BioBuzz by Workforce Genetics

NRx Pharmaceuticals Under New Leadership with a Renewed Focus on Bipolar Drug Candidate

Following the recent retirement of Jonathan Javitt in March, Robert Besthof, Head of Operations and Chief Commercial Officer, has taken over as interim chief executive officer of NRx Pharmaceuticals. He said there was a need for a CEO to be based in the U.S. alongside the rest of the team.

Javitt, an adjunct professor at Johns Hopkins and former health care and biodefense advisor to the White House, has been based in Israel alongside his wife, Marcia Javitt, a pioneer in the field of radiology who is director of the Department of Radiology at Rambam Medical Center in Haifa.

Besthof is focused on guiding the company’s experimental drug being developed to treat severe bipolar depression with acute and sub-acute suicidality through clinical trials and to potential commercialization.

Prior to NRx, Besthof was vice president of Global Commercial Development for Neuroscience & Pain at Pfizer, and prior to that he led other multiple specialty disease areas. Before that, he held roles of increasing responsibility at Eli Lilly and Wyeth. Although Javitt stepped away from the role of CEO, he will still play a role in the company. Javitt has assumed a consulting role as the NRx chief scientist, where he will continue to help advance the company’s pipeline.

With the change in leadership, NRx is also seeing a re-focusing of its developmental pipeline, a shift toward the bipolar drug candidate, NRX-101. The drug, which is being developed specifically for bipolar patients with acute (requiring hospitalization) and sub-acute (not requiring hospitalization) suicidality that does not require hospitalization, had been paused due to the COVID-19 pandemic. In a conversation with BioBuzz, Besthof said the company began a registrational study with NRX-101 in 2019 but that was derailed when the pandemic hit the U.S. They couldn’t enroll patients, and the bipolar drug was paused during that time.

Instead, the company focused its efforts on developing the COVID-19 therapeutic aviptadil. However, last month the ACTIV-3b trial was halted based on a recommendation from the Data Safety Monitoring Board. After a review of the collected data, the board said the drug candidate met futility guidelines outlined in the pre-approved analytical plan. Aviptadil, which was also known by the trade name Zyesami, had seen real-world use through the federal Right to Try programs.

In a previous interview with Javitt when he was still at the helm of the company, NRx data from one hospital showed that 17 of 19 COVID-19 patients treated with the medication under the Right to Try program recovered and have since returned to their families. Besthof said the company is waiting to see all of the data from the NIH study but said the company saw a mortality advantage in its own study, although that study did not meet the primary endpoint. He noted that studies in critical COVID-19 are difficult to undertake. Unlike other antivirals, aviptadil was not designed to combat the SARS-CoV-2 virus, although recently published preclinical data indicates that it does inhibit SARS-CoV-2 virus replication. Instead, it targets the injury to the lungs caused by acute respiratory distress syndrome, which is associated with COVID-19.  For this reason, the company is evaluating other respiratory uses for aviptadil in lung treatments such as asthma, COPD, and lung injury due to chemotherapy, as well as applications in non-lung indications.

As NRx sorts through the aviptadil program, it has returned to NRX-101 with renewed interest. Current antidepressants used to treat psychiatric diseases can increase suicidal thoughts and behavior in some patients. Besthof said NRx Pharmaceuticals is committed to developing NRX-101 as a new treatment option for patients with bipolar depression that are also affected by suicidality. He said there is a high unmet need for this patient population.

NRX-101 is an oral, patented, fixed-dose combination product of D-cycloserine and lurasidone. Besthof noted that D-cycloserine exhibits partial NMDA receptor antagonist activity at above specific dosages.  Both components are approved drugs that are not scheduled, as available data has not shown potential for abuse. He noted that’s important due to concerns about substance abuse, especially when there are concerns of suicide in the patients.

“The risk of suicide is very high in the bipolar population, specifically during the depressive phases.  Epidemiological data indicates that 50% or more of individuals with bipolar disorder will have either suicidal ideation or a suicide attempt over their lifetime, and between 12 and 20% succumb to suicide,” Besthof explained.

NRx started a Phase 2 study for patients with bipolar depression and subacute suicidality and later this year, it anticipates launching a Phase 2b/3 study in patients with bipolar depression and acute suicidal ideation and behavior (ASIB), a condition that requires hospitalization of the patient. The FDA awarded NRx Breakthrough Therapy Designation and a Special Protocol Agreement (SPA) for ASIB.  This SPA will allow NRx to see registration with a single study.

Besthof said the company took aim at the bipolar with acute suicidality indication due to a lack of focus on this area. This disorder ends up taking the lives of a significant portion of the estimated 50,000 people in the U.S. that succumb to suicide each year, he said. Virtually all psychiatric studies tend to exclude patients with suicidality. Because of the unmet need and the Phase 2 data that NRx shared with the FDA, they awarded NRx Breakthrough Therapy Designation.

“If you know two people with bipolar, one of them will attempt suicide. If you know five, one of them will likely succeed,” he said. “We’ve built a company around the conviction of helping patients with high unmet needs, and by applying innovative science to known molecules.”