The promising COVID therapy for respiratory failure few have heard of, but will soon - NeuroRx and Relief Therapeutics RLF-100 (Aviptadil)

The current Zyesami/Aviptadil trial information in the U.S.:

Row	Status	Study Title	Conditions	Interventions	Locations
1	Recruiting	A Clinical Study Evaluating Inhaled Aviptadil on COVID-19	Covid19	Drug: Inhaled Aviptadil Drug: Placebo	Başkent University School of Medicine Ankara, Turkey Hacettepe University School of Medicine Ankara, Turkey Health Sciences University Yedikule Training and Research Hospital Istanbul, Turkey
2	Recruiting	Inhaled Aviptadil for the Treatment of COVID-19 in Patients at High Risk for ARDS	Covid19 Corona Virus Infection ARDS Aviptadil	Drug: Aviptadil 67μg Drug: Placebo 0.9% NaCl solution	Cantonal Hospital Baselland Liestal Liestal, BL, Switzerland Cantonal Hospital St.Gallen St.Gallen, Switzerland
3	Completed	Intravenous Aviptadil for Critical COVID-19 With Respiratory Failure	Critical COVID-19 With Respiratory Failure Acute Respiratory Distress Syndrome (ARDS) Corona Virus Infection Acute Lung Injury	Drug: Aviptadil by intravenous infusion + standard of care Drug: Normal Saline Infusion + standard of care	St. Jude Medical Center Fullerton, California, United States University of California - Irvine Irvine, California, United States Miller School of Medicine / University of Miami Medical Center Miami, Florida, United States (and 7 more...)
4	Recruiting	Inhaled ZYESAMI™ (Aviptadil Acetate) for the Treatment of Severe COVID-19	SARS-CoV 2 COVID ARDS (and 3 more...)	Drug: ZYESAMI™ (aviptadil acetate) Drug: Placebo Device: Nebulized administration of ZYESAMI™ or Placebo	St. Jude Medical Center Fullerton, California, United States University of California - Irvine Irvine, California, United States University of Miami Leonard M. Miller School of Medicine (UMMSM) Miami, Florida, United States (and 4 more...)
5	Available	ZYESAMI (Aviptadil) Intermediate Population Expanded Access Protocol (SAMICARE)	Critical COVID-19 With Respiratory Failure	Drug: ZYESAMI (aviptadil acetate)	Dignity Health-Mercy Gilbert Medical Center Gilbert, Arizona, United States Honor Health Shea Medical Center Scottsdale, Arizona, United States Kaiser Permanente Baldwin Park, California, United States (and 22 more...)
6	Recruiting	ACTIV-3b: Therapeutics for Severely Ill Inpatients With COVID-19	Covid19	Biological: Remdesivir Drug: Remdesivir Placebo Biological: Aviptadil (and 2 more...)	Banner University Medical Center Tucson (Site 206-004), 1501 N. Campbell Avenue Tucson, Arizona, United States Community Regional Medical Center (UCSF Fresno) (Site 203-005), 2823 Fresno Street Fresno, California, United States VA Loma Linda Healthcare System (Site 074-017), 11201 Benton Street Loma Linda, California, United States (and 29 more...)
7	Recruiting	I-SPY COVID-19 TRIAL: An Adaptive Platform Trial for Critically Ill Patients	COVID-19	Drug: Remdesivir Drug: Pulmozyme Drug: IC14 (and 4 more...)	University of Alabama at Birmingham Birmingham, Alabama, United States UC Davis Medical Center Davis, California, United States Long Beach Memorial Medical Center Long Beach, California, United States (and 16 more...)

https://www.clinicaltrials.gov/ct2/results?term=Aviptadil&cond=Covid19&draw=1&rank=7#rowId6

NRx Pharmaceuticals Announces Positive Safety Report for ZYESAMI™ (aviptadil) in NIH Sponsored ACTIV-3 Critical Care Study in Patients with Life-Threatening COVID-19

- After Review of Approximately 140 patients in ACTIV-3 Critical Care Study, No New Safety Concerns Raised by Independent Data Safety Monitoring Board, Study to Continue Enrollment to Target More than 600 Patients
- ACTIV-3 Critical Care is a Public-Private Partnership Sponsored by the US National Institutes of Health to Treat COVID-19
- ACTIV-3 Critical Care is Evaluating ZYESAMI™ and Remdesivir, in Critical COVID-19 Patients, as Monotherapy and in Combination Against Placebo

RADNOR, Pa., Aug. 18, 2021 /PRNewswire/ -- NRx Pharmaceuticals (NRx) (NASDAQ: NRXP), a clinical stage, biopharmaceutical company today provided a safety update on ZYESAMI™ (aviptadil) which is being tested in the ACTIV-3 Critical Care Phase 3 study sponsored by the National Institutes of Health. The study's Data Safety Monitoring Board found no new safety concerns in the trial and recommended continued enrollment.

After Review of Approximately 140 patients, No New Safety Concerns Raised by Independent Data Safety Monitoring Board.

ACTIV-3 is a randomized, blinded, placebo-controlled clinical trial testing ZYESAMI™ and the antiviral remdesivir (Veklury) in hospitalized patients with acute respiratory failure due to COVID-19 who require high-flow supplemental oxygen, delivered by nasal cannula, mechanical ventilation, or extracorporeal membrane oxygenation.

Study investigators are randomizing patients to receive one of four treatment regimens in addition to standard of care: both ZYESAMI™ and remdesivir, ZYESAMI™ and a placebo, remdesivir and placebo, or only placebo. ZYESAMI™ is administered as a daily 12 hour intravenous infusion over three days. Those randomized to receive remdesivir will receive it for up to 10 days via intravenous infusion.

ZYESAMI™ (aviptadil) is a proprietary, synthetic version of Vasoactive Intestinal Peptide or VIP, which is made naturally in the human body and appears to have lung-protective, anti-viral and anti-inflammatory effects.

ACTIV-3 represents one of three ongoing studies of ZYESAMI™ in Severe or Critical COVID-19.

Update on the EUA application (denied at this time) - clearly, FDA continues to prioritize vaccines and where they might stray and approve a therapeutic, it has to come from a $$$ Big Pharma $$$.

The FDA Commits to Working with NRx to Develop ZYESAMI®
ZYESAMI Clinical Trials Funded by the US National Institutes of Health and BARDA Continue and Advance Towards Enrollment in Brazil and Europe
Last week, NRx requested a Type A meeting with FDA officials, a request endorsed by key study investigators, to discuss the development of ZYESAMI
We will work actively with the FDA to deliver the data it has requested
We will move towards filing for accelerated approval based on the unexpectedly strong biomarker results seen in our two clinical trials.
In the meantime, ZYESAMI remains available upon a physician’s request under Federal and state Right to Try laws for those patients who meet the legal criteria for Right to Try.
Currently - US NIH has enrolled more than 300 patients in the ACTIV-3b trial, ZYESAMI® vs. Veklury®
NRx will attempt to coordinate a review by the FDA of the 150 or more additional patients already treated with ZYESAMI in the NIH ACTIV-3b trial
This week, the Data Safety Monitoring Board of the NIH ACTIV-3b trial reported that no new drug-related Serious Adverse Events were seen and approved the trial for continued enrollment.
Currently - 2nd nationwide trial is being conducted on the I-SPY platform

https://www.nrxpharma.com/us-food-and-drug-administration-declines-emergency-use-authorization-for-zyesami-aviptadil-for-patients-with-critical-covid-19-with-respiratory-failure/

CEO Update: ZYESAMI® (aviptadil) Next Steps (11.08.2021)

I recently received the letter below from a shareholder. The correspondence from them (taken exactly from their email) and my response regarding our next steps for ZYESAMI ® (aviptadil) can be found below.

Email from R.B., a shareholder of NRx Pharmaceuticals

Dear Dr. Javitt

I have been heartbroken since the denied emergency approval for Zyesami/Aviptadil. I believed so strongly that a drug had finally been found that would give the seriously ill a chance. However, I do not understand the FDA’s rejection. Surely the safety concerns are completely false because multiple studies have established the safety of the body’s own peptide? So did we really see the biggest placebo effect?

Thank you for your clarifying answers.

Kind regards from R.B., a loyal shareholder of NRXP from the beginning."

Jonathan’s Response:

Dear R.B.,

Most certainly, we are not done. We are certainly disappointed. We believe that our medicine offers a chance at life to those with COVID-19 respiratory failure who have exhausted all currently approved therapies.

FDA has expressed a commitment to working with us and to reviewing additional data as it is presented. We will continue with our application for New Drug Approval under the Accelerated Approval pathway based on biomarker results. Please see FDA’s guidance for Accelerated Approval and note that FDA has already awarded Fast Track designation https://www.fda.gov/drugs/information-health-care-professionals-drugs/accelerated-approval-program.

FDA has previously agreed to allow rolling review of our application (a component of the Fast Track program) so that elements such as CMC, manufacturing, and non-clinical safety and toxicology can be reviewed in advance of reviewing efficacy data. Should the ongoing ACTIV-3b and/or I-SPY trials produce positive results prior to the PDUFA date for the Accelerated Approval application, that application may be converted to a traditional New Drug Application.

The US Government has invested considerable resources in the ongoing ACTIV 3-b and I-SPY trials to test ZYESAMI® (aviptadil) both against placebo and remdesivir, as Dr. Fauci has testified from the White House and before Congress and as Dr. Collins (Director of the NIH) has advised the public in the recent NIH FDA workshop. Dr. Collins said that of 750 drugs initially by NIH, only 22 remain under study. ZYESAMI is one of those remaining drugs listed on the slide that Dr. Collins showed. The US Government, via NIH, BARDA, and DOD, has made a substantial scientific and financial investment in two trials under separate FDA INDs designed to demonstrate whether ZYESAMI improves the likelihood of surviving and recovering from COVID-19 respiratory failure. The decision to make that investment by Dr. Fauci and others was made after a detailed review by NIH of our data, including unblinded data from within the AVICOVID trial with special permission of our independent Data Safety Monitoring Committee. We were actually not able to see the data that NIH was allowed to see at the time NIH decided to invest in ACTIVE-3b because we were still blinded at that point. FDA has asked for more data, large federally-supported trials are underway to generate those data, and we are committed to delivering those data and other information that may emerge to FDA as quickly as we can.

We, together with some of the nation’s leading statistical consultants and regulatory law firms, believe we have demonstrated that ZYESAMI is safe and meets the legal standard of “May be Effective.” The FDA does not agree that the legal standard has been met based upon the data FDA has reviewed so far. Our path forward is to bring the FDA more data. We are determined to satisfy the regulatory requirement and continue to believe that we will do so. That said, any trial can fail, no matter how likely we believe it may be to succeed. Remember that if a trial is conducted at a study power of 80% (the common standard), there is a 20% chance that the trial will fail to detect efficacy, even if the drug is actually effective. That’s what statisticians call a “Type II error.” You can easily demonstrate that to yourself at home. Pick up a die that has the number one on it. You know that if you throw the die 6000 times, it will almost certainly come up “one” on 1000 of those throws. However, if you throw the die six times, it may or may not show you a one on those six throws. Clinical trial statistics are based on similar principles and probabilities cannot be confused with certainties.

We will continue to supply FDA with additional data in support of drug approval for ZYESAMI. We do not believe we saw the “world’s biggest placebo effect” because the 2-fold increased odds of survival for patients treated with ZYESAMI was observed in a placebo-controlled, double-blind study. I made that comment in an interview about “the world’s biggest placebo effect” before we had randomized, placebo-controlled data, and at the time, I was commenting on the dramatic survival and recovery benefit seen in the Houston Methodist open-label study. You may review the information from our trials in our Breakthrough Therapy Designation request posted on our website and form your own conclusions.

Biotechnology development has extraordinary potential to save lives but also has well-known risks, as disclosed in our public filings.

Thank you for following our journey.

Jonathan

https://www.nrxpharma.com/ceo-update-zyesami-aviptadil-next-steps/

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