Zyesami (Aviptadil) COVID-19 Therapeutic Description
Zyesami (Aviptadil) is a formulation of synthetic human Vasoactive Intestinal Peptide (VIP), which was first discovered in 1970. NRx was the first to formulate aviptadil (the synthetic form of VIP) for human intravenous and inhaled use under the "Good Manufacturing Practices" standards required by the U.S. FDA and other regulators in 2020.
Because of its lack of toxicity and low cost of manufacture compared to proprietary biologics, VIP may be uniquely attractive to those focused on global countermeasures against COVID-19, says the company.
VIP is known to target the VPAC1 receptor of the alveolar type II (ATII) cell and protect that cell against all manner of injuries, including smoke inhalation, exposure to stomach acid, and exposure to infectious agents. In addition, VIP prevents apoptosis, blocks cytokines, lowers TNFα levels, reverses CD4/CD8 ratio, and reduces cough and dyspnea in nonclinical and clinical studies.
Although first identified in the intestinal tract, VIP is now known to be produced throughout the body and primarily concentrated in the lungs. In addition, VIP has been shown in more than hundreds of peer-reviewed studies to have potent anti-inflammatory/anti-cytokine activity in animal models of respiratory distress, acute lung injury, and inflammation, says the company.
Zyesami (Aviptadil) COVID-19 Therapeutic has received orphan drug designation from the US Food and Drug Administration (FDA) in acute respiratory distress syndrome, chronic lung diseases, and for the treatment of sarcoidosis. In June 2020, the FDA awarded a Fast Track Designation to NRx for the use of aviptadil for the treatment of Acute Lung Injury/Acute Respiratory Distress Syndrome associated with COVID-19.
Additionally, the U.S. FDA has approved an expanded access protocol for the use of RLF-100 in patients with Critical COVID-19 and Respiratory Failure. RLF-100 remains an investigational drug in clinical trials. The purpose of this expanded access program is to serve patients with a life-threatening need who don’t qualify for or cannot access the FDA phase 2/3 clinical trials currently underway. Patients will be treated with 12-hour infusions of RLF-100 at ascending doses of 50/100/150 pmol/kg/hr on 3 successive days.
"As we continue to identify the beneficial effects of VIP in treating various respiratory disorders, development of a convenient dosing method that offers multi-year stability at room temperature is key to meeting the needs of patients," added Jonathan Javitt, M.D., MPH, CEO and Chairman of NRx, in a press statement issued on August 4, 2021.
"With the conclusion of the analysis of primary and secondary endpoints, we are able to focus on prespecified endpoints that confirm the mechanism of action," stated Prof Jonathan Javitt, M.D., MPH, Chairman and CEO of NRx, on August 30, 2021. "This latest analysis provides confirmatory evidence that aviptadil improves the lung's ability to transmit oxygen within a day of initiating treatment. The benefit was seen across all patients, all baseline severities, and all types of hospitals. We believe this new finding illustrates ZYESAMI's mechanism of action in a placebo-controlled trial and supports our application for Breakthrough Therapy Designation to the U.S. FDA."
Switzerland-based RELIEF THERAPEUTICS Holding AG, a biopharmaceutical company, developed the compound RLF-100™ (aviptadil).
Radnor, PA-based NeuroRx, Inc. is developing innovative therapies for high-mortality unmet needs. NeuroRx has signed an agreement to complete a business combination with Big Rock Partners Acquisition Corporation.
Zyesami (Aviptadil) COVID-19 Therapeutic Indication
Zyesami (Aviptadil) COVID-19 Therapeutic is used to treat SARS-CoV-2 infections known to cause Respiratory Failure, which is the hallmark of Acute COVID-19, as defined by the new NIH/FDA classification. Approximately 50% of those who develop Critical COVID-19 die, despite intensive care and mechanical ventilation.
Patients with Critical COVID-19 and respiratory failure, currently treated with high flow nasal oxygen, non-invasive ventilation, or mechanical ventilation, will be treated with RLF-100 (Aviptadil). The ability to deliver VIP directly to the lung via inhalation could have important therapeutic implications and potentially broaden the application to patients less severely affected with COVID-19, says the company.
Separately, the National Institutes of Health conducts a confirmatory trial that randomizes patients with COVID-19 respiratory failure to ZYESAMI vs. Veklury® (remdesivir) and placebo in a factorial design trial (NCT04843761). In addition, a second nationwide trial to determine if similar benefits may be achieved in critically ill patients with inhaled ZYESAMI™ is being conducted on the I-SPY platform, maintained by the Quantum Leap Healthcare Collaborative.
Zyesami (Aviptadil) Treatment Side Effects
No unexpected side effects were identified as of February 9, 2021. The most common side effects of ZYESAMI in the clinical trial were mild to moderate diarrhea (seen in 30% of ZYESAMI-treated vs. 1.5% of placebo-treated patients) and systemic hypotension (low blood pressure) seen in 31 ZYESAMI-treated patients vs. 25 placebo patients.
Zyesami (Aviptadil) COVID-19 Therapeutic Production
NRx confirmed on August 16, 2021, the development of the first shelf-stable formulation of ZYESAMI, which was announced in early Q3'21, along with engagement in scaling up aviptadil drug substance from 100,000 doses per manufacturing batch to a projected 3 million doses per batch, combined with a 90% reduction in cost per gram of aviptadil drug substance.
Zyesami (Aviptadil) COVID-19 Therapeutic Distribution
NRx finalized and announced its logistics and drug distribution contract with Cardinal Health, Inc., and a drug launch and commercialization support agreement with IQVIA, Inc. Cardinal Health Specialty Pharmaceutical Distribution will serve as the exclusive distributor for ZYESAMI. Cardinal Health services more than 90% of hospitals in the USA. Additionally, Cardinal Health's Third-Party Logistics Services will support the warehousing and distribution, full order to cash, and necessary title model services.
Zyesami (Aviptadil) COVID-19 Therapeutic News
September 10, 2021 - NRX Pharmaceuticals, Inc. Form S-1 (Form 8-K) relevant excerpts.
August 30, 2021 - NRx Pharmaceuticals (Nasdaq: NRXP) announced an additional finding in its phase 2b/3 clinical trial investigating ZYESAMI™ (aviptadil) for the treatment of patients with Acute Respiratory Failure due to Critical COVID-19. NRx's new analysis shows that patients treated with ZYESAMI demonstrated improved blood oxygen, indicating improved lung function, within a day of treatment. The average difference in Respiratory Distress Ratio between those treated with aviptadil and placebo was clinically meaningful and statistically significant. This latest analysis also supports NRx's application for Breakthrough Therapy Designation to the U.S. FDA for ZYESAMI.
August 24, 2021 - NRx Pharmaceuticals (Nasdaq: NRXP) announced the gross proceeds from the private placement were $30 million before deducting placement agent fees and other offering expenses.
August 19, 2021 - NRx Pharmaceuticals announced that it has entered into definitive agreements with investors to purchase common and preferred stock shares in a private placement. The gross proceeds from the private placement are expected to be approximately $30 million before deducting placement agent fees and other offering expenses. The private placement is expected to close on or about August 23, 2021, subject to the satisfaction of customary closing conditions. "The proceeds of this investment will be targeted towards accelerating the forward path of our CNS/psychiatry franchise and COVID vaccine franchises, together with supporting the transition of ZYESAMI from clinical to the commercial stage as regulatory approval is obtained from national regulators," said Jonathan C. Javitt, M.D., MPH, CEO, and Chairman of NRx Pharmaceuticals.
August 18, 2021 - NRx Pharmaceuticals provided a safety update on ZYESAMI™ (aviptadil) 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. 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.
August 16, 2021 - NRx Pharmaceuticals (Nasdaq: NRXP) provided a business update and financial results for the quarter ended June 30, 2021. Primary clinical activities during the quarter centered around the analysis and regulatory filing of data from the phase 2b/3 trial of intravenous ZYESAMI™ for COVID-19 Respiratory Failure, support of the NIH-sponsored ACTIV3b Critical Care study of ZYESAMI compared to Veklury (remdesivir) alone and in combination, support of the BARDA-sponsored I-SPY trial of inhaled ZYESAMI, and the NRx-sponsored trial of inhaled ZYESAMI.
August 4, 2021 - NRx Pharmaceuticals announced it had signed an agreement with MannKind Corporation to develop a dry powder formulation of ZYESAMI™ (aviptadil), a synthetic form of human Vasoactive Intestinal Peptide (VIP), produced by the body to help protect cells against inflammatory conditions. The development will be based on MannKind's proven Technosphere® platform, which is the basis of the US Food and Drug Administration-Approved Afrezza® inhaled insulin product. MannKind Corporation (Nasdaq: MNKD) focuses on developing and commercializing inhaled therapeutic products for patients with endocrine and orphan lung diseases.
July 27, 2021 - NRx Pharmaceuticals announced that the Nation of Georgia’s Prime Minister and Minister of Health had issued an Emergency Use Authorization for intravenous ZYESAMI™ (aviptadil) to treat Critical COVID-19.
July 22, 2021 - NRx Pharmaceuticals Inc. said it had validated the first commercial formulation of Zyesami aviptadil for intravenous use, allowing for high volume manufacture, with an anticipated one year or greater stability, under appropriate storage conditions. The company said it had achieved a 30-to-50-fold increase in its manufactured lot size of aviptadil, with a concurrent 90% reduction in the cost of its peptide supply.
July 19, 2021 - NRx Pharmaceuticals presented data at the Disease Control and Prevention Summit on July 21, 2021, via the following link. The presentation identifies a statistically significant effect of ZYESAMI™ (aviptadil) in preventing the sharp rise in cytokines, commonly associated with mortality in patients with COVID-19. In the recently completed phase 2b/3 trial, patients treated with placebo experienced a statistically significant elevation in interleukin 6 (IL-6) cytokine levels, whereas those treated with ZYESAMI™ had a minimal increase in IL-6. Change in cytokine level was a prespecified endpoint of the study.
June 2, 2021 – RELIEF THERAPEUTICS Holding AG, a biopharmaceutical company with its lead compound RLF-100™ (aviptadil), reported today that its collaboration partner, NRx Pharmaceuticals, Inc. has announced that it has submitted an application to the U.S. Food and Drug Administration seeking Emergency Use Authorization (EUA) for the use of aviptadil in the treatment of critical COVID-19 in patients with respiratory failure.
June 1, 2021 - NRx Pharmaceuticals announced it had filed an application with U.S. Food and Drug Administration (FDA) requesting Emergency Use Authorization (EUA) for ZYESAMI™ (Aviptadil-acetate) to treat Critically Ill COVID-19 patients suffering from respiratory failure. Consistent with previously announced top-line data, the study identified a statistically significant increase in the likelihood that patients treated with ZYESAMI™ would be alive and free of respiratory failure at 60 days, compared to those treated with placebo, and identified a significantly shorter median hospital stay. The clinical study report filed with FDA further documents statistically significant advantages for ZYESAMI™ on all major secondary endpoints.
April 26, 2021 - Dosing of the first patient in phase 3 clinical trial of ZYESAMI (aviptadil acetate) was announced by the National Institutes of Health (NIH). Dr. Anthony Fauci elaborated on the need for new COVID-19 therapeutics and discussed this trial in a White House press briefing on April 23, 2021.
April 6, 2021 - NeuroRx, Inc. reported that Aviptadil, supplied by NeuroRx, was identified by the National Institutes of Health for inclusion in phase III clinical trial in the USA and multiple foreign countries.
March 29, 2021 - NeuroRx, Inc. reported 60-day results of the Phase 2b/3 trial of intravenously administered ZYESAMI™ (aviptadil acetate) to treat respiratory failure in critically ill patients with COVID-19, which is being developed in collaboration with Relief Therapeutics Holding AG (RLFTF). Across all patients and sites, ZYESAMI™ met the primary endpoint for a successful recovery from respiratory failure at days 28 (P = .014) and 60 (P = .013) and also demonstrated a meaningful benefit in survival (P = < .001) after controlling for ventilation status and treatment site.
March 9, 2021 - NeuroRx, Inc. and TFF Pharmaceuticals, Inc. announced that the companies have entered into a feasibility and material transfer agreement (Feasibility Agreement). Under the Feasibility Agreement, NeuroRx is delivering ZYESAMI™ (aviptadil, synthetic VIP) materials to TFF to perform feasibility formulation work and testing. This feasibility work aims to formulate and identify an optimal, long-term stable formulation of ZYESAMI™ into a dry powder form with superior aerosol properties for delivery directly to the lungs. “The work being done by the NeuroRx team with ZYESAMI on behalf of critically ill patients with COVID-19 respiratory failure is both remarkable and gratifying,” said Glenn Mattes, President & CEO of TFF Pharmaceuticals. “The potential opportunity to bring this important new therapy for patients earlier in the treatment cycle is exciting."
February 23, 2021 - NeuroRx, Inc. announced that the Phase 2b/3 trial* of ZYESAMI™ (aviptadil, previously RLF-100™) for the treatment of Respiratory Failure in critically ill patients with Covid-19 had demonstrated multidimensional benefit around its prespecified primary endpoint of Recovery from Respiratory Failure with discharge from hospital and ICU (without relapse) by day 28 in patients with critical Covid-19 who were treated with High Flow Nasal Oxygen. Although not envisioned at the start of the clinical trial, high-flow nasal oxygen has become the predominant form of treatment in Covid-19 respiratory failure. Mechanical ventilation is reserved for those whose blood oxygen levels cannot be maintained on this less invasive modality. The trial was conducted at 10 U.S. hospitals under the direction of NeuroRx in collaboration with RELIEF THERAPEUTICS Holding AG.
February 23, 2021 - Big Rock Partners Acquisition Corp. filed Form 8-K.
February 9, 2021 - NeuroRx, Inc. reported preliminary results from their Phase 2b/3 trial of ZYESAMI™ (aviptadil, previously RLF-100) in collaboration with Relief Therapeutics Holdings, AG in patients with respiratory failure due to Critical COVID-19. The study showed that patients treated with the maximal standard of care plus ZYESAMI were discharged sooner from the hospital than those treated with placebo plus maximal standard of care. Thus, if authorized for use, ZYESAMI would be the first drug indicated specifically for COVID-19 patients critically ill with respiratory failure.
January 18, 2021 - The Government of India's Subject Expert Committee (SEC) meeting examined COVID-19 related proposals under accelerated approval process made in its 140th meeting held on 18.01.2021 & 19.01.2021 at CDSCO, HQ New Delhi.
December 10, 2020 - Last update: Patients with Critical COVID-19 and respiratory failure who are ineligible for enrollment in NCT04311697, who live more than 50 miles from an existing collaborating research center, or who are already hospitalized and cannot safely be transferred to a collaborating research facility may be considered for expanded access by the sponsor. Treating physicians must complete FDA Form 3396 and receive a letter of authorization from NeuroRx, along with local IRB authorization.
January 11, 2021- NeuroRx, Relief, and Quantum Leap announce the inclusion of ZYESAMI™ (RLF-100™: aviptadil) in the I-SPY COVID-19 Trial. "We at NeuroRx, together with our partners at Relief, are honored to have been selected by Quantum Leap for inclusion in the I-SPY trials platform. This will enable us to gather data on the use of inhaled aviptadil to treat Critical COVID-19 as a complement to data on intravenous aviptadil in the phase 2b/3 trial we are just concluding. We also hope to demonstrate in a second phase 2b/3 trial that aviptadil can be given in a more convenient mode of administration and show benefit in patients who can self-administer inhaled medications," said Jonathan C. Javitt, MD, MPH, CEO and Chairman of NeuroRx.
December 30, 2020 - FDA rejects COVID-19 emergency approval. “The FDA did not agree to grant (emergency use authorization), as applied for in September,” said Jonathan Javitt, the chief executive officer of U.S.-based NeuroRx, Inc., which has partnered with Relief on aviptadil, an older drug that the companies are seeking to repurpose during the pandemic. The company is now calling the drug Zyesami in its formulation against COVID-19.
November 24, 2020 - NeuroRx and Relief announce initial successful results from expanded access use of RLF-100™ (aviptadil) in patients with Critical COVID-19 and Severe Comorbidity: 72% survival seen in ICU patients. All patients had severe comorbidities (such as organ transplant, recent heart attack, and cancer) that rendered them ineligible for the ongoing randomized, controlled phase 2b/3 trial to ascertain the safety and efficacy of RLF-100™, and all patients were deteriorating despite treatment with approved therapies for COVID-19. Of the 90 patients who have reached 28 days of follow-up, 72% survived today 28.
August 3, 2020 - According to the companies, the first report of rapid clinical recovery under emergency use was from Houston Methodist Hospital doctors.
August 2, 2020 - Critically ill COVID-19 patients recovered rapidly from respiratory failure after three days of treatment with RLF-100, a therapy granted fast-track designation in the United States, two drug companies said Sunday.
June 9, 2020 - Relief Therapeutics and NeuroRx have expanded the Phase II/III clinical trial of RLF-100 (Aviptadil) to include Covid-19 patients on ventilators, high flow oxygen, and noninvasive ventilation (CPAP).
Zyesami (Aviptadil) COVID-19 Therapeutic Clinical Trials
Zyesami (Aviptadil) COVID-19 Therapeutic continues to be tested in clinical trials.
Inhaled ZYESAMI™ (Aviptadil Acetate) for the Treatment of Severe COVID-19.
Intravenous Aviptadil for Critical COVID-19 With Respiratory Failure (COVID-AIV).