How an Agile Company Addressed the Pandemic: Moving from Psychiatric Medicines to a COVID-19 Therapeutic

NeuroRx was founded to develop novel psychiatric medicines based on seminal research on the role of the NMDA receptor in psychiatric illness. However, the COVID-19 pandemic put enrollment in a phase III trial on hold. During that pause, the company pursued a potential treatment for COVID-19 based on the natural peptide VIP. VIP has demonstrated promising early results in phase II/III clinical trial for critically ill COVID-19 patients, and we hope that this drug candidate will prove to be an effective therapy for COVID-19 and other lung diseases. Simultaneously, we are excited to get back into the clinic with our game-changing treatment for bipolar disorder patients with acute suicidal ideation and behavior.

Pandemic Causes Shift from Psychiatric to Lung Disease Treatments

Many people with bipolar disorder also suffer from acute suicidal ideation and behavior (ASIB). For that reason, people with bipolar disorder, particularly those with ASIB, are at particular risk if treated with traditional selective serotonin reuptake inhibitor (SSRI) antidepressants and have been excluded from clinical trials for these drugs. In addition, few pharma companies in the first two decades of the 21st century had any interest in developing new psychiatric drugs. As a result, the only treatment available for suicidal bipolar depression was electroshock (electroconvulsive) therapy (ECT). 

NeuroRx was founded in 2015 to develop new therapies for psychiatric disorders based on research by Professor Daniel Javitt (my brother), which focused on the NMDA receptor in the brain. This receptor plays a role in regulating human thought processes in general and depression and suicidality more specifically. Our lead treatment regimen is NRX-100™/NRX-101™, the first sequential drug treatment for bipolar depression in patients with ASIB. 

NRX-100™/NRX-101™ has been awarded breakthrough therapy designation from the U.S. FDA, and NeuroRx was actively enrolling patients in a phase III clinical trial when COVID-19 emerged in March 2020. Out of concern for patient safety, this clinical study was temporarily halted.

In the interim, investors in NeuroRx, the Global Emerging Markets (GEM) Fund, had proposed using the Swiss company Relief Therapeutics, which they had acquired, as a vehicle for taking NeuroRx public. GEM thought it had sold off all of Relief’s assets, but one remained – VIP. This drug was originally discovered by the late Professor Sami Said of Stonybrook University, who found that it showed promise as a treatment for acute respiratory distress syndrome (ARDS). VIP had also been studied by Mondo Biotech (a precursor to Relief) and Biogen as a treatment for various lung diseases (e.g., sarcoid, pulmonary hypertension, pulmonary fibrosis), but Said’s original work on ARDS was never pursued.

That changed when Yves Sagot at Relief pointed out to NeuroRx that COVID-19 lung injury was believed similar to lung injury in ARDS, and thus VIP could be relevant for the treatment of patients with SARS-CoV-2 infections. With the phase III NRX-100™/NRX-101™ trial on hold, we switched gears and focused on VIP.

As a result, if proven effective as a treatment for COVID-19, there is a huge opportunity to readily scale the manufacture of RLF-100™ and make it broadly available.

Straight into the Clinic with VIP

Dr. Said’s phase I study was the last time VIP was used intravenously. However, Biogen had established an extensive toxicology file for both intravenous and inhaled VIP, including a six-month study of the toxicity of inhaled VIP in non-human primates. No lethal dose of VIP was ever identified and, as a naturally occurring human peptide, VIP has a remarkable safety profile. 

We satisfied the FDA’s safety questions and quickly received approval from the agency for a phase II/III clinical trial of Aviptadil (RLF-100™), a synthetic form of human VIP, for the treatment of critical COVID-19 with respiratory failure, with the agency granting RLF-100™ Fast Track Designation. NeuroRx was also permitted to produce aviptadil in a formulating 503B pharmacy instead of a traditional GMP manufacturer, making it possible to start treating patients within ten weeks rather than 10 months.

The first patients were treated on May 15, and within two weeks we were receiving reports from different investigator sites about the rapid recovery of patients from respiratory failure in days. Nine patients out of the first 21 who were treated not only experienced rapid recovery, but also rapid clearing of chest X-rays. After examining data on the first 30 patients, the Data Monitoring Committee identified no safety concerns. An open-label study of patients with COVID-19 and severe comorbidity at Houston Methodist Hospital detected a statistically significant difference in recovery from respiratory failure in critical COVID-19 in those treated with Aviptadil versus a placebo. 

We are eagerly awaiting completion of our double-blind study. We are hopeful that RLF-100™ can be applied as a broad treatment, though we initially focused on patients who were in critical condition without other options — there is still much to learn about the effects of the drug. The FDA has already granted NeuroRx permission to start a phase II/III trial for inhaled use in patients who have slightly less severe symptoms, and we feel it is appropriate to make this drug available to patients under the FDA’s Expanded Access (EA) program. We have also asked the agency to turn the EA approval into an Emergency Use Authorization so that this potentially lifesaving drug can be given to people with a high likelihood of dying.

Handling the Cytokine Storm

The initial positive results of Aviptadil in COVID-19 patients were difficult to explain with the view of VIP as a potent anti-cytokine agent alone. It turns out that the drug works via several pathways.

The primary cause of death in COVID-19 patients is acute respiratory failure. Some investigators, particularly those associated with the development of anti-cytokine drugs, attributed this to cytokine storm, or the massive release of inflammatory cytokines as viral particles infect and then cause rupture of pulmonary epithelium cells.1 However, the initial pathology of COVID-19 respiratory failure is increasingly attributed to alveolar collapse — that is, collapse of the air sacs that comprise the respiratory surface of the lung. That’s what causes the “ground glass” signature of COVID-19 on X-ray. The alveolae of the lung are a bit like soap bubbles: the surface tension of the detergent, in the case the surfactant made in the lung, holds them open. Without the surfactant, the alveola collapse, and the lung cannot oxygenate the blood, which is called “respiratory failure.” 

All of the surfactant in the lung is made by a small population of cells, called alveolar type II (ATII) cells. The SARS-CoV-2 virus binds only to the ATII cells in the lung, because its spike protein recognizes the angiotensin-converting enzyme 2 (ACE2) on the surface of the ATII cell. 

When the SARS-CoV-2 virus binds to the ACE2 receptors of ATII cells, the virus is able to enter the cell and take over its metabolism. Surfactant production is shut down and cytokines are synthesized. The virus then replicates and kills the cell, which ruptures and spreads the virus particles elsewhere in the lung where they cause more damage. This behavior only seems to occur in humans, because the surfactant-producing cells of other mammals lack the ACE2 receptors.

VIP has been protecting the lungs of mammals since the class emerged, and in fact, the amino acid sequences of mouse and human VIP are identical, suggesting that native VIP is evolutionarily optimized. In humans, VIP protects from smoke inhalation and inhaled vomit. Dr. Said published more than 300 papers about the role of VIP in protecting the lungs. Like SARS-CoV-2, VIP also binds to the VPAC1 receptors of ATII cells in the lung, protecting them and the surrounding pulmonary epithelium by blocking cytokines, preventing apoptosis, and upregulating the production of surfactant.2 

The Ideal Therapeutic Against SARS-CoV-2

Further evidence for the importance of VIP in fighting COVID-19 infections was developed by researchers at the Oswaldo Cruz Institute in Rio de Janeiro. They reported that VIP blocks the replication of SARS-CoV-2 in human cell lines, specifically the Calu-3 cell line, which is essentially a human ATII cell. The Brazilian researchers also found that of 25 patients with critical COVID-19, the 13 who died had half the blood level of VIP as did the 12 who lived. 

These findings coupled with our results suggest that VIP is likely to have effects in many places within the body. This COVID-19 therapeutic not only blocks cytokine production; it also blocks replication of the SARS virus itself. In addition, it increases surfactant production through well-understood genetic pathways. Furthermore, it blocks cytopathy (viral killing) of the type II pneumocyte. 

Indeed, much remains to investigate. Many peptides are taken for granted (insulin is a good example); we have only a basic understanding of their mechanisms of action. VIP is no exception. We have learned that, as a treatment for COVID-19, it hits four relevant targets, but we may only be scratching the surface. Our hope is that researchers will return to the laboratory and use more sophisticated genomic and proteomic techniques to elucidate all of the functionality of VIP. 

VIP has been protecting the lungs of mammals since the class emerged, and in fact, the amino acid sequences of mouse and human VIP are identical, suggesting that native VIP is evolutionarily optimized.

Additional Promising Results

In mid-October, top-line results from 45 patients assessed in the open-label prospective study where 21 patients were admitted to an ICU with critical COVID-19 and respiratory failure were treated with RLF-100™ and compared to 24 control patients treated in the same setting. All patients had severe comorbidities that rendered them ineligible for the ongoing randomized controlled phase IIb/III trial being conducted to ascertain the safety and efficacy of RLF-100™, and all patients were deteriorating despite treatment with approved therapies for COVID-19. The patients included in this study were representative of those who are too ill to be included in the clinical trials of any known treatment for COVID-19.

Overall, 81% of RLF-100™–treated patients survived beyond 60 days, compared with 27% of control patients. Patients treated with RLF-100™ demonstrated a ninefold increased probability of survival and recovery from respiratory failure, with a high degree of statistical significance. Importantly, the majority of these patients returned safely to their families

The results suggest that there may be substantial hope to mitigate the attack of the coronavirus on the delicate cells that line the lung with a natural peptide. While the number of patients that were treated at Houston Methodist Hospital is modest, the initial results in our nationwide expanded access program suggest similarly encouraging survival with RLF-100™. We look forward to the topline results from the randomized, placebo-controlled phase IIb/III study before the end of 2020.

Ready Scalability

The production of peptides like VIP via solid-based peptide synthesis costs approximately $6,000 a gram. Using yeast fermentation, however, the price is significantly lower. Synthetic insulin, for instance, currently costs about $200/gram, and insulin is twice as large a peptide as VIP.

As a result, if proven effective as a treatment for COVID-19, there is a huge opportunity to readily scale the manufacture of RLF-100™ and make it broadly available. Owing to its lack of toxicity and low cost of manufacture compared with proprietary biologics, VIP may be uniquely attractive to those focused on global countermeasures against COVID-19. VIP may also be the only candidate in human trials that could be produced at a cost structure that is compatible with the needs of the developing world.

Taking NRX-100™/NRX-101™ Back to the Clinic

As the pandemic starts to come under control, we are hoping to get back into the clinic with our psychiatry portfolio before the end of 2020. NRX-100™/NRX-101™ was developed based on research conducted by Dan Javitt in combination with studies performed by Rob Berman at Yale. 

Dan discovered that phencyclidine (i.e., angel dust), which causes psychosis, binds to the NMDA receptor and is critical to memory function. NMDA directly regulates a calcium ion channel that controls the rate of ideation (formation of new ideas) in the brain. Berman found that ketamine, which reversibly binds to the same receptor, had an unexpected antidepressant effect.4

Ketamine is a challenging drug because it is highly hallucinogenic, neurotoxic, and highly addictive — and it is difficult to control its binding to NMDA. Our goal at NeuroRx was to find a better option. That is when we identified d-cycloserine, an old tuberculosis drug that had previously been shown to be a potent antidepressant. Cycloserine is an NMDA inhibitor, but it has psychomimetic side effects. Treatment with d-cycloserine, therefore, requires administration with an antipsychotic to counteract these unwanted side effects. 

The 5-HT2a receptor is a G protein–coupled receptor and a member of the serotonin family known for its role in mediating certain antipsychotic effects. Lurasidone is a 5-HT2a antagonist that is currently approved as an antipsychotic and for use in bipolar depression. Laboratory studies have shown that Lurasidone and other 5-HT2a antagonists have an unexpected synergistic effect with d-cycloserine, potentially enhancing the antidepressant effect while minimizing the potential psychomimetic (hallucinations) side effects. A phase II human study has shown results consistent with this finding.

Dan realized that many antidepressants cause suicidal thoughts because they cause akathisia in 10–15% of patients. He was the first to discover the synergy between NMDA and 5-HT2a-blocking drugs. Ketamine, a potent NMDA blocker, stabilizes these acutely suicidal patients in hours.

NRX-101™’s proprietary combination of d-cycloserine and Lurasidone is designed to be administered orally, daily for approximately six weeks following an initial, single infusion of ketamine (NRX-100™). We believe that this regimen may offer an oral, outpatient treatment with the potential to significantly extend ketamine’s antidepressant/anti-suicidal effect, which could be game-changing.

Versatile Team 

Our experience during the COVID-19 pandemic, in which we applied our same core skill set proven in development of a psychiatric drug to focus on a therapeutic against COVID-19, demonstrates that we at NeuroRx have built an incredibly versatile team. Robert Besthof started out in psychiatry drug development, first at Lilly and then at Pfizer. I met him when he was asked to lead Pfizer Ophthalmology. He went on to lead Pfizer’s entire Neuroscience and Pain Division. Ellis Wilson, who leads our clinical development team, spent years in psychiatry drug development before leading COVID-19 studies for PPD. All those involved in the company were able to get up to speed on a new program quickly. They have demonstrated an appetite for taking on hopeless diseases, and their chief rewarded lies in benefitting patients.

Our corporate motto is taken from a first century philosopher and rabbi, who famously said: “The day is short, the work is endless, the wages are meager, the workers are inadequate, and the Master of the House is knocking on the door.” 


  1. Song, Peipei, et al. “Cytokine storm induced by SARS-CoV-2.” Clin. Chim. Acta. 509: 280–287 (2020). 

  2. Said, Sami. “Vasoactive intestinal peptide in the lung.” Ann. N.Y. Acad. Sci. 527: 450~464 (1988).

  3. Javitt, Daniel C. “Glutamatergic theories of schizophrenia.” Isr. J. Psychiatry Related Sci. 47: 4–16 (2010).

  4. Berman, Robert M., et al. “Antidepressant effects of ketamine in depressed patients.” Biol. Psychiatry. 47: 351–353 (2000).

Jonathan C. Javitt, M.D., M.P.H.

Dr. Javitt has played leadership roles in seven successful healthcare IT and biopharma startups with public exits. He has additionally led drug-development engagements for Merck, Allergan, Pharmacia, Novartis, and Pfizer. He was appointed to healthcare leadership roles under Presidents Reagan, George H.W. Bush, Clinton, and George W. Bush. In the latter role, he was commissioned to lead the White House policy for universal adoption of Health IT and establishment of the Office of the National Coordinator. He is a graduate of Princeton University, Cornell University Medical College, Harvard School of Public Health, the Wills Eye Hospital, and Johns Hopkins Medical School. Dr. Javitt has published more than 200 scientific works in the areas of health outcomes and pharmacoeconomics that have been cited by more than 16,000 people.