Type: A synthetic human vasoactive intestinal polypeptide (VIP). VIP is known to reduce inflammation in the lungs by inhibiting inflammatory cytokines and protecting the alveolar type II cells that are believed to be an entry route for the SARS-CoV-2 to invade the lungs.
2022 Status: New, Narrower EUA Submitted: NRx said January 5 that it submitted an application for Emergency Use Authorization (EUA) to the FDA for the use of ZYESAMI® in patients with Critical COVID-19 who are at immediate risk of death from Respiratory Failure despite treatment with approved therapy including Gilead Sciences’ Veklury® (remdesivir) and who are ineligible for enrollment into the ongoing ACTIV-3b NIH-sponsored trial.
Included with the new EUA filing was an analysis of Phase IIb/III data of ZYESAMI in patients treated with remdesivir or other approved or authorized medicines for critical COVID-19, conducted by Prof. David Schoenfeld, PhD, of Harvard School of Public Health and Massachusetts General Hospital. The analysis, requested by the FDA, showed that the odds of meeting the original primary endpoint of the trial, being “alive and free of respiratory failure at 28 days” were 2.8-fold higher on ZYESAMI than on placebo. There was a four-fold increased odds of surviving to 60 days.
According to the analysis, patients at highest risk—those on ventilators at time of randomization—showed a 10-fold increased odds of survival after doctors administered ZYESAMI. The most common side effects of ZYESAMI noted were mild to moderate diarrhea and systemic hypotension (low blood pressure), NRx added.
2021 Status: FDA REJECTS EUA APPLICATION—NRx Pharmaceuticals acknowledged November 4 that the FDA declined to issue an Emergency Use Application (EUA) for ZYESAMI™ for critical COVID-19 patients with respiratory failure. The FDA cited what it called insufficient data regarding known and potential benefits of ZYESAMI since NRx had to date reviewed safety in only 131 randomized patients treated with the drug.
NRx said it will attempt to coordinate a review by the FDA of the 150 or more additional patients already treated with ZYESAMI in the NIH’s ACTIV-3b trial. A week earlier, the study’s Data Safety and Monitoring Board found no new safety issues. The company has requested an FDA Type A meeting with agency officials “that will include the experience of physicians who have witnessed the effects of our medicine firsthand and the experience of patients who are alive today because they were given one last chance at life.”
NRx Chairman and CEO Jonathan Javitt, MD, MPH, said in a statement that ZYESAMI had shown “a high degree” of safety and a two-fold increase in the odds of surviving the ICU, adding that patients treated at the nation’s top hospitals with ZYESAMI had a four-fold increase in odds of survival.
Commercial Supply Updates—NRx said October 12 that it submitted a revised Investigational New Drug module on the manufacturing of ZYESAMI™ to the FDA. The module confirmed that Nephron Pharmaceuticals is prepared to supply ZYESAMI on a commercial scale.
NRx also said it had been notified that a European QP (Qualified Person) Auditor has completed an inspection at a separate manufacturing facility with no adverse findings. The audit was completed in preparation for submission of European Union-standard ZYESAMI to the EU and U.K. regulators.
Improved One-Year Survival—On September 27, NRx said that topline data from a Phase IIb/III trial showed improved outcomes at one year in highly comorbid patients with COVID-19 who were treated with ZYESAMI™. Topline results showed a statistically significant three-fold advantage in likelihood of being alive at one year post treatment (60% vs. 20%) among those treated with ZYESAMI plus standard of care, compared to those who received the standard of care alone.
The study, conducted between June and September 2020, involved patients with critical COVID-19 whose level of comorbidity excluded them from the randomized phase IIb/III clinical trial of ZYESAMI (NCT04311697). Earlier results from the study showed a statistically significant difference in both survival and recovery from respiratory failure at 28 days. Those findings will soon be published in a peer-reviewed journal, NRx said.
Assignment to ZYESAMI was based on the specific medical team which admitted the patient to the ICU. Once there, all patients were cared for by the same medical team, and according to the same treatment protocols. ZYESAMI is under FDA review for Emergency Use Authorization in patients suffering critical COVID-19 with respiratory failure.
Blood Oxygen Improvement—NRx Pharmaceuticals said August 30 that its Phase 2b/3 clinical trial assessing ZYESAMI™ (aviptadil) in patients with acute Respiratory Failure due to Critical COVID-19 showed improvement in blood oxygen, indicative of improved lung function, within a day of starting treatment. An announcement did not quantify the improvement. The average difference in Respiratory Distress Ratio between those treated with aviptadil and placebo was both clinically meaningful and statistically significant. Moreover, the difference is comparable to that reported a year ago from an open label study at Houston Methodist Hospital by J. Georges Yousef, MD. The analysis also supports NRx’s application for Breakthrough Therapy Designation to the FDA for ZYESAMI, the company added.
Distribution Agreement–NRx Pharmaceuticals (NRx) said August 16 that it signed an agreement with Cardinal Health to provide third party logistics and distribution of ZYESAMI™ (aviptadil) upon potential Emergency Use Authorization (EUA) approval by the FDA. The company submitted an EUA application in May to the FDA for ZYESAMI™ for patients suffering from Critical COVID-19 with respiratory failure.
Cardinal Health Specialty Pharmaceutical Distribution will serve as the exclusive distributor for ZYESAMI, providing broad access to hospitals for the drug upon FDA authorization. Cardinal Health services more than 90% of U.S. hospitals, while its Third-Party Logistics Services (3PL) will support the warehousing and distribution, full order to cash, and necessary title model services.
Cytokine Storm Prevention—NRx Pharmaceuticals said July 19 it was to present data at the Disease Control and Prevention Summit showing a statistically significant effect of Zyesami™ (aviptadil) in preventing the sharp rise in cytokine storm commonly associated with mortality in patients with COVID-19. In the recently-completed Phase IIb/III COVID-AIV trial (NCT04311697), 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.
The anti-cytokine effect of ZYESAMI™ was additionally associated with a significant decrease in 60-day mortality, NRx said. Change in cytokine level was a prespecified endpoint of the study.
Selected for NIH’s ACTIV-3b Trial—Zyesami and Gilead Sciences’ Veklury® (remdesivir) will be evaluated in the NIH’s Phase III ACTIV-3 Critrical Care trial (ACTIV-3b; NCT04843761), the agency said on April 22. ACTIV-3 Critical Care is a master protocol to evaluate the safety and efficacy of drug candidates aimed at improving outcomes for patients with acute respiratory failure related to COVID-19. ACTIV-3 Critical Care allows for sub-studies of different therapeutics to run concurrently. Each sub-study will enroll approximately 640 participants.
For the primary analysis of the trial, participants will be assessed on a six-category ordinal scale 90 days after enrollment, and outcomes will be compared among treatment groups. This scale ranges from recovered and living at home without supplemental oxygen within two weeks of enrollment, to death. Following the assessment at the primary endpoint, participants will receive one additional follow-up at 180 days.
The principal investigator of ACTIV-3 Critical Care is Samuel Brown, MD, of Intermountain Healthcare and the University of Utah, Salt Lake City. ACTIV-3 is supported by two components of the National Institutes of Health, the National Institute of Allergy and Infectious Diseases (NIAID) and the National Heart, Lung and Blood Institute (NHLBI), and is part of the NIH Accelerating COVID-19 Treatment Interventions and Vaccines (ACTIV) public-private partnership.
After Positive Results, EUA Planned — NeuroRx said March 29 that it will apply immediately to the FDA for Emergency Use Authorization (EUA) for Zyesami after releasing 60-day results from the Phase IIb/III COVID-AIV trial (NCT04311697) showing that the drug, which is being developed with Relief Therapeutics, met the study’s primary endpoint for successful recovery from respiratory failure at days 28 and 60 in critically-ill patients with COVID-19. Zyesami also showed a meaningful benefit in survival after controlling for ventilation status and treatment site, NeuroRx said.
NeuroRx said the study’s pre-specified analysis of recovery from respiratory failure was clinically and statistically significant in the 127 patients treated by High Flow Nasal Cannula (HFNC), compared to those treated with mechanical or non-invasive ventilation at tertiary care hospitals. In that group, Zyesami patients showed a 71% chance of successful recovery by day 28 vs. 48% of placebo patients. Zyesami patients also showed a 75% rate of successful recovery by day 60, compared with 55% of placebo patients. Of HFNC patients treated at tertiary medical centers with Zyesami, 84% survived to day 60, compared with 60% of those treated with placebo.
On February 23, NeuroRx said the Phase IIb/III COVID-AIV trial (NCT04311697) of Zyesami (aviptadil, previously RLF-100™) for the treatment of respiratory failure in critically ill patients with COVID-19 has shown 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. The trial was conducted at 10 U.S. hospitals under the direction of NeuroRx and its Swiss partner Relief Therapeutics.
The clinical trial was originally approved as a 28-day study at FDA’s direction. In December, NeuroRx added a 60-day endpoint based on recognizing that the traditional 28-day endpoint adopted in the 1990s for trials in Acute Respiratory Distress Syndrome is not appropriate for critically ill patients with COVID-19, who are frequently maintained in the ICU with advanced technologies well beyond this time point.
At 28 days, patients treated with Zyesami showed 35% higher likelihood of recovery from respiratory failure with continued survival compared to patients treated with placebo. In tertiary care hospitals, Zyesami-treated patients were 46% more likely to recover and return home before day 28. Should those trends continue through day 60, NeuroRx said, it anticipated filing a request for Emergency Use Authorization in critically ill patients on High Flow Nasal Oxygen) who have exhausted all currently approved treatments.
NeuroRx and Relief Therapeutics reported positive preliminary results February 9 on a secondary endpoint in their Phase IIb/III COVID-AIV study assessing intravenous Zyesami in patients with critical COVID-19 with respiratory failure. The study showed that patients who were treated with the maximal standard of care– High Flow Nasal Cannula (HFNC) therapy and mechanical ventilation—plus Zyesami were discharged a median five days earlier from the hospital compared to those treated with placebo plus maximal standard of care. The largest difference observed was among those treated with HFNC, who experienced a median of 11 fewer days in hospital (15 vs. 26).
“We expect to discuss with the [FDA] and other regulatory authorities the submission of an Emergency Use Authorization (EUA) so that ZYESAMI can be available for treating this population that is at immediate risk of death and for which there is no approved therapy,” said Jonathan Javitt, MD, MPH, CEO of NeuroRx.
However, NeuroRx and Relief acknowledged that differences in patient survival were not seen at day 28–patients are being followed through day 60—and that the study had not identified an overall difference in the primary endpoint of recovery from respiratory failure from summary data.
“Investigators are in the process of confirming the timing of each case of recovery from medical records, following which the study’s investigators’ committee will review each case prior to patient-level unblinding of this endpoint. Those data are expected within a few weeks,” NeuroRx stated.
NeuroRx, Relief, and the Quantum Leap Healthcare Collaborative of San Francisco said January 11 that NeuroRx and QLHC agreed to include Zyesami in the Phase II I-SPY COVID-19 trial (NCT04488081). Quantum Leap sponsors the 1,500-participant trial, designed to assess multiple drugs for the treatment of patients with critical COVID-19 who are hospitalized or in intensive care units. Zyesami will be included as one of the first drugs targeting respiratory failure in critically ill COVID-19 patients.
2020 Status: NeuroRx on December 14 announced a $500-million merger with Big Rock Partners Acquisition Corp., in a deal expected to close in the first half of 2021. The combined company is expected to trade on Nasdaq under the symbol NRXP.
Zyesami is under study in two placebo-controlled ongoing Phase IIb/III trials: The AVICOVID-2 study evaluating inhaled Zyesami in patients with moderate and severe COVID-19 (NCT04360096) and the COVID-AIV study assessing intravenous Zyesami in patients with critical COVID-19 with respiratory failure (NCT04311697). Earlier in December, NeuroRx and Relief said they met the 165 patient enrollment target agreed with the FDA for the COVID-AIV trial, for which NeuroRx and Relief are set to announce topline data in early 2021. NeuroRx plans to bring Zyesami to market later in 2021.
Relief Therapeutics and its U.S. partner NeuroRx said November 24 that more than 175 patients with Critical COVID-19 and respiratory failure who also have a severe comorbidity have now been entered into an FDA-sanctioned Expanded Access Protocol (NCT04453839) with RLF-100 in the U.S. All patients had severe comorbidities (such as organ transplant, recent heart attack, and cancer) that rendered them ineligible for the ongoing randomized, controlled Phase IIb/III trial (NCT04311697), designed to assess the safety and efficacy of RLF-100. All patients were deteriorating despite treatment with approved therapies for COVID-19. Of the 90 patients who have so far reached 28 days of follow-up, 72% survived to day 28, Relief and NeuroRx said.
As reported in a paper posted on the preprint server SSRN, 21 patients treated with RLF-100 under the EAP were compared to 24 control patients treated in the same setting. Only 27% of the control patients, all treated with best available ICU Standard of Care, survived to day 28.
On November 13, Relief and NeuroRx said that 150 patients out of a targeted enrollment of 165 have been enrolled in the ongoing randomized controlled Phase IIb/III trial (NCT04360096) of RLF-100™ (aviptadil) for treating respiratory failure in patients with critical COVID-19. As of that day, no drug-related serious adverse events had been reported. Completion of enrollment is expected “in coming weeks,” the companies said.
While the trial remains blinded, illustrative blinded recoveries from signs of Critical COVID-19 on Chest x-ray within 10 days have been reported by study sites and shared with the study’s Data Monitoring Committee and the FDA. Until the study is unblinded, it cannot be known whether this rapid recovery was more frequent among patients treated with RLF-100 or with placebo, Relief and NeuroRx cautioned.
However, in a 45-patient, open-label prospective study, more rapid recovery was seen among 21 patients treated with RLF-100 than those treated with standard of care with an average of nine fewer ICU days in the RLF-100 treated patients compared to 24 control patients treated with Standard of Care in the same setting, the companies said. Results have been submitted for peer review.
According to results from the topline study announced October 13, 81% of RLF-100-treated patients survived beyond 60 days, compared to 17% of control patients. Patients treated with RLF-100 also showed a nine-fold increased probability of survival and recovery from respiratory failure, with a high degree of statistical significance, Relief and NeuroRx reported. All 45 patients had severe comorbidities that rendered them ineligible for the companies’ Phase IIb/III trial of RLF-100™. All were deteriorating despite treatment with unspecified approved therapies for COVID-19, Relief and NeuroRx said.
Also according to the companies, more than 110 patients with similar severity have been treated nationwide under an FDA-sanctioned Expanded Access Protocol (NCT04453839).
Relief and NeuroRx said September 30 that they contracted with Nephron Pharmaceuticals to manufacture commercial supplies of RLF-100, to ensure that enough drug inventory will be immediately available should the companies’ clinical trials show safety and efficacy.
The companies have also contracted with Bachem Americas to manufacture sufficient RLF-100 drug substance to treat 1 million patients, and with an undisclosed “leading nationwide pharmaceutical logistics partner” to ensure overnight supply to U.S. hospitals, should RLF-100 continue to succeed in clinical trials. The value of all three contracts was not disclosed.
On September 21, Relief and NeuroRx completed their partnership agreement for the commercialization of RLF-100™(Aviptadil) worldwide. Under the agreement—whose value was not disclosed—the two companies agreed to share all profits from sales of RLF-100 for all indications related to COVID-19 and potentially other respiratory indications on a global basis. NeuroRx will lead commercialization in the United States, Canada, and Israel, while Relief will lead commercialization in Europe and the rest of the world.
Profits from sales will be allocated to Relief and NeuroRx on a 50/50 basis in the U.S., Canada, and Israel; 85/15 in favor of Relief in Europe; and 80/20 in favor of Relief elsewhere in the world. NeuroRx agreed to pursue trademarks for RLF-100 in the U.S., Canada and Israel, with Relief doing so in all other territories.
The companies also said they are in the final stages of contracting with a fill/finish manufacturer, along with a national distribution partner. By January 2021, Relief and NeuroRx said, they expect to have manufacturing, distribution, and logistics capacity in place to produce enough RLF-100 to treat 150,000 patients per month. The companies added that they continue to anticipate reporting topline data from the ongoing randomized, double-blinded, placebo-controlled trial of intravenously-administered RLF-100 before the end of 2020. A separate trial of inhalation-administered RLF-100 is slated to begin enrollment “within the coming weeks.”
In August, NeuroRx was granted IND approval to test RLF-100 in a Phase II/III trial (NCT04360096) designed to evaluate inhaled use RLF-100 in patients with moderate and severe COVID-19 in order to prevent progression to respiratory failure. Phase II began with patients hospitalized for severe COVID-19 who do not yet have respiratory failure. Upon promising results seen among inpatients, the trial expanded to Phase III assessment of patients at home with mild and moderate COVID-19 in order to prevent the need for hospital admission.
Jihad Georges Youssef, MD, section chief of General Academic Pulmonary Medicine at the Houston Methodist Hospital, serves as the study’s principal investigator. He also serves as national co-chair for the ongoing randomized controlled trial.
Four days earlier, Relief and NeuroRx said that RLF-100 showed rapid recovery from respiratory failure in the most critically ill patients with COVID-19—those on ventilators and ECMO (extracorporeal membrane oxygenation)—who were treated under FDA Emergency Use IND authorization.
The first report of rapid clinical recovery under emergency use IND was reported in a preprint posted August 2 by doctors from Houston Methodist Hospital The report described a 54-year-old man who came off a ventilator within four days of treatment after he developed COVID-19 while being treated for rejection of a double lung transplant.
Similar results were later seen in more than 15 patients treated under emergency use IND and an FDA expanded access protocol which is open to patients too ill to be admitted to the ongoing Phase II/III COVID-AIV trial (NCT04311697). Patients with critical COVID-19 were shown to have a rapid clearing of classic pneumonitis findings on x-ray, accompanied by an improvement in blood oxygen and a 50% or greater average decrease in laboratory markers associated with COVID-19 inflammation, NeuroRx said.
Clinical findings, the company added, may be based on evidence that VIP inhibits replication of SARS-CoV-2 in human lung cells and immune cells—research that was reported by Brazilian scientists working in a level-4 biocontainment laboratory.
The FDA has granted NeuroRx an Expanded Access Protocol (NCT04453839) for treatment of respiratory failure in COVID-19 with RLF-100. The protocol made RLF-100 available to patients who have exhausted approved therapies and are not eligible for the COVID-AIV trial because of other medical conditions, as well as to pregnant women.
The multicenter randomized placebo-controlled trial aims to enroll 144 patients with COVID-19 who have ARDS and require intensive care with mechanical ventilation. Patients will be randomized to intravenous RLF-100 plus maximal intensive care or placebo plus maximal intensive care. The trial’s primary endpoints will be mortality and index of respiratory distress. The secondary endpoint will include levels of TNFa and multi-system organ failure free days
On July 16, the independent Data Monitoring Committee of the COVID-AIV trial determined that the study should continue until its next scheduled evaluation in four weeks. The data monitoring committee reviewed safety findings from the first 30 patients treated in Fast Track FDA trials of RLF-100 in patients with critical COVID-19 with respiratory failure. The committee noted that as of the review date, RLF-100 had generated no drug-related Serious Adverse Events or other safety concerns that would mandate stopping. The committee also concluded that the study appeared capable of reaching a statistically significant endpoint within its 144-patient sample size.
However, at the committee’s recommendation, the primary endpoint was changed to “alive and free of respiratory failure at 7-10 days” from mortality at 28 days—a change that Relief and ReuroRx said was driven by the general decrease in mortality with advances in treatment for critical COVID-19 and by initial observations in the clinical trial.
On June 24, the FDA awarded its Fast Track designation to NeuroRx for investigating RLF-100 in acute lung injury/acute respiratory distress syndrome associated with COVID-19. The FDA has requested that NeuroRx submit a publicly-available expanded access policy, so that physicians may request RLF-100 for patients who are being treated in hospitals that are not participating in ongoing Phase II/III clinical trials.
Earlier in June, Relief and NeuroRx said the first patients had been treated with RLF-100 at the University of Miami Miller School of Medicine in the Phase II portion of COVID-AIV, designed to assess RLF-100 as a treatment for Acute Respiratory Distress Syndrome (ARDS) in COVID-19 patients on mechanical ventilation.
Relief and NeuroRx are also assessing RLF-100 in the the Phase IIb/III AVINALI trial (NCT04360096), a multicenter randomized placebo-controlled study which also aims to enroll 144 patients with COVID-19 with shortness of breath and early pulmonary symptoms in an effort to slow COVID-19 progression.
Relief Therapeutics and NeuroRx said they are also in talks with clinical trials authorities in the European Union, the United Kingdom, Russia, and Australia.
Relief has cited recent studies suggesting that the type-2 alveolar cells were particularly vulnerable to coronavirus because of cell surface receptors that allow the virus to enter the cell. The type-2 cells are essential to replenishing the pulmonary epithelium and to manufacturing surfactant, which coats the inside of the lung and allows oxygen exchange to occur. Without surfactant, the alveolae do not stay open and blood oxygen drops quickly.
COVID-19: 300 Candidates and Counting
To navigate through the >300 potential therapeutic and vaccine options for COVID-19, GEN has grouped the candidates into four broad categories based on their developmental and (where applicable) clinical progress:
● FRONT RUNNER – the most promising therapeutics/vaccines based on clinical progress, favorable data or both.
● DEFINITELY MAYBE – earlier phases with promising partners, or more advanced candidates in development that have generated uneven data.
● KEEPING AN EYE ON… – interesting technology, attracting notable partners, or both, but preliminary data.
● TOO SOON TO TELL – longshots pending additional experimental and/or clinical data.
GEN has also tagged the most common treatment types: