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Update on ZYESAMI™ Application for Emergency US Emergency Use Authorization

The FDA continues to actively review NRx’s request for Emergency Use Authorization for ZYESAMI™.

This week, we are responding to an FDA information request for various, supplemental statistical analyses regarding the Phase 2b/3 data.  In our experience, such requests are a routine part of the regulatory process and indicative of active engagement by the regulator.

In our regulatory response, we presented a statistical analysis showing a statistically significant two-fold increase in odds of survival at 60 days post treatment among those treated with aviptadil, compared to those treated with placebo. The analysis considers all patients at all sites of care and controls for baseline severity of illness using the baseline severity criteria that were prespecified in our protocol.  We are similarly sharing these results with partners and regulators around the globe at the request of Health Ministries as the Delta and subsequent variants continue to escalate the COVID public health emergency.

About ZYESAMI™

ZYESAMI™ (Aviptadil acetate), a synthetic form of human Vasoactive Intestinal Peptide, an endogenous substance produced by the body that amongst other functions helps protect cells against inflammatory conditions. (VIP) has been granted Fast Track Designation by the U.S. Food and Drug Administration (FDA)for the treatment of Critical COVID-19 with respiratory failure, and is now in clinical trials. Rapid recovery from Critical COVID-19 with respiratory failure has been reported in patients treated with open label VIP under an FDA Emergency Use IND and/or the Expanded Access program. It must also be noted that Administered as an intravenous infusion the key side effects seen in the Expanded Access Program as well as the placebo controlled trial are diarrhea (~ in 1/3 of patients), hypotension (lowering of blood pressure). Emerging data indicates that VIP binds uniquely to receptors on Alveolar Type II cells in the lung, the same cells that bind the SARS-CoV-2 virus via their ACE2 receptors. VIP protects those cells and the surrounding pulmonary epithelium by blocking cytokines, preventing cytopathy (cell death), and upregulating the production of surfactant, the loss of which is increasingly implicated in COVID-19 respiratory failure. Furthermore, emerging preclinical data suggests that VIP inhibits the replication of the SARS-CoV2 virus.

FOR PATIENTS:

ZYESAMI™ is currently in clinical trials.

The US FDA has granted NRx™ two designations to speed up review of ZYESAMI™ for severe or critical covid with respiratory failure. Fast Track Designation and an Expanded Access Protocol, making a determination as provided in section 506(b) of the Food, Drug, and Cosmetics Act that ZYESAMI™ is “intended, whether alone or in combination with one or more other drugs, for the treatment of a serious or life-threatening disease or condition, and it demonstrates the potential to address unmet medical needs for such a disease or condition.”

Please note that FDA at this point has not determined if ZYESAMI™ is safe and effective. The above designation only indicates that it has the potential to demonstrate safety and efficacy in clinical trials for treating COVID-19 Respiratory Failure.

Therefore, ZYESAMI™ is currently being investigated in clinical trials. If you or your loved one can participate in one of those clinical trials, we hope that you will do so.

The three clinical trials currently enrolling patients in the United States are listed on www.clinicaltrials.gov, where you can learn about them in detail. These trials are offered only in selected hospital study sites across the US. In brief, those trials are:

1. AVICOVID-2, sponsored by NRx: This trial enrolls patients who have severe COVID-19, but have not yet developed respiratory failure. Patients are randomly assigned to either ZYESAMI™ or placebo in order to determine whether treatment with ZYESAMI™ is associated with a reduced likelihood of progressing to Critical COVID-19, improved survival, and with a shortened length of hospital stay.
2. ACTIV3b/TESICO sponsored by the National Insitutes of Health. This trial enrolls patients with Critical COVID-19 who have already developed respiratory failure and seeks to determine whether treatment with intravenous ZYESAMI™ is associated with an increased likelihood of being alive and free from respiratory failure at 90 days compared to treatment with placebo or Veklury (remdesivir) alone or in combination with Zyesami.
3. I-SPY sponsored by the Biomedical Advanced Research and Development Authority (BARDA) of the US Department of Health and Human Services. This trial enrolls patients with Critical COVID-19 who have already developed respiratory failure and seeks to determine whether treatment with inhaled ZYESAMI™ is associated with an increased likelihood of being alive and free from respiratory failure at 90 days compared to treatment with placebo or other drugs.

What if you have Critical COVID-19 and cannot access one of the existing trials?

• First, you should always discuss the situation with the treating physicians to evaluate all available options at your current hospital.
• NRx continues to make ZYESAMI™ available through an FDA-approved expanded access protocol at a very limited number of hospitals but will not add additional study sites (hospitals) under this program. US hospitals that are still active in this program are listed at (add link to EAP). The expanded access protocol is available to patients who are unable to access a clinical trial treatment site or who are ineligible to enter one of the currently operating clinical trials because of coexisting medical conditions. Please note that your treating physician as well as NRx’s medical advisors will evaluate if ZYESAMI™ has the potential to be of benefit. Furthermore, as an investigational treatment manufacturing at this time is focused on the clinical studies, so availability of ZYESAMI™ may be limited
• Patients and physicians who believe that treatment with ZYESAMI™ is the only remaining option in the setting of Critical COVID-19 may request treatment under the Federal “Right to Try” Act (cite the law). Under this law, patients with a life-threatening illness who have exhausted approved therapies may be treated with an investigational drug upon physician request. NRx will evaluate making ZYESAMI™ available for a limited number of cases under the Right to Try Act, provided our medical advisors believe that the drug may have the potential to be of benefit on a case by case basis. As allowed in the Right to Try legislation, NRx does charge for the costs of making ZYESAMI™ available to patients under this program. (Patients or their Legally Authorized Representative should check with their hospital and Health Insurance regarding coverage of this cost.) NRx additionally requires that the patients consent to physicians providing information on the safety and efficacy results of treatment so that NRx can comply with its FDA reporting obligations.

Before asking your doctor to consider requesting ZYESAMI™ under the Right to Try act, please read the patient consent form. And, make sure that you are willing to give your consent for treatment if your doctor decides that you are eligible for this program.

We hope that the above information has been helpful. NRx Pharma continues its work with the FDA to learn more about ZYESAMI™ as a potential treatment for Critical and Severe COVID-19. We reiterate that ZYESAMI™ is an investigational drug that has not been approved by the US FDA or any other regulatory agency for COVID-19 related conditions.

On behalf of all of us at NRx Pharma, our prayers are with you for a speedy recovery.

Jonathan C. Javitt, MD, MPH
CEO and Chairman, NRx, Inc.

NRX-101

An investigational, rapid-onset and sustained treatment for Bipolar Depression in patients with Acute Suicidal Ideation and Behavior

NRx’s investigational medicine regimen NRX-100/NRX-101, if approved by the US FDA and other health-regulatory agencies, would be the first medicine regimen to treat suicidal Bipolar Depression. Today, no drug is approved to treat patients with bipolar depression and suicidal ideation and the only FDA-approved treatment for this lethal condition is electroconvulsive therapy (ECT), which has well known adverse side effects.

NRX-101 is a patented, oral fixed-dose combination of two FDA-approved drugs: D-cycloserine, an NMDA receptor modulator; and Lurasidone, a 5-HT2a receptor antagonist that has been awarded Breakthrough Therapy Designation and a Special Protocol Agreement by the FDA. NRX-101. The product has been awarded a composition of matter patent because of the synergistic mechanism of action discovered by Prof. Daniel Javitt, PhD, MD by which the two components of the medicine are seen to cancel each other’s side effects in laboratory experiments. Dr. Javitt ranks among the world’s most quoted scientists and was the first to recognize the role of the brain’s NMDA receptor in psychiatric disease in 1987 and has led this area of neurochemistry with more than 600 scientific publications that have been cited by 46,000 people.

NMDA-antagonist drugs have recently been widely-recognized to treat depression and suicidality. However, those that directly block the NMDA channel, such as ketamine and dextromethorphan are well known to cause neurotoxicity (i.e. kill brain cells) and to be highly addictive. The D-cycloserine component of NRX-101 has demonstrated no propensity for neurotoxicity or addiction (abuse liability) in the standard laboratory tests required by FDA. NMDA-antagonist drugs also have high potential to cause hallucination, which makes ketamine and dextromethorphan popular as drugs of abuse. The patented discovery underlying the NRX-101 patent in part shows that the lurasidone component of, NRX-101 blocks the potential for D-cycloserine to cause hallucination in laboratory experiments and hallucination has not been seen in association with NRX-101 in human clinical trials.

FDA awarded Breakthrough Therapy Designation to NRX-101 for the “Treatment of severe depression and acute suicidal ideation and behavior in patients with bipolar depression after initial stabilization with ketamine or other effective therapy.” NRx’s intitial phase 3 trials of NRX-101 target both patients who are in emergency care with active suicidal ideation and require an initial single dose of ketamine (NRX-100) to stabilize their condition and also patients being treated in the outpatient setting who have less acute suicidal ideation.

Potential clinical advantages of NRX-100/NRX-101, currently studied in clinical trials, include:

• Specific Focus on Bipolar Depression in Patients with ASIB: More than 50% of individuals with Bipolar Disorder attempt suicide during their lifetime.¹ Medicines currently approved are indicated for Major Depressive Disorder (MDD), Treatment Resistant Depression (TRD) and other forms of depression.
• Potential Rapid Stabilization for Patients after a single dose of NRX-100 (ketamine): The sequential medicine treatment regimen* will only require a single, initial administration of NRX-100 (ketamine). In clinical studies, ketamine has shown rapid-onset, antidepressant/anti-suicidal effects.² Ketamine can cause dissociative effects (hallucinations); repeated administration could further increase these dissociative effects..
  
• Convenience: Unlike other treatments, NRX-101 is being developed to allow treatment on an outpatient basis, after an initial stabilization with NRX-100 (ketamine) or other effective therapy.

Safety Considerations of NRX-101 so far have been limited to observed side effects of mild sedation, headaches and hypomania. However, both D-cycloserine and lurasidone have broader side effect profiles in their FDA-approved labels and those side effects may be seen as more patients are treated with NRX-101.

Mechanism of Action

NMDA regulates the speed of thoughts:
Too little NMDA activity > Increased Ideation, hallucinations, psychosis
Too much NMDA activity > Reduced Ideation, depression, suicide

NRX-101’s proprietary dual-mechanism of action targets the NMDA and 5-HT2a receptors – two key receptors in the brain.

The NMDA receptor is a glutamate receptor found in nerve cells.  It is critical to the memory function as it controls signaling from neuron to neuron.  NMDA also directly regulates a calcium ion channel that controls the rate of ideation (formation of new ideas) in the brain. D-cycloserine, one of the active ingredients in NRX-101, targets the NMDA receptor and modulates NMDA activity, potentially fostering a normal pace of thought generation. Multiple human studies have demonstrated that administration of D-cycloserine triggers an antidepressant effect. However, our ongoing research indicates that the treatment requires administration with an antipsychotic to counteract the psychomimetic side effects.

The 5-HT2a receptor is a G protein-coupled receptor and a member of the serotonin family. It is known for its role in mediating certain antipsychotic effects. Lurasidone, the other active ingredient in NRX-101, is a 5-HT2a antagonist that is currently approved as an antipsychotic, and indicated for bipolar depression. Laboratory studies have shown that Lurasidone and other 5-HT2a antagonists have an unexpected synergistic effect with D-cycloserine, potentially enhancing the antidepressant effect while minimizing the potential psychomimetic (hallucinations) side effects.

NRX-101’s proprietary combination of D-cycloserine and Lurasidone is designed to be taken orally, each day for approximately six weeks following an initial, single infusion of NRX-100 (ketamine). This therapeutic approach may offer an oral, outpatient treatment, with the potential to significantly extend NRX-100 (ketamine)’s antidepressant/anti-suicidal effect.

Clinical Data

Full results from NRx’s STABIL-B trial, a phase 2 study conducted under FDA Good Clinical Practices (GCP) were presented at the American College of Neuropsychopharmacology in December 2019.  The US Food and Drug Administration granted Break Through Therapy Designation (BTD) to NRX-101 based on this study.

A BTD is a process designed to expedite the development and review of medicines that are intended to treat a serious condition and preliminary clinical evidence indicates that the therapy may demonstrate substantial improvement over available medicines on a clinically significant endpoint(s).

In this trial, 20 patients who presented to emergency care with Severe Bipolar Depression and Acute Suicidal Ideation were initially stabilized with a single infusion of intravenous ketamine (NRX-100).  Study details may be seen on www.clinicaltrials.gov.³

Following stabilization, patients were randomly assigned (2:1) to either NRX-101 or to lurasidone alone, in order to maintain remission from depression and suicidal ideation. As can be seen in the top-line analysis shown below, those treated with NRX-101 demonstrated a significantly lower level of depression at 14 days, compared to those treated with lurasidone (P=0.03).  This trend persisted at 42 days (P=0.032).

Relapse in either depression or suicidality was seen in 2/5 of control patients treated with lurasidone, while no instances of relapse were seen in patients treated with NRX-101, (P=.095).  No drug-related serious adverse events were observed and no instances of hallucination were seen in the oral drug phase of the study. This information does not constitute the full safety profile of either arm in the clinical trial.

Findings from a prior study were published in the Journal of Clinical Psychiatry in 2015. In this study, patients with Bipolar Depression, who were already receiving a 5-HT2a antagonist, received a single infusion of IV ketamine followed by daily, oral D-cycloserine. Results showed a >50% reduction in symptoms of depression and a 75% reduction in suicidal ideation. The therapeutic effect for these patients was sustained for eight weeks or longer.⁴

Preclinical data shows that the combination of lurasidone (and other 5HT2a antagonists) and D-cycloserine led to a significant reduction in akathisia compared to control and to lurasidone alone. These findings are described in detail in several US and ex-US patent filings. Akathisia is defined as a state of agitation, distress, and restlessness that is an occasional side-effect of antipsychotic and antidepressant drugs.

1. Pallaskorpi, et al. Bipolar Disorders 2017; 19: 13-22
2. Zarate, C. et al. Biological Psychiatry 2012; 71(11); 939-946
3. https://www.clinicaltrials.gov/ct2/show/NCT02974010?term=stabil-b&rank=1
4. Kantrowitz, et al: J Clinical Psychiatry 2015; 76(6): 737-738

Bipolar Depression in Patients with Acute Suicidal Ideation and Behavior (ASIB)

In the United States,
More than 100 People End
Their Lives Each Day
Nearly half of those who die of suicide suffer from Bipolar Depression

Bipolar depression is a potentially lethal disease impacting up to three million Americans, as it can sometimes lead to Acute Suicidal Ideation/Behavior (ASIB). This means they have suicidal thoughts, potentially also with a method in mind. Even though patients with bipolar depression constitute only 10% of the 33 million people with depression nationwide, they constitute nearly half of those who take their lives each year. Tragically, if you know two people with bipolar depression, one is likely to attempt suicide and if you know five people with bipolar depression, one is likely to succeed.

Despite the lethal nature of bipolar depression, people who suffer from this condition have been systematically excluded from the clinical trials of nearly all antidepressant medications because of the high risk of self-harm. While there are approved therapies for the manic phase of bipolar disease, there is no approved medication for the treatment of Bipolar Depression in people with acute suicidal ideation or behavior.

Patients with Bipolar Depression are 20-30x more likely to attempt suicide than the general population.¹ During a time span of 5 years, 1 in 5 patients suffering from Bipolar Depression will attempt suicide.² Estimates indicate that more than 11% of those with Bipolar Disorder succumb to suicide over their lifetimes.³

Those with Acute Suicidal Ideation/Behavior, as classified by FDA-recognized scales, have a 33% chance of death within six months of onset. Although only 10% of the 30 million Americans suffering with depressive disorders have bipolar disorder, patients with bipolar depression may account for up to 60% of all depression-related suicides.⁴

The current standard of care, as published by the American Psychiatric Association consists of voluntary or forced admission to a psychiatric hospital and electroconvulsive therapy (ECT).  Although ECT is associated with a decrease in suicide deaths, it requires 6 – 10 sessions of general anesthesia and is known to cause memory loss and confusion.

Currently marketed SSRI/SNRI-based antidepressants are well known to increase the risk of suicide and bear an FDA-mandated warning label identifying that risk. Furthermore, these traditional antidepressants are not effective for many patients and typically require more than three weeks to show effect. Other treatments, such as electro-convulsive therapy (ECT), are physically and emotionally draining and require extended hospitalization. Scientific findings indicate that thoughts and impulses for suicide have biological underpinnings.⁵

Recent scientific breakthroughs indicate that the chemical target for suicidality in bipolar depression may be modulated by the brain’s NMDA receptor, providing a rationale for developing new therapies focused on this target. Ketamine, although it is highly-addictive and neurotoxic serves as a prototype drug and scientists are rapidly gaining an understanding that NMDA antagonists such as ketamine may “rewire” the brain, causing brain cells to form new connections with one another and permanently altering the brain “circuits” that lead to rumination (persistent negative thoughts) and other phenomena that may be associated with suicide.

A study led by Prof. Conor Liston6, a neuroscientist, and psychiatrist at Weill Cornell Medicine, has confirmed that synapse growth is involved and reveals how ketamine activates changes in the brain circuit function, improving depressive symptoms in as little as three hours. As ketamine therapy continues, the drug triggers the regrowth of synapses in the brain. This study opens new channels and questions on how to sustain antidepressant effects long term. Although NRx has an FDA-approved IND for use of single-dose ketamine to induce rapid remission from acute suicidal ideation and behavior, our focus is on the use of D-cycloserine and potentially other glycine-site antagonists of the NMDA receptor that may achieve the benefits of ketamine without the harmful and potentially neurotoxic side effects of repeated ketamine administration.

In addition to a significant impact on patient health, ASIB in Bipolar Depression takes a dramatic economic toll on the U.S. healthcare system. Given the lack of suitable alternatives, the majority of patients are managed in the inpatient setting, which is costly to the patient, their families, employers and payers.

1. Pompili, M. Gonda, X. Bipolar Disorders 2013; 15: 457-490
2. Holma, K. Haukka J. Bipolar Disorders 2014; 16: 652-661
3. Pallaskorpi, et al. Bipolar Disorders 2017; 19: 13-22
4. Pompili, M. Gonda, X. Bipolar Disorders 2013; 15: 457-490
5. Johnston et al. American Journal of Psychiatry 2017; 174: 667-675
6. Moda-Sava et al. Science 2019 364:147 12 April 2019