or other tribunal. After the SUNY license agreement is terminated for any reason, we must stop all use of the Foundation theme.

As of the date of signing this agreement, we have not received any notice from the foundation accusing NRx of serious violations of the State University of New York licensing agreement.

The license granted by the foundation is subject to the rights (if any) arising from any funding of the foundation theme by the US government. This may include (i) reserve a royalty-free, non-exclusive, non-transferable license for the US government to use Foundation themes, and (ii) require any products produced using Foundation themes to be used or products sold in the United States must be substantial The above is manufactured in the United States, unless the relevant U.S. government agency grants an exemption under 35 USC section 204.

Binding cooperation agreement with Relief Therapeutics

We have signed a binding cooperation agreement dated September 18, 2020 with Relief Therapeutics Holding AG and its wholly-owned subsidiary Therametrics Discovery AG.

The relief agreement stipulates that NRx and the relief treatment company will cooperate and assist each other to maximize the revenue of relief products in their respective territories. NRx territories include the United States, Canada, and Israel. The territory of Relief Therapeutics includes the European Union, Switzerland, Iceland, Norway, the United Kingdom, Channel Islands, Liechtenstein, Monaco, Andorra, San Marino and Vatican City. The cooperation will be carried out on an exclusive basis, and the two parties have agreed not to develop or commercialize any drugs that may compete with relief products.

The Relief agreement stipulates that Relief Therapeutics will fund the costs associated with clinical trials and development of inhaled Relief products in the United States. These costs will be conducted and managed by NRx. We are responsible for ensuring that the cost of clinical trials and development activities does not exceed 30% of the expected budget accepted by all parties.

The relief agreement also provides options for both parties to develop relief products to treat health conditions outside the COVID-19 region and to commercialize relief products outside their respective territories.

Other assets brought by the two parties to the cooperation include:

For U.S. regulatory purposes, NRx is the sole applicant for any NDA or other regulatory approval application for relief products submitted to the FDA. However, both parties jointly control all major decisions related to any confidentiality agreement and any related matters.

The Relief agreement stipulates that Relief Therapeutics will fund the costs associated with clinical trials and development of inhaled Relief products in the United States. These costs will be conducted and managed by NRx. We are appointed to direct, design, and implement the entire pathway of drug approval for relief products in the United States. According to the relief agreement, NRx is responsible for keeping the original sample size ("initial budget") of the 144 participants in the trial budget of relief products not exceeding 30% (approximately US$10.7 million) of US$8.3 million. In October 2020, the data security monitoring committee and statistical consultants of the study recommended that we expand the scale of the study to at least 200 participants, resulting in an additional $4 million in potential research costs. The relief agreement stipulates that the cost of pharmaceutical formulations, manufacturing, CMC, and stability are not included in the initial budget. However, relief is needed to fund the formulation, stability and manufacturing costs of MedisourceRx, Bachem and Nephron Pharmaceuticals.

The relief agreement stipulates that if Relief Therapeutics does not approve the additional overspending of the initial budget, NRx shall be free to introduce other parties to complete the relief product research. The Relief agreement further stipulates that Relief Therapeutics will fund the costs associated with the clinical development of inhaled Relief products in the United States in accordance with our agreement to develop, manage, supervise and supervise its clinical development. If Relief Therapeutics does not fund the costs associated with the clinical development of inhaled Relief products in the United States, then we will be free to bring in alternative investors.

As of August 30, 2021, Relief Therapeutics has reimbursed us approximately US$10.9 million in expenses, but has not paid approximately US$10 million in invoice costs related to clinical trials, reformulations, and ZYESAMI manufacturing of Relief products. In addition, Relief Therapeutics refused to approve the budget and did not fund the cost of the inhalation test. We have informed Relief Therapeutics that we are using funds provided by other investors to fund these costs. Therefore, Relief Therapeutics' lack of funding will not negatively affect our ability to continue to develop ZYESAMI. We reiterate our commitment to fulfill the cooperation agreement with Relief Therapeutics and are committed to solving these problems with Relief Therapeutics in a friendly manner, although these circumstances may lead to disputes with Relief Therapeutics over the share of profits that Relief Therapeutics should be entitled to. Participation decreased.

According to the relief agreement, each party has a wide range of rights and can use the other party’s intellectual property rights to develop and commercialize relief products in their respective territories. To the extent necessary, each party must grant or obtain a cross-license from a third party to allow the other party to use its intellectual property in the territory of the other party.

Both parties will continue to own the intellectual property rights they had before the cooperation. Any intellectual property rights related to relief products jointly developed by both parties will be jointly owned by both parties, and both parties will have the right to use any common products. Intellectual property in its territory. Each party is responsible for filing and prosecuting applications for patents, trademarks and other intellectual property rights in their respective territories, and is responsible for the protection, maintenance and enforcement of such intellectual property rights in that territory.

According to the relief agreement, each party will develop a commercialization plan for relief products in its territory, which must be approved by the other party, and each party is obliged to take commercially reasonable efforts to commercialize relief products in its territory. Approved commercialization plan.

According to the approved commercialization plan, each party will have all the rights to commercialize Relief products within its territory, including the right to cooperate with licensees, distributors, research organizations, marketing organizations and other third parties. The parties have agreed not to commercialize it

Relief products in the territory of the other party. Relief Therapeutics reserves the right to determine commercialization partners for countries/regions outside the territories of the parties, and any arrangements with such commercialization partners will be bound by the terms of the relief agreement.

According to the terms of the rescue agreement, both parties will share the net profit from the sale of rescue products as follows:

Each party must keep books and records sufficient to confirm the net profit generated by the sales of relief products in its respective region, and each party has the right to audit the other party's books and records. Net profit will be calculated after reimbursing Relief Therapeutics for the cost of any supplies related to the manufacture of Relief products funded by Relief Therapeutics.

If we fail to achieve at least 70% of the sales target agreed by both parties from time to time (the market environment has not undergone macro changes), our profit share in our territory may be at risk. In this case, Relief Therapeutics hires an external sales entity to manage the United States The right to sell.

As stated in the section titled "-Funded by Relief Therapeutics" and other parts of this prospectus, we reiterate our commitment to fulfill our cooperation agreement with Relief Therapeutics and are committed to solving the above problems with Relief Therapeutics in a friendly manner, although These circumstances may lead to disputes with Relief Therapeutics over the share of profits that Relief Therapeutics is entitled to due to reduced participation in the project. Relief Therapeutics told us that although it did not provide funding for the project, and despite the non-replicability of the formula data provided by Relief Therapeutics to NRx, it still hopes to obtain the initially agreed profit share.

We have signed an exclusive distribution agreement with Cardinal Health 105, Inc. ("Cardinal Health") with an effective date of September 25, 2020 ("CHDA"). According to CHDA, we designate Cardinal Health as the exclusive third-party logistics distribution agent and as the authorized distributor of certain NRx products ("products") in the United States, its territories, territories, and the Commonwealth.

According to CHDA, Cardinal Health will provide us with services, including but not limited to storage, distribution, returns, customer support, financial support, EDI and system access support ("CHDA Services"). CHDA services will be provided by Cardinal Health in accordance with one of the following two operating model guidelines: traditional third-party logistics ('3PL') operating guidelines ('OPG') or title model operating guidelines ('TMOPG')). Both OPG and TMOPG are attached to CHDA and incorporated into CHDA by reference. NRx and Cardinal Health have not yet decided which of these two operating model guidelines will govern the provision of CHDA services; this decision will be made closer to the FDA’s approval of our first commercial product.

According to OPG, Cardinal Health will accept our products on consignment, and the products will be transported by us or our shipping agent to Cardinal Health's safe passage 3PL storage facility. Cardinal Health has established standard operating procedures to manage all activities in its storage facilities, which are approved and controlled by Cardinal Health's centralized distribution management system. All Cardinal Health warehouse personnel have received training in compliance with applicable federal and state laws and regulations, as well as written plans for cGMP. Our products are stored by Cardinal Health under controlled temperature conditions, and any temperature drift that lasts more than one hour will be reported within two (2) business days after the drift is discovered. Products are selected from Cardinal Health’s warehouse inventory in accordance with the "first expiration, first out" principle.

Pricing and sales conditions are set by us, and we also publish a price list of the products that will be sold to its customers. Cardinal Health will send the invoice to the customer via email on the day the product is shipped or via email the next morning after shipment. The customer then remits the payment to our bank lockbox via EFT, ACH or wire transfer, and then the NRx bank forwards the payment information to Cardinal Health, and then Cardinal Health reconciles the account and applies the cash receipt to the account receivable.

Most of the logistics regulations in TMOPG are the same as those in OPG. The main significant difference between TMOPG and OPG is that, according to TMOPG, after Cardinal purchases the product from NRx or its manufacturing agent, the ownership and ownership of the product is transferred from NRx to Cardinal. Cardinal Health handles all sales, shipping/distribution, customer service, and AR activities in the same manner as described in the OPG model, except that Cardinal Health maintains a bank lockbox for receiving customer invoice payments instead of the lockbox NRx maintained by the following personnel .

Pricing and payment; forecasts and price lists

As compensation for the CHDA services provided by Cardinal Health, we are responsible for paying the fees specified in the CHDA. The fee schedule is confidential to Cardinal Health and may not be disclosed without Cardinal Health's permission. Each contract year (after the first contract year) fees can be adjusted up to 3%, or if Cardinal Health can reasonably prove that the cost of providing CHDA services has increased substantially.

According to CHDA, we are responsible for providing forecasts of the number of products processed by Cardinal Health. Any discrepancies from the forecast, as well as any adjustments that may be required to the future forecast, shall be handled by both parties through good faith negotiation. We are also responsible for providing product price lists to Cardinal Health and setting prices for products sold or distributed by Cardinal Health. We must notify Cardinal Health of any changes to product pricing at least 72 hours before the effective date of such price changes.

The initial period of CHDA after the FDA-approved product is first shipped to commercial customers is three (3) years (the "initial period"), and it is automatically renewed for an additional period of one (1) year (each period is the "renewal period" ), unless CHDA is terminated early during the initial period or any renewal period by either party giving a written termination notice to the other party at least 90 days before the end of the initial period or any renewal period. In the following circumstances, either party can terminate CHDA immediately: (1) The other party applies for bankruptcy protection or enters into takeover or custody, and if it enters into bankruptcy or bankruptcy order

The order was not lifted within 30 days; (2) The other party seriously violated any of the provisions of CHDA, and the breach was not corrected within 30 days after receiving the non-defaulting party’s notification of breach, unless NRx failed to pay the invoice in time, Cardinal Health may terminate CHDA's receipt of payment from Cardinal Health within 15 days of receipt of Cardinal Health's written notice of non-payment. After termination for any reason, the rights and obligations of the parties before the termination date shall continue to be valid after termination, and all products stored in Cardinal Health's 3PL facilities will be returned to NRx or its designated personnel.

We have signed a feasibility study and material transfer agreement with TFF Pharmaceuticals, Inc. ("TFF"), with an effective date of January 6, 2021 ("TFF Agreement"). TFF is the licensee of certain intellectual property rights related to the "film freezing" process, which aims to increase the solubility of poorly water-soluble drugs by generating dry powder particles with delivery characteristics for inhalation.

The TFF agreement provides a framework for a feasibility study of the applicability of TFF's thin-film frozen drug manufacturing technology ("TFF technology") in the production of aviptadil for NRx inhalants. We will provide TFF with its proprietary ZYESAMI compounds, which will be used by TFF to determine whether TFF technology is suitable for the production of ZYESAMI's storage-stable inhalable dosage form for use in ongoing NRx clinical trials to examine inhaled ZYESAMI to treat severe COVID-19 in humans The effectiveness of patients and the possibility of subsequent production of such dosage forms on a commercial scale.

According to the TFF agreement, the feasibility study is managed by TFF, but according to the subcontract between TFF and the University of Texas at Austin, the research and development work will be carried out at the University of Texas at Austin.

The TFF agreement refers to a statement of work ('SOW'), which aims to provide complete details and agreements and budget plans for TFF to conduct a feasibility study. As of August 30, 2021, the parties have not finalized and signed any SOW. However, TFF has chosen to conduct a feasibility study without our compensation.

According to the TFF agreement, we have all rights, ownership and interests in all achievements, inventions, discoveries, innovations and know-how. These achievements, inventions, discoveries, innovations and know-how are extensions to the background intellectual property rights (defined below) of NRx Or improve, or otherwise combine with ZYESAMI compounds. In a similar manner, TFF owns all rights, ownership and interests in all achievements, inventions, discoveries, innovations and know-how that are extensions or improvements of TFF's background intellectual property rights, or Other aspects related to TFF technology. In the TFF agreement, "background intellectual property rights" refers to any intellectual property rights and know-how that are owned or controlled by one party or generated by a party independent of the feasibility study prior to the signing of the TFF agreement. Each party reserves its exclusive rights to the background intellectual property rights and any new intellectual property rights that it owns as a result of the feasibility study, and both parties agree to cooperate and cooperate in good faith to ensure that the intellectual property rights of any new intellectual property rights are jointly generated by both parties ( "Joint Intellectual Property Rights"), NRx is responsible for the submission, prosecution, maintenance and defense of such joint intellectual property rights. If any party refuses to participate in or continue to support such submission, prosecution, maintenance and/or defense of any joint intellectual property rights, that party must immediately sign or cause to sign all necessary documents to transfer such joint intellectual property rights to the other party.

The TFF agreement remains valid until one (1) year from the earlier completion of the feasibility study and the effective date of the TFF agreement (ie, January 6, 2022). TFF agreement can be earlier

Either party terminates due to the other party's breach of contract (after the expiration of the 30-day remedial period), or either party terminates without cause with 30 days' written notice to the other party.

We have signed a master service agreement with Nephron SC, Inc. and Nephron Pharmaceuticals Corporation, a subsidiary of Nephron, Inc. (collectively referred to as the "supplier"), effective August 25, 2020 ("Nephron Agreement") ). The Nephron agreement was subsequently revised on September 2, 2020, November 5, 2020, and February 8, 2021.

According to the Nephron agreement, the supplier is the main ZYESAMI supplier of NRx in the United States, and its form is suitable for injection and inhalation. We will be responsible for purchasing and supplying ZYESAMI's active pharmaceutical ingredients (VIP), other raw materials, and the label information required by the supplier to manufacture and supply ZYESAMI to us. The supplier is responsible for providing the auxiliary materials (inactive ingredients), ingredients, packaging and other materials required for the manufacture and delivery of ZYESAMI according to the purchase order placed by us.

Suppliers will be required to produce ZYESAMI in accordance with cGMP, NRx specifications and the requirements of the Nephron agreement, which includes strict quality assessment, inspection, testing, storage and record keeping regulations. The quality system, process and technical control related to the quality assurance requirements of ZYESAMI's manufacturing and supply have been further detailed in the separate quality agreement between the two parties. We have the right to inspect and audit the supplier’s facilities from time to time.

The initial term of the Nephron Agreement is five (5) years from the date of the first commercial shipment to NRx, which can be extended by a one (1) year renewal for one consecutive year. In the event of a major breach or bankruptcy of the other party, either party can terminate the Nephron Agreement before the expiry of the period, subject to the applicable remedial period. In addition, if certain events occur, we have the right to terminate the contract by sending a notice to the supplier, including the FDA’s notification to the supplier about the use of ZYESAMI for manufacturing, testing, verification, labeling, packaging or storage or the quality of ZYESAMI we receive A large number of documented customer complaints.

During the term and one (1) year thereafter, the supplier shall not develop, manufacture, supply, distribute or market ZYESAMI or its bioequivalents for or on behalf of itself or any third party, unless it obtains certain rights from NRx.

Government regulation and product approval

Government authorities in the United States and other countries, at the federal, state and local levels, extensively regulate research, development, testing, manufacturing, packaging, storage, record keeping, labeling, advertising, promotion, distribution, and marketing related to the drugs we are developing , Import and export, pricing and government contracts. The process of obtaining marketing approval in the United States and abroad, and subsequent compliance with applicable laws and regulations, requires a lot of time and financial resources.

In the United States, the FDA regulates drugs in accordance with FFDCA and its implementing regulations. The process of obtaining marketing authorization and subsequent compliance with appropriate federal, state, local, and foreign laws and regulations requires significant time and financial resources. Failure to comply with applicable U.S. requirements during the product development process, approval process, or at any time after approval may expose the applicant to various administrative or judicial sanctions or other actions, such as FDA delaying review or refusing to approve pending NDAs, and withdrawing approval , Implementation of clinical suspension or research termination, issuing warning letters or untitled letters, compulsory modification of promotional materials or issuing corrective information, product recall requests, consent orders, company

Integrity agreement, extension of prosecution agreement, product seizure or seizure, refusal to allow product import or export, full or partial suspension or restriction or imposing other requirements related to production or distribution, prohibition, fine, cancellation of government contract and refusal of existing contract Future orders, exclusion from federal and state health care programs, FDA prohibitions, restitution, return or civil or criminal penalties, including fines and imprisonment.

Before a new drug may be marketed in the United States, the process required by the FDA usually includes the following:

In addition, if a drug is considered a controlled substance, the DEA must also determine the controlled substance timetable before starting to sell it, taking into account the FDA's recommendations.

Pre-clinical research and IND submission

Preclinical research includes laboratory evaluations of product chemistry, pharmacology, toxicity, and formulation, as well as animal studies to evaluate potential safety and effectiveness. As part of the IND, the IND sponsor must submit to the FDA the results of preclinical testing, as well as production information, analytical data, and any available clinical data or literature. Even after the IND is submitted, some preclinical testing may continue. After submitting the IND, the sponsor must wait 30 calendar days before starting any clinical trials. During this period, among other things, the FDA has the opportunity to review the safety of the IND to ensure that the research subjects are not exposed to unreasonable risks. The FDA may raise concerns or questions related to one or more proposed clinical trials and place the clinical trials on clinical hold. In this case, the IND sponsor and FDA must resolve any outstanding issues before the clinical trial begins. Therefore, submitting an IND may not result in FDA's permission to start a clinical trial.

We have submitted an IND, and the FDA has accepted IND 134025 and 129194 for NRX-100 and NRX-101, respectively. The FDA has informed us that no further preclinical studies are required for NDA submission of NRX-100. The FDA has advised us and we agree that genotoxicity studies and non-clinical maternal/fetal impact studies are required before submitting an NDA. We intend to complete these studies in 2021. FDA guidelines exempt drugs used in carcinogenicity studies for less than 12 weeks. We intend to seek a written exemption from the FDA for carcinogenicity studies on the grounds that the treatment of NRX-101 is expected to last less than 12 weeks.

As we all know, because the cells that line the lungs are extremely vulnerable to potential damage, the FDA has strict requirements on the safety of lung drugs. Between 2005 and 2011, Mondo Biotech and Biogen, Inc. ('Biogen'), the predecessors of Relief Therapeutics ('Mondo'), accumulated a large number of non-clinical studies, and finally submitted an investigational drug file ('IMPD') with the FDA and European regulatory agency. Mondo has held four regulatory meetings with the FDA and agreed on a series of acute and chronic toxicity, clinical pharmacology, and pharmacokinetic studies that need to be carried out before human studies on aviptadil in the United States. Although Biogen has never entered the U.S. market due to its decision to focus on other therapeutic areas, all required research is completed by GLP-compliant contract research organizations in accordance with FDA's specifications. We have received a written notice from the FDA, and all non-clinical safety studies related to ZYESAMI (aviptadil) have been submitted to the FDA for review. Prior to submitting an NDA for ZYESAMI, no further non-clinical studies are required or expected.

Clinical trials involve the administration of IND to human subjects under the supervision of qualified investigators who meet GCP requirements, including requiring all research subjects to provide written informed consent to participate in any clinical trial, and an IRB. The clinical trial is conducted in accordance with the agreement, which specifies the trial objectives, trial procedures, parameters used to monitor safety and effectiveness standards to be evaluated, as well as a statistical analysis plan. Each clinical trial protocol and any subsequent protocol amendments must be submitted to the FDA as part of the IND. In addition, the central or local IRB of each institution participating in a clinical trial must review and approve any clinical trial plan before the institution starts, and the IRB must continue to monitor the clinical trial, including any changes, while it is ongoing. Information about certain clinical trials, including descriptions of studies and research results, must be submitted to NIH within a specific time frame for public release on its clinical trials.gov website.

Human clinical trials are usually conducted in three consecutive phases, and these phases may overlap or merge. In the first phase, the drug was initially introduced into healthy human subjects or subjects with target diseases or conditions, and tested for its safety, dose tolerance, absorption, metabolism, distribution, and excretion, and tested it in Get early signs of its effectiveness when possible. In the second stage, the drug is usually administered to a limited population of subjects with the target disease or condition through a well-controlled study to identify possible adverse reactions and safety risks, initially assess the product’s efficacy against specific target diseases and determine the dose tolerance Receptivity and optimal dosage. In Phase 3, in two adequate and well-controlled clinical trials, the drug is used in an expanded population of subjects, usually in geographically dispersed clinical trial locations, to generate sufficient data to statistically evaluate the effectiveness of the product And safety for approval to determine the overall risk-benefit profile of the product and provide sufficient information for the product label.

The production of investigational drugs for human clinical trials is subject to cGMP requirements. Research drugs and active pharmaceutical ingredients imported into the United States are also subject to FDA supervision of their labeling and distribution. In addition, the export of research drugs outside the United States is subject to the regulatory requirements of the receiving country and the United States export requirements under FFDCA.

Progress reports and other summary information detailing the results of clinical trials must be submitted to the FDA at least annually. If certain serious adverse events occur or other important safety information is discovered, they must be submitted more frequently. Phase 1, Phase 2, and Phase 3 clinical trials may not be successfully completed within any specified period, or may not be completed at all. In addition, the FDA or the sponsor may suspend or terminate clinical trials at any time for various reasons, including discovering that the research subjects are facing unacceptable health risks or the trials are not conducted or agreed in accordance with applicable regulatory requirements. Similarly, if the clinical trial is not conducted in accordance with the requirements of the IRB, or if the drug causes accidental and serious harm to the subject, the IRB can suspend or terminate the approval of the clinical trial by its institution. In addition, some clinical trials are supervised by independent qualified expert groups organized by the clinical trial sponsors, called data safety supervision committees or committees. The team regularly reviews the accumulated data and advises the research sponsor on the continued safety of trial subjects and potential trial subjects, as well as the continued effectiveness and scientific value of clinical trials. We may also suspend or terminate clinical trials based on changing business goals and/or competitive environment.

As far as NRX-100/101 is concerned, the FDA has agreed in writing that our research product meets the standard of 505.b.2 (commonly referred to as drug reuse) pathway, that is, a large amount of safety literature on individual ingredients can cite NRX-101 instead Repeat various preclinical and phase I clinical studies.

Due to recent examples of sponsors receiving a complete response letter due to the lack of agreement with the FDA on the research path required for NDA submission, we have cooperated with the FDA for one (1) year to negotiate a special agreement agreement ('SPA') ) Will manage the development of NRX-101 and will define the phase 3 trials required for drug approval if the clinical trial is successful. The SPA was issued to us in April 2018 and defines the single clinical trial required to approve NRX-101 for the treatment of bipolar depression with acute suicidal ideation or behavior.

In the case of ZYESAMI, the route of drug approval is based on 505.b.1. In addition, due to the use of RLF-100 (ZYESAMI's previous formulation) in ARDS in 2001, the FDA granted orphan drug status to the State University of New York. The FDA has informed us that any potential benefits provided by the designation of aviptadil based on the orphan drug do not apply to its use in the treatment of COVID-19. See "Risk Factors-Risks Related to Our Business and Industry-We don't expect to receive orphan drug protection for COVID-19."

Assuming that the required clinical tests are successfully completed, the results of preclinical and clinical studies, together with detailed information related to product chemistry, manufacturing, control, and proposed labeling, are submitted to the FDA as part of the NDA request for approval to use the product for one or Multiple indications. In most cases, submitting a non-disclosure agreement requires a large amount of application user fees. These user fees must be submitted when the application is first submitted, even if the application is submitted on a rolling basis. Applicants can seek to waive the application user fee. One basis for waiving the application user fee is that if the applicant employs less than 500 employees, including employees of affiliated companies, the applicant has not been approved and introduced or delivered into the interstate drug commerce based on the human drug application. , Including its affiliates, is submitting its first human drug application. According to the currently effective prescription drug User Fee Act ('PDUFA') guidance, the FDA has agreed to certain performance targets regarding the timing of its application review. FDA's goal is to review 90% of standard review applications within 10 months after acceptance and filing and within 6 months after acceptance and filing.

In addition, according to the Pediatric Research Equity Act, NDA or NDA supplements for new active ingredients, indications, dosage forms, dosing regimens, or routes of administration must contain sufficient data to evaluate the safety and effectiveness of the drug. Declare indications in all relevant pediatric subgroups, and support the safe and effective dosage and administration of each pediatric subgroup of the product. The FDA may voluntarily or at the request of the applicant, approve the postponement of the submission of some or all of the pediatric data until the product is approved for use in adults, or exempt the pediatric data requirements in whole or in part.

The FDA may also require REMS to be submitted during the application process or after the drug is approved to ensure that the benefits of the drug outweigh the risks. REMS plans may include medication guidelines, physician communication plans, evaluation plans, and elements to ensure safe use, such as restricted distribution methods, patient registration, or other risk minimization tools.

The FDA conducts a preliminary review of all NDAs within the first 60 days after submission, and then accepts their submissions to determine whether they are sufficiently complete to allow substantive review. The FDA may request more information instead of accepting the NDA for filing. In this case, you must resubmit the application with additional information. The resubmitted application also needs to be reviewed before the FDA accepts the submission. Once the submission is accepted, the FDA will begin an in-depth substantive review. The FDA reviews the NDA to determine whether the drug is safe and effective, and whether the facilities where it is manufactured, processed, packaged, or stored meet standards designed to ensure continued product safety, quality, and purity.

According to FFDCA, before approving a drug with an active ingredient (including any ester or salt of the active ingredient) that has not been approved by the FDA, the FDA must submit the drug to an external advisory committee or provide it in a letter of action. The FDA did not submit the drug Summary of reasons for advisory committee. Due to certain other issues, including clinical trial design, safety and effectiveness, and public health issues, other drugs may also need to be reviewed by an external advisory committee. The Advisory Committee is a group of independent experts, including clinicians and other scientific experts, responsible for reviewing, evaluating, and making recommendations on whether the application should be approved and under what conditions. The FDA is not bound by the recommendations of the advisory committee, but it will carefully consider these recommendations when making a decision.

Before approving the NDA, the FDA will inspect one or more facilities where the product is manufactured. The FDA will not approve the application unless the FDA determines that the manufacturing process and facilities comply with cGMP requirements and are sufficient to ensure that the manufacturer and all of its subcontractors and contract manufacturers consistently produce products in accordance with the required specifications. In addition, before approving the NDA, the FDA will inspect one or more clinical trial sites to ensure compliance with GCP regulations.

The NDA testing and approval process requires a lot of time, energy, and financial resources, and each process may take several years to complete. The data obtained from preclinical and clinical trials are not always conclusive and may be subject to different interpretations, which may delay, restrict or prevent marketing approval. The FDA may not approve the NDA in time or at all.

After evaluating the NDA and all relevant information (including advisory committee recommendations (if any) and inspection reports on manufacturing facilities and clinical trial sites), FDA may issue an approval letter, or in some cases, issue a complete response letter. The complete response letter usually contains a statement of specific conditions that must be met to ensure final approval of the NDA, and may require additional clinical or preclinical testing or other information in order for the FDA to reconsider the application. The FDA’s review goal is to complete the review of 90% of the resubmissions within two to six months of receipt, depending on the type of information contained. Even if this additional information is submitted, the FDA may ultimately determine that the application does not meet the approved regulatory standards. If these conditions are met and the FDA is satisfied, the FDA may issue an approval letter. The approval letter authorizes the commercial marketing of the drug and contains specific prescription information for specific indications.

Even if the FDA approves a product, it may restrict the approved product's use indications, require contraindications, warnings or precautions to be included in the product label, including boxed warnings, require post-approval studies, including phase 4 clinical trials, It is used to further evaluate the safety of the drug after approval, requires testing and monitoring procedures to monitor the product after commercialization, or imposes other conditions, including distribution restrictions or other risk management mechanisms under REMS, which may have a significant impact on the potential market Impact and profitability of the product. FDA may block or restrict further marketing of products based on the results of post-marketing research or surveillance programs. After approval, certain circumstances may require FDA notification, review or approval, and further testing. These may include certain types of changes to approved products, such as the addition of new indications, manufacturing changes and additional labeling statements, or new safety information.

Special FDA rapid review and approval plan

The FDA has various plans, including fast track designation, accelerated approval, priority review, and breakthrough therapy (defined below) designation to speed up or simplify the process

The development and FDA review of drugs for the treatment of serious or life-threatening diseases or conditions have proven the potential to solve unmet medical needs or make major improvements to existing therapies. The purpose of these programs is to provide patients with important new drugs earlier than the standard FDA review process.

In order to be eligible for fast-track designation, the FDA must determine that the product is intended to treat a serious or life-threatening disease or condition based on the requirements of the sponsor and demonstrate the potential to address unmet medical needs. If the product will provide a therapy that does not exist or the therapy provided may be superior to existing therapies, then the product will meet unmet medical needs, and the therapy is based on efficacy, safety, or public health factors. If fast track designation is granted, drug sponsors may be eligible to participate in more frequent development meetings and communications with the FDA. In addition, the FDA may initiate a review of the NDA section before the application is completed. This "rolling review" can be used if the applicant provides and FDA approves the timeline of the remaining information.

In some cases, fast-track products may be eligible for accelerated approval or priority review.

The FDA may give priority to reviewing drugs designed to treat serious diseases and significantly improve the safety or effectiveness of treating, diagnosing, or preventing serious diseases. Priority review means that the FDA's goal is to review applications within six months, rather than ten months in accordance with the current PDUFA guidelines. The 6-month and 10-month review periods are calculated from the "application" date instead of the date of receipt of the NDA. This usually adds about two months to the review and decision from the date of submission. Products eligible for Fast Track designation may also be considered suitable for priority review.

In addition, the safety and effectiveness of research products in the treatment of serious or life-threatening diseases or conditions and products that meet unmet medical needs may be eligible for accelerated approval and may be based on adequate and well-controlled clinical trials Approved drug products have an impact on surrogate endpoints, can reasonably predict clinical benefits, or have an impact on clinical endpoints that can be measured before irreversible morbidity or mortality, and can reasonably predict irreversible morbidity or mortality or other aspects The impact on clinical benefit, taking into account the severity, rarity or prevalence of the disease, and the availability or lack of alternative treatments. As a condition of approval, the FDA may require the sponsor of an accelerated approval drug to conduct a post-marketing study to verify and describe the predictive effect on irreversible morbidity or mortality or other clinical endpoints, and the drug may be accelerated withdraw from the program .

In addition, in accordance with the regulations of the New Food and Drug Administration Safety and Innovation Law promulgated in 2012, sponsors can request to designate candidate products as "breakthrough therapies." Breakthrough therapy is defined as a drug that is designed to treat serious or life-threatening diseases or conditions alone or in combination with one or more other drugs, and preliminary clinical evidence indicates that the drug may have a significant improvement over existing therapies. One or more clinically significant endpoints, such as the substantial therapeutic effects observed in the early stages of clinical development. Drugs designated as breakthrough therapies are eligible for the above-mentioned fast-track designation features, the enhanced guidance of effective drug development plans that began as early as phase 1 trials, and the FDA’s commitment to involve senior management and experienced reviewers in collaborative, cross-border Subject review.

Even if a product meets the eligibility of one or more of these programs, the FDA may decide in the future that the product no longer meets the eligibility requirements, or decide that it will not shorten the time period for FDA's review or approval.

After the release of the SPA, in November 2018, the FDA also issued a breakthrough therapy designation to NRX-101. Breakthrough therapy designation is granted to drugs that have proven preliminary evidence that they can treat serious diseases and have unmet medical needs.

The FDA also granted NRx Fast Track Designation for the development of ZYESAMI in accordance with IND 149152 to treat critical COVID-19. There are unmet medical needs.

Drugs manufactured or distributed under FDA approval are subject to FDA's general and continuous supervision, which includes requirements related to record keeping, manufacturing, periodic reporting, product sampling and distribution, advertising and promotion, and reporting of adverse experiences. There is a shortage of products and medicines. After approval, most changes to the approved product, such as adding new indications or other labeling statements, require prior review and approval by the FDA. For any marketed products and institutions that produce such products, there are also ongoing annual user fee requirements, as well as new application fees for supplementary applications with clinical data.

As a condition for NDA approval, the FDA may impose some post-approval requirements. For example, the FDA may require post-marketing testing, including phase 4 clinical trials and monitoring, to further evaluate and monitor the safety and effectiveness of products after commercialization.

In addition, drug manufacturers and other entities involved in the production and distribution of approved drugs must register their agencies with the FDA and national agencies, and list the drugs produced by their factories in the FDA. These facilities are also subject to regular announcements and unannounced inspections by the FDA and these state agencies to ensure compliance with cGMP and other regulatory requirements. Changes to the manufacturing process are strictly regulated and may require prior approval or notification from the FDA before or after implementation. FDA regulations also require the investigation and correction of any deviations from cGMP, and impose reporting and documentation requirements on the sponsor and any third-party manufacturers that the sponsor may decide to use. Therefore, manufacturers must continue to spend time, money, and energy in production and quality control to maintain cGMP compliance.

Once approved, the FDA may withdraw the approval if it does not meet regulatory requirements and standards, or if there is a problem after the product is on the market.

Later discovering of previously unknown problems with the product, including adverse events of unexpected severity or frequency, or adverse events of the manufacturing process, or failure to comply with regulatory requirements, may lead to mandatory revisions to approved labels to add new safety information ; Conduct post-marketing studies or clinical trials to evaluate new safety risks; or impose distribution or other restrictions under the REMS plan. Other potential consequences include:

The FDA strictly supervises the marketing, labeling, advertising, and promotion of products placed on the market. Although doctors may prescribe approved drugs for unapproved indications in medical practice,

Pharmaceutical companies are prohibited from marketing or advertising their drugs for purposes other than the indications approved in the approved prescription information. The FDA and other agencies actively enforce laws and regulations that prohibit the promotion of off-label uses. Companies that are found to be improperly marketing or promoting off-label uses may bear significant responsibilities, including bans from participating in federal health care programs and government contracts under the FFDCA and false declaration laws And reject future orders under existing contracts, and compulsory compliance plans under the company’s integrity agreement or deferred prosecution agreement.

In addition, the distribution of prescription drug products, including samples, is governed by the Prescription Drug Marketing Act ("PDMA"), which, among other things, regulates the distribution of drugs and drug samples at the federal level and sets minimum standards for use The state's registration and supervision of drug distributors. Both PDMA and state laws restrict the distribution of samples of prescription drug products and impose requirements to ensure accountability for distribution.

In addition, the recently promulgated "Drug Quality and Safety Law" imposes new obligations on drug manufacturers related to product tracking and traceability. In the requirements of this new legislation, manufacturers will be required to provide certain information about drugs to individuals and entities whose product ownership is transferred, label drugs with product identifiers, and keep certain records about drugs. The transmission of information from the manufacturer to the subsequent product owner will eventually need to be done electronically. The manufacturer also needs to verify that the purchaser of the manufacturer's product has obtained the appropriate license. In addition, under this new legislation, manufacturers will be responsible for drug investigation, quarantine, disposal, and notification of FDA and trading partners related to counterfeit, diversion, stolen, and deliberately adulterated products that will cause serious adverse health consequences or Death, and products that are the subject of fraudulent transactions or are not suitable for distribution, so they may cause serious health consequences or death.

Drug Enforcement Administration Supervision

We need to evaluate the abuse potential of our product candidates. If any of our product candidates are considered controlled substances, we will need to comply with additional regulatory requirements. NRX-100 (ketamine) is a controlled substance with high potential for abuse. Both components of NRX-101 are approved drugs (DCS and Lurasidone), and neither are controlled substances. We have completed the DCS's abuse liability study and determined that there is no potential for abuse. ZYESAMI is not a CNS active drug, so the assessment of its potential for abuse is not relevant.

According to the definitions of the Controlled Substances Act of 1970 and the DEA Regulations, certain drugs may be regulated as “controlled substances”. DEA defines controlled substances as Schedule I, II, III, IV or V substances. By definition, Schedule I substances have no established medicinal use and cannot be sold or sold in the United States. Drugs may be classified as Schedule II, III, IV, or V, among which Schedule II substances are considered to have the highest risk of abuse, while Schedule V substances have the relatively lowest risk of abuse. The FDA advises the DEA on whether a drug should be classified as a controlled substance and the appropriate level of control. If DEA scheduling is required, the drug may not be on the market until the scheduling process is completed, which may delay the launch of the product.

According to the schedule, drugs may need to comply with DEA-administered registration, safety, record keeping, reporting, storage, distribution, import, export, inventory, quotas and other requirements, which directly apply to product applicants, contract manufacturers, and regulated Distributors, prescribers and distributors of substances. DEA regulates the handling of controlled substances through a closed distribution chain. This control extends to equipment and raw materials used in manufacturing and packaging to prevent loss and transfer to illegal commercial channels.

Any facility that manufactures, distributes, distributes, imports or exports any controlled substance requires annual registration. Registration is specific to specific locations, activities, and controlled substances programs. For example, import and manufacturing require separate registrations, and each registration will specify which controlled substance lists are authorized. Similarly, separate facilities also need to be registered separately.

DEA usually inspects the facility regularly to review its security measures before issuing the registration certificate. Safety requirements vary according to the list of controlled substances, the most stringent of which applies to Schedule I and Schedule II substances. Records of handling all controlled substances must be kept, and the distribution of certain controlled substances may need to be reported to the DEA on a regular basis. The theft or major loss of any controlled substances must also be reported. In order to implement these requirements, DEA conducts regular inspections of registered companies that handle controlled substances. Failure to comply with applicable requirements, especially in terms of loss or transfer performance, may lead to administrative, civil or criminal enforcement. DEA may seek civil penalties, refuse to renew necessary registrations, or initiate administrative procedures to revoke these registrations. In some cases, violations may lead to criminal proceedings or consent orders. Each state also independently regulates controlled substances.

Federal and state healthcare related, fraud and abuse, and data privacy and security laws and regulations

In addition to FDA restrictions on the marketing of pharmaceutical products, federal and state fraud and abuse, and other laws, regulations and requirements, commercial practices in the biopharmaceutical industry are also restricted. These laws include anti-kickback and false claims laws and regulations, state and federal transparency laws regarding payments or other items of value provided to healthcare professionals, as well as data privacy and security laws and regulations and other requirements that apply to the healthcare industry, including Drug maker. There are also laws, regulations, and requirements that apply to the award and performance of federal contracts and grants.

Federal anti-kickback regulations prohibit the intentional and deliberate provision, payment, solicitation, or acceptance of remuneration to induce or in return for the purchase, lease, order, or arrangement or recommendation of the purchase, lease, or order of any item or may be available under Medicare, Medicaid, or other federal health care plans Services that are fully or partially reimbursed. The term "remuneration" has been broadly interpreted to include anything of value. Anti-kickback regulations are interpreted as applying to drug manufacturers on the one hand, and to arrangements between prescribers, purchasers, formulary managers, and beneficiaries on the other. Although there are many statutory exceptions and regulatory safe harbors to protect some common activities from prosecution, the scope of exceptions and safe harbors is very narrow. Remuneration-related behaviors that do not meet statutory or regulatory exceptions or safe harbor requirements may be accused of inducing prescriptions, purchases, or recommendations that may be subject to scrutiny. Some courts interpreted the intent requirements of the statute as a violation of the statute if the purpose of any arrangement involving compensation is to induce referrals for federal healthcare services.

The Affordable Care Act also expands the scope of anti-kickback regulations. Among other things, the bill modifies the intent requirements of the federal anti-kickback regulations and certain provisions of the Criminal Medical Fraud Regulations (discussed below), such as individuals or entities that are no longer required Actually understand the law or the specific intention of violating the law to implement the illegal act. In addition, the "Affordable Care Act" stipulates that, as far as the "Civil False Claims Act" is concerned, the government can claim that a claim for payment for goods or services caused by a violation of the federal anti-kickback law constitutes a false or fraudulent claim. Penalties for violating the Anti-Kickback Act include criminal fines, imprisonment, civil penalties and damages, and prohibition from participating in federal health care programs and company integrity agreements or deferred prosecution agreements. Convictions or civil judgments are also reasons for canceling government contracts.

The Federal Civil False Claims Act prohibits anyone from deliberately submitting or causing false claims to the federal government, or deliberately making, using, or causing making or using false records or presentation materials to provide false information. Or file fraudulent claims with the federal government, including payments based on federal grants. The claim includes "any demand or demand" for money or property submitted to the U.S. government. The "False Declaration Law" also applies to false declarations that cause the government to pay less than its due amount, such as tax refunds. According to the "Civil False Claims Act", no intention to deceive is required to determine liability. Under these laws, several pharmaceutical companies and other healthcare companies have been sued for allegedly providing customers with free products and expecting customers to charge federal programs.

For the product. Companies have also been sued for making false claims because they marketed products for unapproved or off-label purposes. In addition, the federal health care plan requires drug manufacturers to report drug pricing information, which is used to quantify discounts and determine reimbursement rates. Several pharmaceutical companies and other healthcare companies have been sued for reporting suspected false pricing information, which has caused manufacturers to underestimate the rebates owed or to overpay suppliers when used to determine reimbursement rates. Violation of the Civil False Declaration Act may result in civil penalties and damages, as well as being excluded from federal health care plans and corporate integrity agreements or deferred prosecution agreements. The government may further prosecute acts that constitute false declarations under the Criminal False Declaration Act. The Criminal False Declaration Act prohibits making or filing claims against the government while knowing that such claims are false, fictitious or fraudulent, and unlike the Civil False Declaration Act, it requires proof of intent to submit false claims. Violation of the Criminal False Declaration Act may result in criminal fines and/or imprisonment, as well as exclusion from federal health care programs. Convictions or civil judgments and other actions are also reasons for canceling government contracts and funding.

HIPAA has also formulated federal criminal regulations that prohibit intentionally and deliberately executing or attempting to execute plans that defraud any healthcare benefit plan (including private third-party payers), knowingly and intentionally misappropriating or stealing healthcare benefit plans, and deliberately obstructing crimes against healthcare Criminal investigations, and the provision or payment of medical benefits, goods or services. As mentioned above, the Affordable Care Act amends the intent standards of certain HIPAA healthcare fraud clauses so that individuals or entities no longer need to actually understand the regulation or the specific intent to violate the regulation in order to commit a violation. Violation of HIPAA's fraud and abuse regulations may result in fines or imprisonment, as well as exclusion from federal health care programs, depending on the behavior. In addition, many states have similar fraud and abuse laws or regulations that apply to items and services that are reimbursed under Medicaid and other state programs, or in some states, regardless of the payer.

The civil fines statutes penalize any individual or entity, including those who are determined to have filed or caused a claim with the Federal Health Program to know or should have known that the person knew or should have known that the following items or services were not provided as claimed or were false Or fraud.

The Veterans Health Care Act requires manufacturers of covered drugs to sell them under a federal supply plan, which requires compliance with applicable federal procurement laws and regulations, and exposes us to contractual remedies and administrative, civil, and criminal sanctions.

In addition, there has recently been an increasing trend in federal and state regulation of payments to doctors and other health care providers. The Affordable Care Act establishes new federal requirements that require manufacturers of applicable covered drugs to report payments and other value transfers to doctors and teaching hospitals, as well as ownership and investment interests held by doctors and other healthcare providers and their immediate family members . Certain states also require the implementation of commercial compliance programs and compliance with the voluntary compliance guidelines of the pharmaceutical industry and applicable compliance guidelines issued by the federal government, or otherwise restrict payments or other valuable payments that may be made to healthcare providers and others. thing. Potential sources of referrals; impose restrictions on marketing practices; and/or require drug manufacturers to track and report information related to payments, gifts, and other items of value to doctors and other healthcare providers.

We may also be subject to the data privacy and security regulations of the federal government and the states in which we do business. HIPAA has been revised by HITECH and its implementing regulations, and has put forward specific requirements for the privacy, security and transmission of personally identifiable health information. 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 partners", defined as individuals or organizations other than the labor members of the covered entity, creating, receiving, maintaining or transmitting representatives are protected Of protected health information for entities performing functions or activities regulated by HIPAA. HITECH has also increased the civil and criminal penalties that may be imposed on covered entities, business partners, and possibly others, and granted state prosecutors

General new powers to file civil litigation damages or injunctions in federal courts to enforce federal HIPAA laws and seek attorney fees and expenses related to federal civil litigation.

In addition, other federal and state laws govern the privacy and security of health and other information under certain circumstances. Many of these laws differ from each other in major ways and may not have the same requirements, thereby complicating compliance efforts.

If any of our products are sold abroad, we may be subject to similar foreign laws and regulations. For example, they may include applicable post-marketing requirements, including safety oversight, anti-fraud and abuse laws, and implementation of corporate compliance programs and Healthcare professionals report payments or value transfers.

The commercial success of our product candidates and our ability to successfully commercialize any approved product candidates will depend in part on government authorities, private health insurance companies and other third-party payers providing insurance for our therapeutic products and establishing adequate reimbursements The level of the candidate. In the United States, the European Union, and other potentially important markets for our product candidates, government authorities and third-party payers are increasingly imposing additional requirements and restrictions on coverage, trying to limit the level of reimbursement or regulate the cost of drugs and other medical products. Prices and services, especially for new and innovative products and therapies, which usually result in lower average selling prices than other situations. For example, in the United States, the federal and state governments reimburse covered prescription drugs at different rates that are usually lower than the average wholesale price. The federal plan also implements price controls by imposing mandatory price ceilings on the procurement of federal agencies and federally funded hospitals and clinics, as well as mandatory rebates for retail pharmacy prescriptions paid by Medicaid and Tricare. These restrictions and restrictions affect the purchase of healthcare services and products. Legislative proposals to reform healthcare or reduce costs based on government plans may result in lower reimbursements for our product candidates or exclude our product candidates from coverage. In addition, Medicare and Medicaid are increasingly being used as models for how private payers and other government payers formulate insurance and reimbursement policies.

In addition, the increasing emphasis of the United States on managed healthcare and pricing and reimbursement control in EU countries and regions will put additional pressure on product pricing, reimbursement and use, which may adversely affect our future product sales and operating results. These Pressure may come from the rules and practices of managed medical groups, competition within treatment categories, availability of generic drugs, judicial decisions, and government laws and regulations related to health insurance, Medicaid and health care reform, coverage and reimbursement policies, and general pricing. The cost control measures being taken by healthcare payers and providers and any healthcare reforms implemented in the future may significantly reduce our revenue from the sale of any approved candidate products. We cannot provide any guarantee that we will be able to obtain and maintain third-party coverage or adequate compensation for our candidate products in whole or in part.

The impact of healthcare reform on coverage, reimbursement and pricing

The Medical Insurance Modernization Act puts forward new requirements for the distribution and pricing of prescription drugs for medical insurance beneficiaries. According to Part D, Medicare beneficiaries can participate in prescription drug plans provided by private entities that provide insurance for outpatient prescription drugs and pharmacy drugs in accordance with federal regulations. The Part D plan includes an independent prescription drug benefit plan and prescription drug insurance as a supplement to the Medicare Advantage plan. Unlike Medicare Part A and Part B, the coverage of Part D is not standardized. Generally speaking, Part D prescription drug plan sponsors have flexibility in the coverage of Part D drugs, and each drug plan can develop its own drug formulary to determine which drugs will be covered and at what level or level. However, the Part D prescription drug formulary must include drugs in each treatment category and Part D covered drug category, but not necessarily all drugs in each category or category, with certain exceptions. Any formulary used in the Part D prescription drug plan must be developed and reviewed by the pharmacy and treatment committee. The government's payment of part of the cost of prescription drugs may increase demand for any products for which we obtain marketing authorization. However, any negotiated prices for our future products covered by Part D prescription drugs

The plan may be discounted, thereby lowering the net price of our sales to pharmacies. In addition, although the Medical Insurance Modernization Act only applies to medical insurance beneficiaries’ drug benefits, private payers usually follow medical insurance coverage policies and payment restrictions when setting their own payment rates. Any reduction in payments caused by part D of the medical insurance may result in a reduction in payments from non-government payers.

The American Recovery and Reinvestment Act of 2009 provided funding for the federal government to compare the effectiveness of different treatments for the same disease. The Department of Health and Human Services, the Agency for Healthcare Research and Quality, and NIH will develop a research plan and will regularly submit reports on the research status and related expenditures to Congress. Although the results of the comparative effectiveness study are not intended to mandate insurance coverage policies for public or private payers, it is not clear what impact (if any) the study will have on the sales of any products, if any such products or The condition it aims to treat is the subject of research. The comparative effectiveness research that proves the advantages of competitors' products may also adversely affect the sales of our candidate products. If third-party payers do not consider our product candidate to be cost-effective compared to other available therapies, they may not include our product candidate as a benefit in their plan after approval, or if they do, pay The level may not be enough for us to sell our products on a profitable basis.

The United States and some foreign jurisdictions are considering enacting or have already enacted some additional legislation and regulatory proposals to change the healthcare system in ways that may affect the profitability of our products sold. Among policymakers and payers in the United States and elsewhere, with the stated goals of controlling medical costs, improving quality, and expanding accessibility, they have a keen interest in promoting changes in the healthcare system. In the United States, the pharmaceutical industry has been a particular focus of these efforts, and has been significantly affected by major legislative initiatives, including the recent Affordable Care Act, which became law in March 2010, drastically changing the way healthcare is financed Provided by the government and private insurance companies. Among other cost control measures, the Affordable Care Act provides for non-deductible annual expenses for any entity that manufactures or imports specific branded prescription drugs and biological agents; the new Medicare Part D coverage gap discount program; expands Medicaid benefits and Increase the new formula for rebates that manufacturers must pay under the Medicaid Drug Rebate Program; expand the 340B Drug Discount Program, which requires discounts for certain hospitals, community centers, and other eligible providers. In the future, other proposals related to the reform of the U.S. healthcare system may continue, some of which may further limit the price we can charge or the amount of reimbursement that our candidate products can receive after approval.

Foreign Corruption Act

The FCPA prohibits any U.S. individual or company from directly or indirectly paying, offering, or authorizing the payment or offering of anything of value to any foreign official, political party, or candidate to influence any behavior or decision of a foreign entity in the United States. To assist individuals or businesses to obtain or retain business. The FCPA also requires companies whose securities are listed in the United States to comply with accounting regulations, requires us to keep accurate and fair accounts and records that reflect all transactions of the company (including international subsidiaries), and to design and maintain appropriate internal systems. Accounting control of international business. Activities that violate the FCPA, even if they occur entirely outside the United States, may result in criminal and civil fines, imprisonment, illegal income, supervision, and disqualification from government contracts.

Exclusivity and approval of competing products

When seeking drug approval through the NDA, the applicant must list each patent to the FDA, whose claims cover the applicant's product or method of using the product. After the drug is approved, each patent listed in the drug application will be published in the FDA-approved drug product with therapeutic equivalence assessment, usually called the Orange Book. In turn, the drugs listed in the Orange Book can be cited by potential competitors to support simplified new drug application ('ANDA') or 505(b)(2) NDA approval. Generally speaking, ANDA regulates the marketing of pharmaceutical products with the same activity

The ingredients have the same strength, dosage form and route of administration as the listed drugs, and have been proved to be bioequivalence with the listed drugs through in vitro or in vivo tests or other means. Except for bioequivalence test requirements, ANDA applicants do not need to conduct or submit the results of preclinical or clinical trials to prove the safety or effectiveness of their drugs. Drugs approved in this way are often referred to as the "universal equivalents" of the listed drugs, and can often be replaced by a pharmacist based on a prescription written for the reference listed drugs. 505(b)(2) NDA is usually used to change a previously approved drug, such as a new dosage form or indication.

An ANDA or 505(b)(2) NDA applicant is required to provide FDA with a certificate of any patents listed in the FDA's Orange Book for approved products in the product application, except for patents covering the applicant's method of use. Do not seek approval. Specifically, the applicant must prove for each patent:

Generally, ANDA or 505(b)(2) NDA cannot be approved before all listed patents expire unless the ANDA or 505(b)(2) NDA applicant challenges the listed patents or the listed patents Patents are uses for which patented methods have not sought approval. The proof that the proposed product does not infringe the listed patents of the approved product or that such patents are invalid or unenforceable is called the paragraph IV certification. We may seek Section IV certification for our product candidates. If the applicant does not challenge the listed patents or indicates that it does not seek approval for the use of the patent, the ANDA or 505(b)(2) NDA application will not be approved until all the listed patents require the reference The patented product has expired.

If the ANDA or 505(b)(2) NDA applicant has provided the FDA with paragraph IV certification, once the application is accepted and submitted by the FDA, the applicant must also send a paragraph IV certification notice to the NDA and the patent holder. Food and Drug Administration. The NDA and the patentee can then file a patent infringement lawsuit based on the notice certified in Section IV. Filing a patent infringement lawsuit within 45 days after receiving the paragraph IV certification notice will automatically prevent the FDA from approving ANDA or 505(b)(2) NDA until 30 months, patent expiration, and earlier litigation in settlement, infringement cases Decisions in favor of the ANDA applicant or other periods determined by the court.

The market and data exclusivity clauses under FFDCA may also delay the submission or approval of applications for certain competing products. FFDCA provides the first applicant to obtain NDA approval for a new chemical entity with a five-year exclusive right to non-patent data in the United States.

If the FDA has not previously approved any other new drug containing the same active part, the drug is a new chemical entity, and the active part is the molecule or ion responsible for the therapeutic activity of the drug. During the exclusive period, the FDA may not accept another company's ANDA or 505(b)(2) NDA containing the previously approved active part for review. However, if the ANDA or 505(b)(2) NDA contains proof of invalidity or non-infringement of the patent, it can be filed after four (4) years.

FFDCA also provides three (3) years of marketing exclusivity for NDAs, 505(b)(2) NDAs, or supplements to existing NDAs or 505(b)(2) NDAs, if new clinical studies, in addition to bioavailability Research, conducted or sponsored by the applicant, is considered by the FDA to be essential for the approval of the application or supplement. Changes to previously approved drug products, such as new indications, dosages, strengths or dosage forms of existing drugs, can be granted exclusive rights for three years. This three-year exclusivity only covers the conditions of use related to the new clinical study, and as a general matter, does not prohibit the FDA from approving the original unmodified generic drug ANDA or 505(b)(2) NDA products. Five years

The three-year exclusivity period will not delay the submission or approval of a complete NDA; however, applicants who submit a complete NDA will need to conduct or obtain references to all preclinical studies and sufficient and well-controlled clinical trials necessary to demonstrate safety and effectiveness right.

Pediatric exclusivity is another type of non-patent marketing exclusivity in the United States. If approved, six months of marketing protection will be added to any existing regulatory exclusivity period, including the aforementioned non-patent exclusivity period. If the NDA sponsor submits The pediatric data fairly responds to the FDA’s written request for such data, and this 6-month exclusivity can be granted. The data does not need to show that the product is effective for the pediatric population under study; instead, if the clinical trial is deemed to have fairly responded to the FDA's requirements, additional protection is granted. If the required pediatric research report is submitted to the FDA and accepted by the FDA within the statutory time limit, whether it is the statutory or regulatory exclusivity period or the patent protection period listed in the Orange Book, it will be extended by six months. This is not an extension of the patent term, but it effectively extends the regulatory period during which the FDA cannot approve ANDA or 505(b)(2) applications due to regulatory exclusivity or market patents.

Orphan drug designation and exclusivity

The Orphan Drug Act provides incentives for the development of drugs for the treatment of rare diseases or conditions that usually affect less than 200,000 people in the United States each year, or more than 200,000 people in the United States, and is there a reasonable expectation that they will be sold in the United States Recover the cost of developing and producing the drug in the United States.

In addition, if there is a drug that has been approved by the FDA for the same indication and deemed by the FDA to be the same as the approved drug, the sponsor must propose a reasonable clinical advantage hypothesis to obtain orphan drug designation. This hypothesis must be proven to obtain an orphan drug Exclusive right of medicine. Orphan drug designation entitles a party to financial incentives, such as funding opportunities for clinical research costs, tax incentives, and user fee reductions. In addition, if a product is approved by the FDA to have an orphan drug designation, the product is usually entitled to the exclusive right of an orphan drug, which means that the FDA may not approve any other applications to sell the same drug for the same indication. Seven (7) years, except in limited circumstances, such as showing clinical advantages over products with orphan drug franchise. See "Risk Factors-Risks Related to Our Business and Industry-We don't expect to maintain orphan drug protection for COVID-19."

In order to sell any product outside the United States, we need to comply with many different regulatory requirements in other countries regarding safety and effectiveness, as well as management (including) clinical trials, marketing authorization, commercial sales and the distribution of our products. For example, in the European Union, We must obtain authorization for clinical trial applications in each member country where we intend to conduct clinical trials. Regardless of whether our products are approved by the FDA, we need to obtain the necessary approvals from comparable foreign regulatory agencies before we can start clinical trials or product marketing in these countries. The approval process varies from country to country and may involve additional product testing and additional administrative review periods. The time required to obtain approval in other countries may be different and longer than the time required to obtain FDA approval. Regulatory approval in one country does not guarantee regulatory approval in another country, but failure or delay in obtaining regulatory approval in one country may have a negative impact on the regulatory process in other countries.

EU drug approval process

In order to obtain marketing authorization for a drug in the EU, we can submit an MAA under the so-called centralized or national authorization procedure.

The centralized procedure stipulates that a single marketing authorization is granted after the EMA submits a favourable opinion, which is valid in all EU member states as well as Iceland, Liechtenstein and Norway. For drugs produced through specific biotechnological processes, products designated as orphan drug products, and products containing new active substances for the treatment of specific diseases (such as HIV/AIDS, cancer, diabetes, neurodegenerative diseases or autoimmune diseases) Products, concentrated procedures are mandatory and other immune dysfunctions. For products that represent major treatments, scientific or technological innovations or whose authorizations will be in the public health interest, centralized procedures are optional. Under the centralized procedure, the maximum time for EMA to evaluate MAA is 210 days, excluding the clock stop time. At this time, the applicant needs to provide additional written or oral information to answer questions raised by the Human Medicines Committee ('CHMP'). Under special circumstances, the CHMP may approve an accelerated evaluation when the drug product is expected to have significant public health benefits, especially from the perspective of therapeutic innovation. The time frame for evaluating MAA under the accelerated evaluation procedure is 150 days, not including stopping the clock.

There are two other possible ways to approve medicines in several EU countries, which can be used for investigational medicines outside the scope of the centralized procedure:

In the European Union, new products (ie, reference products) that have received marketing authorization are eligible for eight (8) years of data exclusivity, and an additional two (2) years of market exclusivity after obtaining marketing authorization. The data exclusivity period prevents generic drug applicants from relying on the preclinical and clinical trial data contained in the reference product dossier when applying for a generic drug marketing authorization in the EU within eight (8) years. The reference product was first authorized in the European Union. The market exclusivity period prevents successful generic drug applicants from commercializing their products in the EU until ten (10) years after the initial authorization of the reference product in the EU. If within the first eight (8) years of these ten (10) years, the marketing authorization holder obtains authorization for one or more new therapies, the ten-year market exclusivity period can be extended to a maximum of eleven (11) years. During the scientific evaluation period before approval, an indication that has significant clinical benefits compared to existing therapies.

NRX Pharmaceuticals Inc. published this content on September 10, 2021 and is solely responsible for the information contained therein. Distributed by the public at 10:11:03, September 10, 2021, UTC time, unedited and unaltered.