A core goal of the Joint Science and Technology Office (JSTO) for Chemical and Biological Defense (CBD) is [to] enable the Warfighter to operate effectively within battlefields exposed to chemical and biological (CB) agents and avoid technological surprise. However, rapid growth in technological capabilities and vastly expanded knowledge base are fueling the broadening and accelerating threat agent development. As a result, it is crucial that the JSTO-CBD develop systems capable of rapid medical countermeasure (MCM) development to quash the risk of technological surprise. 

Fortunately, there have been a multitude of technical developments that enable rapid in vitro toxicological assessment, precise structural resolution of novel MCM targets, and high-throughput MCM screening. Artificial intelligence (AI) systems and machine learning (ML) algorithms also hold promise to reduce the need for iterative laboratory-based target and MCM validation but currently lack the large data sets necessary to support predictive drug development. Although each of these technologies have potential to provide utility in and of themselves, there has yet to be an effort to fully integrate these platform technologies into a system of systems, which would enable the discovery of MCMs against novel entities and generate large data sets to support future AI/ML-driven rapid MCM discovery. 

The intent of DOMANE is to bring together teams with diverse technical capabilities and identify an effective workflow that enables integration and rapid resolution of threat agent mechanism of action (MOA), MCM target discovery and MCM development. In doing so, DOMANE will create a broad candidate pipeline (Figure 1), which in turn will facilitate drug development against priority CB threats. 

The fast-growing list of possible treatments for the novel coronavirus includes an unlikely candidate: famotidine, the active compound in the over-the-counter heartburn drug Pepcid. On 7 April, the first COVID-19 patients at Northwell Health in the New York City area began to receive famotidine intravenously, at nine times the heartburn dose. Unlike other drugs the 23-hospital system is testing, including Regeneron’s sarilumab and Gilead Sciences’s remdesivir, Northwell kept the famotidine study under wraps to secure a research stockpile before other hospitals, or even the federal government, started to buy it. “If we talked about this to the wrong people or too soon, the drug supply would be gone,” says Kevin Tracey, a former neurosurgeon in charge of the hospital system’s research.

As of Saturday, 187 COVID-19 patients in critical status, including many on ventilators, have been enrolled in the trial, which aims for a total of 1174 people. Reports from China and molecular modeling results suggest the drug, which seems to bind to a key enzyme in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), could make a difference. But the hype surrounding hydroxychloroquine and chloroquine—the unproven antimalarial drugs touted by President Donald Trump and some physicians and scientists—has made Tracey wary of sparking premature enthusiasm. He is tight-lipped about famotidine’s prospects, at least until interim results from the first 391 patients are in. “If it does work, we’ll know in a few weeks,” he says.

A globe-trotting infectious disease doctor named [Dr. Michael Vincent Callahan (born 1962)] was the first to call attention to the drug in the United States. Callahan, who is based at Massachusetts General Hospital and has extensive connections in the biodefense world, has spent time in disease hot zones around the world, including the 2003 outbreak of another coronavirus disease, SARS, in Hong Kong. In mid-January, he was in Nanjing, China, working on an avian flu project. As the COVID-19 epidemic began to explode in Wuhan, he followed his Chinese colleagues to the increasingly desperate city.

The virus was killing as many as one out of five patients older than 80. Patients of all ages with hypertension and chronic obstructive pulmonary disease were faring poorly. Callahan and his Chinese colleagues got curious about why many of the survivors tended to be poor. “Why are these elderly peasants not dying?” he asks.

In reviewing 6212 COVID-19 patient records, the doctors noticed that many survivors had been suffering from chronic heartburn and were on famotidine rather than more-expensive omeprazole (Prilosec), the medicine of choice both in the United States and among wealthier Chinese. Hospitalized COVID-19 patients on famotidine appeared to be dying at a rate of about 14% compared with 27% for those not on the drug, although the analysis was crude and the result was not statistically significant.

But that was enough for Callahan to pursue the issue back home. After returning from Wuhan [(when did he return?)], he briefed [Robert Peter Kadlec (born 1957)], assistant secretary for preparedness and response at the Department of Health and Human Services, then checked in with [Dr. Robert Wallace Malone (born 1959)], chief medical officer of Florida-based Alchem Laboratories, a contract manufacturing organization. Malone is part of a classified project called [DOMANE  ( "Discovery of Medical Countermeasures Against Novel Entities" , created by the Defense Threat Reduction Agency  in Dec of 2019 )] that uses computer simulations, artificial intelligence, and other methods to rapidly identify U.S. Food and Drug Administration (FDA)-approved drugs and other safe compounds that can be repurposed against threats such as new viruses.

[Dr. Robert Wallace Malone (born 1959)] had his eyes on a viral enzyme called the papainlike protease, which helps the pathogen replicate. To see whether famotidine binds to the protein, he would ordinarily need the enzyme’s 3D structure, but that would not be available for months. So Malone recruited computational chemist [Dr. Joshua Pottel (born 1989)], president of Montreal-based Molecular Forecaster, to predict it from two crystal structures of the protease from the 2003 SARS coronavirus, combined with the new coronavirus’ RNA sequence.

It was hardly plug-and-play. Among other things, they compared the gene sequences of the new and old proteases to rule out crucial differences in structure. [Dr. Joshua Pottel (born 1989)] then tested how 2600 different compounds interact with the new protease. The modeling yielded several dozen promising hits that pharmaceutical chemists and other experts narrowed to three. Famotidine was one. (The compound has not popped up in in vitro screens of existing drug libraries for antiviral activity, however.)

“If it does work, we’ll know in a few weeks,” says Northwell Health’s Kevin Tracey, who leads the famotidine study,

With both the tantalizing Chinese data and the modeling pointing toward famotidine, a low-cost, generally safe drug, Callahan contacted Tracey about running a double-blind randomized study. COVID-19 patients with decreased kidney function would be excluded because high doses of famotidine can cause heart problems in them.

After getting FDA approval, Northwell used its own funds to launch the effort. Just getting half of the needed famotidine in sterile vials took weeks, because the injectable version is not widely used. On 14 April, the U.S. Biomedical Advanced Research and Development Authority (BARDA), which operates under Kadlec, gave Alchem a $20.7 million contract for the trial, most of which paid Northwell’s costs.

The study’s draft protocol was aimed only at evaluating famotidine’s efficacy, but Trump’s “game-changer” antimalarial drug was rapidly becoming the standard of care for hospitalized COVID-19 patients. That meant investigators would only be able to recruit enough subjects for a trial that tested a combination of famotidine and hydroxychloroquine. Those patients would be compared with a hydroxychloroquine-only arm and a historic control arm made up of hundreds of patients treated earlier in the outbreak. “Is it good science? No,” Tracey says. “It’s the real world.”

Anecdotal evidence has encouraged the Northwell researchers. After speaking to Tracey, David Tuveson, director of the Cold Spring Harbor Laboratory Cancer Center, recommended famotidine to his 44-year-old sister, an engineer with New York City hospitals. She had tested positive for COVID-19 and developed a fever. Her lips became dark blue from hypoxia. She took her first megadose of oral famotidine on 28 March. The next morning, her fever broke and her oxygen saturation returned to a normal range. Five sick co-workers, including three with confirmed COVID-19, also showed dramatic improvements after taking over-the-counter versions of the drug, according a spreadsheet of case histories Tuveson shared with Science. Many COVID-19 patients recover with simple symptom-relieving medications, but Tuveson credits the heartburn drug. “I would say that was a penicillin effect,” he says.

After an email chain about Tuveson’s experience spread widely among doctors, Timothy Wang, head of gastroenterology at Columbia University Medical Center, saw more hints of famotidine’s promise in his own retrospective review of records from 1620 hospitalized COVID-19 patients. Last week, he shared the results with Tracey and Callahan, and he added them as a co-authors on a paper now under review at the Annals of Internal Medicine. All three researchers emphasize, though, that the real test is the trial now underway. “We still don’t know if it will work or not,” Tracey says.

Callahan has kept busy since his return from China. Kadlec deployed him on medical evacuation missions of Americans on two heavily infected cruise ships. Now back to doing patient rounds in Boston, he says the famotidine lead underscores the importance of science diplomacy in the face of an infectious disease that knows no borders. When it comes to experience with COVID-19, he says, “No amount of smart people at the [National Institutes of Health] or Harvard or Stanford can outclass an average doctor in Wuhan.”

Pepcid: From Poor Man’s Cure to $20M COVID-19 Trial

Remember Hydrocychloroquine?  The drug that doesn’t work for COVID-19?

Well, here’s some good news for you. A crazy rock climber/mountain rescue nut named Michael Callahan and a brilliant group of 3D modelers working nights, weekends and in between, got one that does work. This story reads like a spy novel but it’s true! (As told by Science).

It starts with…. “Inside a hospital in Wuhan, a globetrotting Infectious Disease doctor” … with, shall we say, deep biodefense connections, was examining COVID-19 patients with his Chinese physician colleagues when they noticed that poorer patients were doing better. What turned out to be protective was a cheap OTC drug for heartburn known as Pepcid (Famotidine).

It just turns out that Robert Malone [see Dr. Robert Wallace Malone (born 1959)], a biodefense expert and member of a classified project called DOMANE (hmmm, how do we know that?), was working with the team at MIT Lincoln Labs using artificial intelligence and 3D modeling to rapidly identify FDA-approved drugs that can be repurposed for new viruses. Of course Michael and Robert connected and a trial was swiftly coordinated, with BARDA financial backing of over $20 million USD. Now, based on this recent study, it may save the life of someone you know.

Yes, Pepcid. (Where are the trumpets, damn it!).  But the story is not over yet. Stay tuned for the dénouement. 

Meanwhile, for those of us who neither globe-trotting-spy-doctors nor 3D-DARPA-scientists, but just trying to save people from death and destruction due to COVID-19 with nothing but our wits and bare hands, we have the following WEBINAR to offer you!, Please join us! 

Doctors and scientists are studying many existing drugs with the hope of finding therapies they can repurpose to fight COVID-19. Some of these, like Gilead Sciences’ remdesivir, directly go after the virus SARS-CoV-2, which causes the disease. Others, like Incyte’s ruxolitinib, aim to dampen the overactive immune response that characterizes later stages of disease in COVID-19.

And then there are the oddballs. Take famotidine, the active ingredient in the over-the-counter heartburn drug Pepcid. The histamine-H2-receptor antagonist works by preventing stomach acid production. That it would have any activity in an infectious disease is a bit of a head-scratcher.

Doctors first became interested in famotidine after hearing reports that people in China who took the drug for heartburn were surviving COVID-19, while other people who essentially had the same risk factors but were taking different heartburn drugs like cimetidine or omeprazole (sold in the US as Tagamet and Prilosec, respectively) were dying from the disease. Perhaps famotidine was somehow bolstering these patients and improving their chances for survival.

In early April, doctors began a clinical trial at New York’s Northwell hospitals to test that theory. [See SARS-COV2 famotidine trials (2020)] They reasoned that even if evidence for famotidine’s effectiveness was largely anecdotal, the drug has been around since the 1980s and has a good safety profile. If it worked, it would be a fast and cheap way to ease the symptoms of COVID-19.

They decided to use high doses of intravenous famotidine. Their goal was to enroll 1,200 people with moderate to severe COVID-19 and see if those that got famotidine were less likely to die or require a ventilator. Then, in late April, the first news report about the trial appeared in Science. Boxes of Pepcid began to fly off of pharmacy shelves as people sought out any potential remedy during the pandemic.

Shortly afterward, on May 8, a team, led by Columbia University doctors Daniel Freedberg and Julian Abrams, posted a study on the preprint server medRxiv that compared the outcomes of people with COVID-19 who were prescribed famotidine within 24 hours of being admitted to the hospital to those who didn’t get the heartburn drug. They looked at the records of more than 1,600 patients at Columbia University Irving Medical Center between late February and mid-April. Of those, 84 patients received 10–40 mg of intravenous famotidine daily over the course of about 6 days.

The patients who got famotidine fared better. According to the study, they were far less likely to die or require a ventilator—a twofold decrease in risk—than those not receiving the drug. The results were published in the peer-reviewed journal Gastroenterology later in May (2020, DOI: 10.1053/j.gastro.2020.05.053).

“This is merely an association, and these findings should not be interpreted to mean that famotidine improves outcomes in patients hospitalized with COVID-19,” the team says in a statement. “It is also not clear why those patients who received famotidine had improved outcomes.”

For clarity on famotidine’s effectiveness, the team recommends awaiting the outcome of the trial going on at Northwell hospitals. “Hopefully the results from this trial will determine whether famotidine is efficacious for the treatment of COVID-19,” the team says in its statement.

Meanwhile, in early June, the journal Gut published a small case series of 10 people who developed COVID-19 and reported taking famotidine during their illness (2020, DOI: 10.1136/gutjnl-2020-321852). These people were not sick enough to go to the hospital, but their symptoms, such as cough and shortness of breath, improved within a day or two of taking the heartburn drug. It’s a small study, and the researchers acknowledge that it’s not enough to establish there’s any real benefit from taking famotidine for people who have COVID-19. Those authors recommend a clinical trial with famotidine be carried out with patients with milder disease in addition to the trial going on at Northwell hospitals.

Matthew D. Hall, acting director of biology and group leader, Early Translation Branch, at NIH’s National Center for Advancing Translational Sciences :    "I think there’s going to be some intriguing science trying to draw a connection between the activity—if it is proven to have that in patients—and how it’s actually working in the context of SARS-CoV-2 infection."

But the Northwell trial has slowed for two reasons, says Joseph Conigliaro, the physician who is leading it. Cases of COVID-19 in New York have declined, making it challenging to reach the enrollment requirements for the study.

And shifting treatment approaches have further complicated efforts. When the trial began, COVID-19 patients in New York were getting the antimalarial hydroxychloroquine as part of their treatment regimen. So the study was designed to compare patients receiving hydroxychloroquine and famotidine with patients receiving hydroxychloroquine and a placebo. But that standard treatment regimen has changed, and hydroxychloroquine is no longer given routinely. As a consequence, the researchers are looking to modify the study’s protocol, Conigliaro says.

Until the results of the study are in, Conigliaro can’t say whether famotidine works. “As a physician, I can’t tell people ‘go out and buy famotidine, and if you start getting an inkling of anything start taking it,’ ” he says. Even though the drug has long been considered safe, it’s unclear how to guide people to take it in terms of dose and disease stage. “We need to wait for the results of our trial,” he says.

Scientists are meanwhile trying to figure out why a heartburn medicine might also fight COVID-19. Using computational methods, a group in China used SARS-CoV-2 genes to predict the structures of viral proteins. The group then computationally screened existing drugs to see which could potentially act on those protein targets. Their study suggests that famotidine could inhibit the virus’s 3-chymotrypsin-like protease, which plays a role when the coronavirus makes copies of itself while inside the host (Acta Pharm. Sin. B 2020, DOI: 10.1016/j.apsb.2020.02.008).

Similarly, computational chemists at the scientific software company Molecular Forecaster virtually docked a library of 2,700 existing drugs and nutraceuticals to see which fit into a model of the papain-like protease, another key protein in SARS-CoV-2 replication. They were collaborating with scientists working for a US Department of Defense project called [DOMANE]. Famotidine was one of a few drugs that appeared to interact with the protease in the computational studies, says [Dr. Robert Wallace Malone (born 1959)], a physician and consultant who is on the [DOMANE] team.

But other evidence derails those computational studies. Matthew D. Hall, acting director of biology and group leader, Early Translation Branch, at the National Center for Advancing Translational Sciences (NCATS), part of the US National Institutes of Health, points out that his group did studies in cells that show famotidine doesn’t have any ability to fight SARS-CoV-2. “In a direct antiviral assay, we don’t see any activity for any of the compounds in this class,” he says.

As a drug-repurposing candidate, Hall says, famotidine is attractive because it’s safe, affordable, and accessible. But making further conclusions about its usefulness in COVID-19 will require clinical trial data. If those trials show promise, Hall says, “I think there’s going to be some intriguing science trying to draw a connection between [clinical] activity and how it’s actually working in the context of SARS-CoV-2 infection. Understanding the primary mechanism may also drive long-term development of new therapeutics that are more potent.”

[Dr. Robert Wallace Malone (born 1959)] has been working with a team of scientists to get a better understanding of just how famotidine might be working. Results of his team’s study, which have not yet been peer reviewed, appeared on a preprint server on May 23 (Research Square 2020, DOI: 10.21203/rs.3.rs-30934/v1).

Like the NCATS work, the team’s tests showed that famotidine has no effect on SARS-CoV-2’s papain-like protease, nor does it kill the virus. Instead, Malone and colleagues think the drug is working through its usual target—histamine H2 receptors. Famotidine treats heartburn by blocking H2 receptors, which when activated by histamine stimulate cells in the stomach to secrete acid.

Joseph Conigliaro, chief, General Internal Medicine, Northwell Health :  "As a physician, I can’t tell people ‘go out and buy famotidine and if you start getting an inkling of anything start taking it.’ "

But H2 receptors aren’t just in the stomach—they’re all over the body. Malone and colleagues argue that COVID-19 is disrupting mast cells, which release histamine and other signaling molecules in response to an inflammatory or allergic reaction. These cells can be found at the boundary between tissue and an external environment. They’re on the skin and line the gut and lungs. Malone reasons that mast cells could be responsible for the overactive immune response, often described as the cytokine storm, which does damage to patients with severe cases of COVID-19. By blocking the histamine that mast cells release, famotidine can dampen some of that response.

If famotidine is effective in COVID-19, why isn’t the other commonly used H2 blocker, cimetidine? The answer, Malone claims, comes down to pharmacokinetics: famotidine makes it into the bloodstream more readily than cimetidine.

Adrian M. Piliponsky, an immunologist at Seattle Children’s Research Institute who studies mast cells, says that it’s possible mast cells are playing a role in the inflammatory response to COVID-19. He notes that mast cells play a role in infections with other viruses. He thinks the idea proposed by Malone and colleagues merits further study, and he’s interested in seeing the results of the clinical trial.

[Dr. Robert Wallace Malone (born 1959)] also would like to see a comprehensive trial of famotidine in people who are in the early stages of COVID-19. But he doesn’t think the drug alone will resolve the world’s COVID-19 pandemic. “We’re committed to trying to create an outpatient cocktail of drugs that will significantly reduce morbidity and mortality for COVID-19 and have it ready for deployment in the fall,” he says.

In the meantime, doctors are urging caution for people who might see these early results and rush out to stock up on Pepcid. Carl J. Lavie, medical director of cardiac rehabilitation and prevention at the John Ochsner Heart and Vascular Institute, recently cowrote a letter to the editor of Mayo Clinic Proceedings encouraging doctors to wait for the clinical trial results.

He tells C&EN that it’s premature to recommend famotidine just for COVID-19, but he adds, “I also think that it is benign, so it would seem very reasonable to use for upper GI symptoms now” before giving other heartburn drugs like omeprazole.

1. CORRECTION :   This story was updated on June 16, 2020, to correctly characterize famotidine as a histamine-H2-receptor antagonist, not an agonist.

2. CORRECTION :   This story was updated on June 22, 2020, to correctly identify the group that did a virtual docking study. It was chemists at Molecular Forecaster, not [DOMANE].

FORT BELVOIR, Va. - The COVID pandemic took the world by surprise. Researchers were left scrambling to devise a way to best mitigate the negative impact this disease has on global health. However, at the Defense Threat Reduction Agency (DTRA) it is common to operate in the “what if” space when it comes to potential biological threats. In fact, DTRA investments in technologies that detect, mitigate, or neutralize chemical and biological threats to the military and the nation date back more than 20 years.

“In late 2019, DTRA started a new program called Discovery of Medical Countermeasures Against Novel Entities ([DOMANE]) to address novel and emerging threats,” stated [Dr. David Michael Hone (born 1960)], Chief Scientist within the Vaccines and Therapeutics Division at DTRA. “Based on previous work, we decided DOMANE would not only focus on FDA-approved drugs but also combination therapeutics, as we believe that no single drug will be completely effective in treating new diseases. COVID-19 has provided us an opportunity to test our hypotheses using DOMANE."

DOMANE provides rapid decision-making capabilities to identify FDA-approved drugs that will most likely be effective therapeutics for COVID-19. Repurposing candidate drugs from a pool about 7,500 FDA-approved drugs to advance an effective COVID-19 therapeutic allows for a more rapid response in developing a therapeutic regimen. The end-result is a response that modifies COVID-19 in treated patients and promotes a speedy recovery.

Veklury®, which is more commonly referred to as Remdesivir, is a ribonuclease inhibitor developed by Gilead Sciences. It delivers broad-spectrum antiviral activity and has proven to be a modestly effective therapeutic for the treatment of COVID-19. Originally developed as an Ebola Zaire countermeasure, this DTRA-funded inhibitor transitioned for more advanced testing due to promising pre-clinical trials. Remdesivir inhibits viral replication in a wide variety of pathogens and was one of the first therapeutics identified in the Defense Department for repurposing to treat COVID-19. In the summer of 2020, Remdesivir received authorization for emergency use only in COVID-19 patients with continued FDA oversight.

To complement the modest therapeutic effect of Remdesivir, [DOMANE] also identified Famotidine, a COVID-19 disease modifier from Johnson & Johnson [See SARS-COV2 famotidine trials (2020)]; Pfizer’s Celecoxib, an anti-inflammatory product; and Merck’s Mectizan®, Ivermectin, an antiviral for clinical trials. To learn whether a combination of these FDA-approved drugs is more efficacious than current treatments, DTRA partnered with Quantum Leap Healthcare to conduct a clinical trial. This volunteer trial will evaluate drug combinations in COVID-19 patients who are having difficulty breathing.

DTRA also collaborated with Leidos to develop a new clinical trial prototype to evaluate new drug combinations in two clinical studies: one in COVID-19 patients who have symptoms but are still breathing without assistance and another in COVID-19 that are not displaying any symptoms.

“We believe that the evaluation of additional repurposed drugs in clinical trials will find a successful treatment option and will pave the road toward FDA-approval of a greatly improved therapeutic treatment for COVID-19 patients,” said [Dr. David Michael Hone (born 1960)].

DTRA is committed to supporting global health biosecurity efforts through continued vaccine and therapeutic discovery actions to treat COVID-19, as well as the next biological threat the nation faces.

The Defense Threat Reduction Agency’s (DTRA) Chemical and Biological Technologies Department, in its role as the Joint Science and Technology Office (JSTO), is developing a system-of-systems called DOMANE — Discovery of MCMs (medical countermeasures) Against Novel Entities — an interdisciplinary effort with team members whose expertise include computer science, physics, and medicine. DTRA CB posits that one drug may be insufficient towards countering a threat, so it is developing DOMANE to rapidly identify a combination of drugs to impact the novel biological threat from multiple targets, which may prove effective in promoting a disease-modifying effect to counter the biological threat.

Systems within DOMANE include machine learning, high-throughput screening, in silico predictive tools, cryogenic electron microscopy (cryo-EM), organ-on-a-chip, and other emergent technologies. Machine-learning algorithms greatly reduce the time needed to search vast amounts of data on drugs and diseases. DOMANE is possible, in part, because of research studies that have occurred over the past several decades on biological threat agents and MCMs. The studies resulted in the global availability of a large repository of laboratory and clinical data (“big data”) on how biological threats affect the human body.

The COVID-19 pandemic and the resulting national human and economic toll demonstrate a clear and present vulnerability of the U.S. to emerging and unknown contagious infectious diseases. For Joint Forces on the battlefield, the possibility of illness due to emerging biological threats can impact their mission. Ideally, they should be equipped with the MCMs they need to lessen the influence of emerging biological threats.

DOMANE started in 2019, before the current pandemic, with the goal to shorten the traditional, multi-year timeline for developing MCMs to treat novel diseases. Utilizing drugs already approved by the Food and Drug Administration (FDA), DOMANE will evaluate the feasibility of repurposing them as MCMs to combat emerging threats. Some of the advantages to using FDA-approved drugs are that they are already manufacturable, have well-known toxicological profiles, and can proceed directly to human efficacy or Animal Rule studies. This can reduce or eliminate the time-intensive animal toxicology and human safety studies and enhance current good manufacturing practice to scale up process and ongoing stability assessment.

DTRA-JSTO is testing DOMANE using COVID-19 as a proof of concept to evaluate whether the DOMANE concept can identify drugs that are an effective treatment against the disease. DOMANE has already identified several FDA-approved drugs that can be repurposed to treat COVID-19, and these drugs have shown indications of potential efficacy in numerous case studies.

The next step is setting up randomized clinical trials to fully demonstrate the effectiveness of these repurposed drugs. To do this, adaptive, platform clinical trials will evaluate multiple drug combinations, dosages, and administration schedules performed in parallel. The adaptive nature of the trials enables clinical scientists to react to initial data from the trials. For example, if a drug and its approved dosage are ineffective or are having unanticipated effects, then clinicians can change the dosage or add another drug to the combination to pursue another therapeutic option.

The efficacy of COVID-19 drugs identified by DOMANE will be tested with two inpatient clinical trials and a planned virtual clinical trial. One inpatient trial is evaluating the efficacy of DOMANE-identified drugs for patients with severe, late-stage COVID-19 and the other inpatient trial is assessing the efficacy of drugs in COVID-19 patients newly admitted to hospitals. The virtual clinical trial will include outpatients who are newly diagnosed with COVID-19. Virtual outpatient trials dramatically reduce the cost of clinical trials and offer the Department of Defense (DoD) an opportunity to conduct these studies wherever patients with the disease are located, such as on a military ship or base.

DTRA-JSTO recently held a two-day virtual workshop consisting of subject matter experts in synthetic biology, artificial intelligence and machine learning, organs-on-a-chip, high-throughput screening, microcrystal electron diffraction, cryo-EM, animal model development, and other fields. The goal of the workshop was to bring together a collaborative team with diverse technical capabilities to develop an operational workflow for rapidly discovering MCMs of interest. The workshop included presentations and panel discussions among experts from academia, industry, national laboratories, DoD, and other U.S. government organizations. The workshop identified capability gaps that will need to be addressed as well as collaborative opportunities to advance DOMANE that will begin the process of changing our defense against emerging biological and chemical threats.

The current COVID-19 pandemic has demonstrated the impact of biological diseases on national security and everyday life, which could set the stage for an era when there will be significant temptation for both state and non-state actors to intentionally execute a biological attack to cause pandemic-level devastation. Successful development of DOMANE will produce a discovery and verification engine for identifying MCMs for emerging biological threats. The engine will produce in months, not decades, MCMs ready for pre-clinical and clinical development to protect the Joint Force and the nation against biological threats. With DOMANE, DoD has the capability to fight not only COVID-19 but also diseases that have not yet surfaced, thereby ensuring the maintenance of a strong and lethal force.

POCs: Revell Phillips, Ph.D., l.r.phillips.civ@mail.mil; Dale Taylor, dale.e.taylor4.civ@mail.mil

Summary

• • • The etiology of COVID-19 delayed post-vaccination cutaneous hypersensitivity (COVID Arm) remains unknown. We propose that the observed pathology results from locally activated mast cells triggered by the Spike protein in COVID-19 vaccines (predominately by mRNA-1273). Candidate treatments are proposed based on observed efficacy in COVID-19 patient responses that align with the proposed hypothesis of locally activated mast cells.

    • Messenger RNA (mRNA) and adenoviral vectored COVID-19 vaccines encoding the SARS-CoV-2 Spike protein employ gene therapy technology to express a viral protein in the cells of vaccine recipients. In theory and practice, this strategy elicits cellular and humoral immune responses akin to natural viral infection without co-expression of evolved viral functions that facilitate escape from immune surveillance. However, when an expressed viral protein has intrinsic immunomodulatory activities, then it becomes more than just an antigen.

Delayed post-vaccination cutaneous hypersensitivity, “COVID Arm”, “COVID vaccine arm” [1], or delayed sensitivity reactions (DSR) appears 5 to 9 days after vaccination in 2.1% (312 of 15,210) of vaccine participants receiving the mRNA-1273 SARSCoV- 2 vaccine [2,3]. These reactions are characterized by delayed onset of erythema, induration, and tenderness that resolve over the following 4 to 5 days [2]. Most patients develop the hypersensitivity following the second vaccine dose [4]. These reactions are not limited to the injection site [5]. Cutaneous reactions including urticaria (hives) are also observed at low levels associated with the CoronaVac vaccine [6], BNT162b2 (Pfizer-BioNTech) [1,7], and AZD1222 (AstraZeneca) [7]. The majority of cases are reported following vaccination with mRNA-1273 SARS-CoV-2 vaccine [5,8-10]. Delayed hypersensitivity reactions have been misdiagnosed as cellulitis (a common bacterial skin infection) [11]. Rare immunogenic dermal filler reactions after vaccination have also been reported [12]. In common, these COVID-19 vaccines express a version of the SARS-CoV-2 Spike protein in host cells with differences in dosage and expression levels.

Hypothesis

We posit that expression of functional SARS-CoV-2 Spike protein may activate mast cells in susceptible vaccinees. We propose a pathogenesis model which may account for this form of vaccine reactogenicity (inflammatory response to vaccination). Multiple COVID-19 vaccines include or encode a full-length SARS-CoV-2 Spike protein as a key antigen. By inference of parallel functionality of SARS-CoV-1 Spike protein, the vaccineassociated SARS-CoV-2 Spike protein likely interacts with the Tumor Necrosis Factor alpha (TNF-α)-converting enzyme (TACE), thereby inducing TNF-α production akin to that observed for the wild type SARS-CoV-1 Spike protein [13]. The SARS-CoV-1 Spike protein activates the nuclear factor kappa B (NF-dB) pathway by inducing I-κBα degradation [14]. Supporting this parallel functionality of SARS-CoV-2 and SARSCoV- 1 Spike proteins, elevated TNF-α levels are observed in COVID-19 patients [15]. TNF-α stimulates COX-2 expression [16] resulting in elevated levels of prostaglandin E2 (PGE2) and additional inflammatory molecules [17]. Excessive levels of PGE2 were observed in the urine of COVID-19 patients [17]. Elevated PGE2 levels are likely to locally activate mast cell degranulation cascades [18]. Enrichment of mast cells is not observed histologically [3]; but mast cell enrichment is not required for this model. The localized Spike expression level varies by vaccine (highest for mRNA-1273) and may exceed a minimum activation threshold for individuals who develop COVID arm. This pathogenesis model proposes that the observed delayed cutaneous hypersensitivity results from a self-reinforcing dysfunctional feedback loop of histamine and other inflammatory molecules released from these locally activated mast cells.

Proposed evaluation and treatment options for this hypothesis

Based on this model, it is proposed that celecoxib [17,19] (a COX-2 inhibitor), famotidine [20] (targeting mast cells histamine receptor H2 [HRH2] receptor), cetirizine (targeting mast cells histamine H1 [HRH1] receptor) [21], dexchlorpheniramine (HRH1) [21], montelukast (leukotriene receptor antagonist) [22], and aspirin (mast cell stabilizer and COX-2 inhibitor) [23, 24] treatments may exhibit efficacy for treating COVID-19 vaccine recipients experiencing “COVID Arm”. Antihistamines (including cetirizine and famotidine) [8] have been used to treat a small number of COVID-19 vaccinees with delayed post-vaccination cutaneous hypersensitivity [3,8]. Premedication with H1 and H2 antihistamines followed by montelukast after vaccination has been used in conjunction with Pfizer-BioNTech BNT162b2 vaccine for two health care workers with cutaneous and systemic mastocytosis [25]. By targeting mast cells and COX-2-related pathways, post-vaccination treatment with these agents may provide relief to individuals experiencing the signs and symptoms of delayed cutaneous hypersensitivity reactions.

Acknowledgments

The author acknowledges the Department of Defense (DoD), Defense Threat Reduction Agency (DTRA), and the Joint Science and Technology Office (JSTO) of the Chemical and Biological Defense Program (CBDP) for their support under the Discovery of Medical countermeasures Against Novel Entities (DOMANE) initiative.

Funding

This material is based upon work supported under Air Force Contract No. FA8702-15-D-0001. Any opinions, findings, conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the U.S. Air Force.

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TrialSite showcases various repurposed drug trials that demonstrate potential against SARS-CoV-2, the virus behind COVID-19. Famotidine is one such repurposed drug that exhibits real potential as a low-cost, available treatment. TrialSite advisory committee member Dr. Michael Goodkin shared in “The Promise of Famotidine as a Possible Low Cost COVID-19 Treatment” the potential of Pepcid, the over-the-counter heartburn drug. In addition to blocking H2 receptors on parietal cells, this drug blocks H2 histamine receptors on mast cells. A type of white blood cell usually associated with allergic phenomena, but which respond to infection and contain many chemicals besides histamine, it turns out there are many of these cells near blood vessels and in the lungs. In the current prescription form (oral or IV), famotidine is used for several conditions, including gastroesophageal reflux disease (GERD), active benign gastric ulcer, and other conditions involving excess stomach acid. An inexpensive and overall safe treatment, over a dozen studies have investigated use targeting COVID-19. Now thanks to funding via the U.S. Department of Defense,  Leidos Life Sciences (the former SAIC) leads a major phase 2 clinical trial testing the efficacy and safety of combinations of two common agents: famotidine and celecoxib in patients hospitalized with moderate-to-severe COVID-19. Employing cutting-edge trial technology, this study, while not in the limelight, represents truly exciting potential for a repurposed, economical treatment targeting COVID-19.

Background

TrialSite reported during the early stages of the pandemic that Dr. Robert Malone, the early mRNA pioneer, identified the potential link between famotidine and SARS-CoV-2. The Virginia-based physician-researcher and colleagues early in the pandemic started testing various repurposed drugs for potential against COVID-19.

Using applied advanced supercomputing tools to identify existing drugs approved by the Food and Drugs Administration (FDA), Malone and colleagues identified famotidine as a potential treatment.

Based on its 3-dimensional structure, it was pondered that famotidine blocked an enzyme involved with viral replication. Consequently, high doses of IV famotidine were tested in a federally funded inpatient trial at Northwell Health first.

Some Early Famotidine-based Research

By May 2020, the research journal Gastroenterology reported retrospective data on hospitalized patients treated with oral or IV famotidine, suggesting a significant mortality benefit. By September, Hartford Hospital reported similar findings. By this point in 2020, some scientists began to ponder the potential that famotidine was an H2 blocker receptor blocker on mast cells and that inflammation caused by mast cells was possibly an issue with SARS-CoV-2.

Fast forward to August 2020 when Mississippi-based researchers reported positive results in ICU patients with famotidine plus cetirizine, the generic of over-the-counter Zyrtec, an H1 mast cell receptor blocker. There was a favorable report of high dose oral famotidine plus celecoxib in 25 patients in a trial that Dr. Robert Malone also advised. In January 2021, researchers in Spain reported benefits in treating infected nursing home patients with Azithromycin and various antihistamines. Antihistamines alone were beneficial as prophylaxis. Northwell Health gave 10 patients an average of 80 mg famotidine orally 3 times a day. All were much better in 48 hours. It was published in Gut, September 2020. 

Also by September 2020, TrialSite reported on research led by some physician/investigators at Beloit Memorial Hospital in Wisconsin involving 25 COVID-19 hospitalized patients treated with celecoxib and HD famotidine as adjuvant therapy. They reported that all 25 patients in the series survived hospitalized COVID-19 without the need for mechanical ventilation or renal replacement therapy. The researchers observed statistically significant improvements from admission to discharge. Of course, this was a small study as were investigations out of Cold Spring Harbor Laboratory and Northwell—but the signals were interesting.

The Current Study

This new study led by Leidos Life Sciences was indirectly funded by the U.S. Department of Defense.  Currently enrolling, the phase 2 randomized, single-blind, placebo-controlled clinical trial team tests the combination of famotidine and celecoxib as a treatment in moderate-to-severe patients hospitalized with COVID-19.

Led by Brian A Roberts and Tilly Lawrence, both of Leidos Life Sciences, the study runs from January 2022 until April 2022, the estimated primary completion date. The final wrapped-up output is forecast for November 2022.

TrialSite spoke with Robert Malone, who reports this innovative study combines aspects of cutting-edge patient-reported outcomes and other technology to better assess the potential of this low-cost, available regimen to target COVID-19. A breakthrough would be particularly beneficial for managing the disease in the transmission from pandemic to endemic stage.

Participants are enrolled and randomly assigned in a 1:1 ratio to one of two regimens, each with 202 participants (subjects). The study arms include:

• Group 1

  • • Study drug combo-- subjects will receive 80 mg famotidine by mouth (PO) 4 times per day (QID) + 400 mg celecoxib as a first dose, followed by 200 mg celecoxib PO, 2 times per day (BID), for 5 days. Following this 5-day period, subjects will continue their famotidine treatment for an additional 9 days. 

    • Subjects will receive 80 mg famotidine (PO) QID and 400 mg celecoxib as a first dose, followed by 200 mg (PO) BID celecoxib, for 5 days. Following this 5-day period, subjects will continue their famotidine treatment for an additional 9 day

• Group 2

  • • (Reference therapy) subjects will receive matching placebos QID and BID, for 5 days. Following this 5-day period, subjects will continue to receive matching famotidine placebo, QID, for an additional 9 days

    • Subjects will receive matching placebos QID and BID, for 5 days. Following this 5-day period, subjects will continue to receive matching famotidine placebo, QID, for an additional 9 days.

Each participant receives the standard of care (SOC), which typically involves the following:

• Remdesivir

• Dexamethasone 

• Lovenox

• Tocilizumab 

• Convalescent plasma

Per the protocol, the study investigator has the leeway to drop the study combination drug and use dexamethasone for those study participants who require supplemental oxygen as outlined in the National Institutes of Health COVID-19 Treatment Guidelines. Also, for example, if any subjects require high-flow oxygen, non-invasive ventilation, invasive mechanical ventilation, or extracorporeal membrane oxygenation the investigator can switch to established protocols involving dexamethasone.

What about primary endpoints?

The study protocol includes two primary endpoints of the study, including 1) evaluation of the time-to-event to achieve a World Health Organization (WHO) level score of ?3 and 2) Evaluation of the time-to-event where all-cause mortality occurs. The study includes seven secondary endpoints, which we include in the source study disclosure.

Who is Leidos?

Leidos sponsors this study indirectly via a Department of Defense grant. A well-known Department of Defense and other federal agency contractor, this group was formerly known as SAIC or Science Applications International Corporation. They have both technology and life science/biomedical divisions focusing on the delivery of technical services. They merged with Lockheed Martin’s IT sector by August 2016 to create the industry’s largest IT services provider. Thus, the Leidos-Lockheed Martin merger is one of the largest mergers associated with the ongoing consolidation of the defense sector. Leidos works extensively with the Department of Defense and several other federal agencies as well as targeted commercial markets.

Leidos Life Sciences employs a broad range of Doctoral and master’s level scientific and analytical professionals who execute a diverse portfolio of biopharmaceutical, medical science, program management, and peer/program review contracts. From improving program processes to optimizing business operations, we design and deliver customized solutions that help our customers perform more efficiently and overcome their most difficult challenges 

Long-term customers include the U.S. Army Medical Research and Materiel Command (25 years), the National Institute of Allergy and Infectious Diseases (13 years), and the Department of Homeland Security (DHS) (11 years). Additional clients comprise domestic and international pharmaceutical and biotechnology companies seeking drug development, regulatory affairs, and current Good Manufacturing Practice (GMP)/Good Laboratory Practice (GLP) compliance support. 

Their newest clients are public and private funders of biomedical research, where the group provides support through their Health Research Management Practice (HRMP) for mission and vision support, patients/stakeholder engagement, and business operations.

Study Lead

Registered as the study lead, Brian A. Roberts, MS, PMP, oversees the famotidine/celecoxib study. Roberts served in the U.S. Army as a biological science assistant, working in Biosafety level (BSL) 3 and 4 laboratories performing virus and antibody production for a rapid diagnostic laboratory at the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID).  He then continued this work in his civilian career developing deep expertise in a range of drug development competencies including good laboratory practice (GLP) for the submission of new drugs for study in humans. Later, he moved into broader program management covering SAIC’s Regulatory Affairs and Special Immunization Program (RASIP) contract with USAMMDA—a $8.3 million contract. His expertise has been used in other areas of drug development involving good manufacturing practices (GmP) serving preclinical studies in a contract with the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH).