Once critical and hopeful COVID-19 treatment reaches futility

With the COVID-19 pandemic well into its third year, doctors have limited options for treating critically ill patients – and now they will have one less option. ZYESAMI, (aviptadil), reviewed by NRx Pharmaceuticals, failed an exam conducted by the Data Safety and Monitoring Board (DSMB), with the board recommending that the arm of the trial cease.

The ACTIV-3b trial began in April 2021 and was designed to determine the effectiveness of certain COVID-19 treatments. The National Institute of Allergy and Infectious Diseases (NIAID), part of the US National Institutes of Health (NIH), sponsored and managed the study.

The phase III trial consisted of critically ill patients with COVID-19. In a control arm, patients received aviptadil, a corticosteroid, as monotherapy and in combination versus placebo. It has been tested against several other experimental drug combinations, including a combination of aviptadil and Gilead’s antiviral remdesivir.

The primary endpoint of the study was patient recovery, measured by the need for supplemental oxygen. Patients were measured on a six-point scale ranging from being home with supplemental oxygen to worst-case scenario of death.

As part of the study, the DSMB safety and effectiveness reviewed given at least once a month. When the study was last reviewed on Wednesday, the DSMB measured 460 patients enrolled in the trial. Since about 75% of the patients had already reached the end of the 90-day period of the trial, reviewers knew the study was close to missing its primary endpoint.

A secondary endpoint, patient mortality, was also of concern. The aviptadil group of patients experienced mortality rates of 37%, while the placebo group had a mortality rate of 36%.

The DSMB recommended that the NIH stop the evaluation of aviptadil because of its futility.

There have been no safety issues with aviptadil. Even though the drug was not effective in treating critical COVID-19, the known side effects – diarrhea and hypotension – were well managed.

“We thank the NIH and Trial Leadership for their extensive work in studying Zyesami® (aviptadil). We will continue to work closely with them to better understand the data over the coming months. This will also allow us to evaluate options for Zyesami ® in lung protection in other respiratory disorders, as well as its potential in other therapeutic areas,” said Robert Besthof, Acting CEO of NRx Pharmaceuticals. “Critical COVID-19 remains a very high unmet need associated with significant mortality.”

Aviptadil is a synthetic form of human vasoactive intestinal peptide (VIP), which reduces lung inflammation and protects type II alveolar cells, thought to be one of the ways SARS-CoV-2 enters the lungs .

In June 2020, aviptadil was granted United States Fast Track Designation Food and drug administration for the treatment of respiratory distress in COVID-19. In 2001, the FDA granted avipdatil orphan drug designation for the treatment of acute respiratory distress syndrome. In 2005, the FDA granted it orphan drug designation, this time for the treatment of pulmonary arterial hypertension.

After the disappointing news, NRx said it would focus its attention on another drug, NRX-101.

“Our corporate goal remains to apply innovative science to known molecules to address very high unmet needs. We have a flexible infrastructure that allows us to focus our resources on our Breakthrough Therapy Designation drug. NRX-101. We are already actively recruiting patients into our Phase II study in bipolar depression,” Besthof said.

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