Virus World

Respiratory virus infections in humans cause a broad-spectrum of diseases that result in substantial morbidity and mortality annually worldwide. To reduce the global burden of respiratory viral diseases, preventative and therapeutic interventions that are accessible and effective are urgently needed, especially in countries that are disproportionately affected. Repurposing generic medicine has the potential to bring new treatments for infectious diseases to patients efficiently and equitably. In this study, we found that intranasal delivery of neomycin, a generic aminoglycoside antibiotic, induces the expression of interferon-stimulated genes (ISGs) in the nasal mucosa that is independent of the commensal microbiota.

Prophylactic or therapeutic administration of neomycin provided significant protection against upper respiratory infection and lethal disease in a mouse model of COVID-19. Furthermore, neomycin treatment protected Mx1 congenic mice from upper and lower respiratory infections with a highly virulent strain of influenza A virus. In Syrian hamsters, neomycin treatment potently mitigated contact transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In healthy humans, intranasal application of neomycin-containing Neosporin ointment was well tolerated and effective at inducing ISG expression in the nose in a subset of participants. These findings suggest that neomycin has the potential to be harnessed as a host-directed antiviral strategy for the prevention and treatment of respiratory viral infections.

Published in PNAS (April 22, 2024):

https://doi.org/10.1073/pnas.2319566121

Significance

Abstract

Antiviral drugs are used globally as treatment and prophylaxis for long-term and acute viral infections. Even though antivirals also have been shown to have off-target effects on bacterial growth, the potential contributions of antivirals to antimicrobial resistance remains unknown. Herein we explored the ability of different classes of antiviral drugs to induce antimicrobial resistance. Our results establish the previously unrecognized capacity of antivirals to broadly alter the phenotypic antimicrobial resistance profiles of both gram-negative and gram-positive bacteria Escherichia coli and Bacillus cereus. Bacteria exposed to antivirals including zidovudine, dolutegravir and raltegravir developed cross-resistance to commonly used antibiotics including trimethoprim, tetracycline, clarithromycin, erythromycin, and amoxicillin.

Whole genome sequencing of antiviral-resistant E. coli isolates revealed numerous unique single base pair mutations, as well as multi-base pair insertions and deletions, in genes with known and suspected roles in antimicrobial resistance including those coding for multidrug efflux pumps, carbohydrate transport, and cellular metabolism. The observed phenotypic changes coupled with genotypic results indicate that bacteria exposed to antiviral drugs with antibacterial properties in vitro can develop multiple resistance mutations that confer cross-resistance to antibiotics. Our findings underscore the potential contribution of wide scale usage of antiviral drugs to the development and spread of antimicrobial resistance in humans and the environment. Bacteria exposed to antiviral drugs in vitro can develop multiple resistance mutations that confer cross-resistance to antibiotics.

Published (Aug.12, 2023) in Communications Biology:

https://doi.org/10.1038/s42003-023-05177-3

The National Institutes of Health, in collaboration with the Administration for Strategic Preparedness and Response (ASPR) at the U.S. Department of Health and Human Services, has launched the Home Test to Treat program, an entirely virtual community health intervention that will provide free COVID-19 health services—at-home rapid tests, telehealth sessions and at-home treatments—in selected communities. The program, first announced by the White House(link is external) in September 2022, will make antiviral treatment available for eligible individuals who receive a positive test result, which could prevent severe illness, hospitalization or death. “At-home testing for COVID-19 is now widely available in the United States, as are antiviral treatments, and this program combines easy home access to both,” said Bruce Tromberg, Ph.D., director of the National Institute of Biomedical Imaging and Bioengineering (NIBIB) at the National Institutes of Health and leader of the Rapid Acceleration of Diagnostics (RADx®) Tech program. “The Home Test to Treat program allows those who are sick an alternative to venturing out for testing or treatment, potentially reducing the spread of COVID-19 in the community.” Later this month, local and state officials in Berks County, Pennsylvania, will be the first to pilot the Home Test to Treat program. Up to 8,000 eligible residents are anticipated to participate in the program. Program organizers will gather information from participants to identify best practices and make improvements to the Home Test to Treat model that can be used to implement the program on a larger scale. Additional communities across the country will be selected to participate based on level of community need, access to healthcare treatment, expected COVID-19 infection rates and socio-economic factors.

Through collaborations with local health departments, Home Test to Treat aims to offer services to approximately 100,000 people across the United States in the coming year. Telehealth services provider eMed will implement the Home Test to Treat program. Their services are provided under a contract award by NIBIB contractor, VentureWell. Having administered millions of verified at-home telehealth sessions during the pandemic, eMed will host the user-friendly Home Test to Treat website, where participants can sign up for the program, report symptoms, receive telehealth and antiviral treatment delivery, and coordinate telehealth enabled test kits. NIBIB also has issued a contract with UMass Chan Medical School, whose researchers, in collaboration with eMed, will analyze data collected from each participating community, including the impacts of a home-based process for testing and treatment, individual attitudes about the Home Test to Treat program, and clinical outcomes from treatments. HHS, through ASPR, has led a national COVID-19 Test to Treat initiative since March 2022, that includes thousands of treatment access points nationwide. These include CDC’s Increasing Community Access to Testing (ICATT) program, composed of federally funded health centers, long-term care facilities and community-based sites. Participants in the Home Test to Treat program can be tested at local ICATT centers. The Test to Treat initiative has evolved to include more mobile and telehealth-based models that reduce barriers to access for the highest-risk individuals. NIH’s Home Test to treat program will provide an important additional pathway to rapidly access lifesaving treatments for COVID-19 in vulnerable communities.

Home Test to Treat will promote equitable solutions and help to identify best practices that may save lives in this and future pandemics. In each community, the research team will identify and implement improvements that leave us in a much better position to respond to specific needs at the local, state and federal levels. The National Institute of Biomedical Imaging and Bioengineering (NIBIB) has supported development of Home Test to Treat through the RADx Tech program. About the Rapid Acceleration of Diagnostics (RADx®) initiative: The RADx initiative was launched on April 29, 2020, to speed innovation in the development, commercialization, and implementation of technologies for COVID-19 testing. The initiative has four programs: RADx Tech, RADx Advanced Technology Platforms, RADx Underserved Populations and RADx Radical. It leverages the existing NIH Point-of-Care Technology Research Network. The RADx initiative partners with federal agencies, including the Office of the Assistant Secretary of Health, Department of Defense, the Biomedical Advanced Research and Development Authority, and U.S. Food and Drug Administration. Learn more about the RADx initiative and its programs: https://www.nih.gov/radx. 

About the National Institute of Biomedical Imaging and Bioengineering (NIBIB): NIBIB’s mission is to improve health by leading the development and accelerating the application of biomedical technologies. The Institute is committed to integrating the physical and engineering sciences with the life sciences to advance basic research and medical care. NIBIB supports emerging technology research and development within its internal laboratories and through grants, collaborations, and training. More information is available at the NIBIB website: https://www.nibib.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

The antiviral Molnupiravir (Lageviro) is widely used across the world to treat SARS-CoV-2 infection. Molnupiravir reduces viral replication by inducing mutations throughout the genome, yet in patients that do not clear the infection, the longer-term impact of the drug on virus evolution is unclear. Here, we used a case-control approach to monitor SARS-CoV-2 genomes through time in nine immunocompromised -patients with five treated with Molnupiravir. Within days of treatment, we detected a large number of low-frequency mutations in patients and that these new mutations could persist and, in some cases, were fixed in the virus population. All patients treated with the drug accrued new mutations in the spike protein of the virus, including non-synonymous mutations that altered the amino acid sequence. Our study demonstrates that this commonly used antiviral can supercharge viral evolution in immunocompromised patients, potentially generating new variants and prolonging the pandemic.

Preprint available in  medRxiv (Dec. 22, 2022):

 https://doi.org/10.1101/2022.12.21.22283811 

An oral antiviral drug that targets a key part of the respiratory syncytial virus (RSV) polymerase has been identified, a finding that could provide an effective treatment against RSV disease, according to researchers in the Center for Translational Antiviral Research at Georgia State University.  The findings, published in the journal Science Advances, identify AVG-388 as the lead drug candidate, which effectively blocks the activity of the viral RNA polymerase, an enzyme responsible for replication of the viral genome. RSV is a leading cause of lower respiratory infections in infants and immunocompromised individuals, but no efficient therapeutic exists. The virus caused an estimated 33.1 million cases worldwide in 2015 that required 3.2 million hospitalizations and resulted in 59,800 deaths. Finding effective drugs to fight RSV has been challenging. Through mutations, RSV has escaped advanced candidate classes that prevent the virus from entering a cell. To overcome this issue, recent drug development efforts have focused on the viral RNA-dependent RNA polymerase complex of RSV because of the possible broader window of opportunity to fight the virus during viral genome replication and transcription.

"We have identified the AVG class of inhibitors of RSV RNA synthesis. Through chemical optimization, we have developed the clinical candidate AVG-388, which is orally efficacious against RSV in animal models of infection." Dr. Richard K. Plemper, senior author of the study, Distinguished University Professor and director of the Center for Translational Antiviral Research in the Institute for Biomedical Sciences at Georgia State

In addition, the researchers demonstrated potent antiviral activity in human airway epithelium organoid cultures. "In this study, we have mapped an exciting druggable target in the RSV RNA-dependent RNA-polymerase and established the clinical potential of the AVG inhibitor class against RSV disease," said Dr. Julien Sourimant, first author of the study and a postdoctoral fellow in the Center for Translational Antiviral Research in the Institute for Biomedical Sciences at Georgia State. The research team investigated the effect of treatment on viral replication at different oral doses intended to prevent or cure disease. They demonstrated that treatment reduced virus load by several orders of magnitude in the different disease models. "Our results lay the foundation for formal development of the AVG class and the structure-guided identification of companion drugs with overlapping target sites but distinct resistance profiles," Plemper said. Co-authors of the study include Julien Sourimant (first author), Carolin M. Lieber, Jeong-Joong Yoon, Mart Toots and Richard K. Plemper of the Center for Translational Antiviral Research in the Institute for Biomedical Sciences at Georgia State; Mugunthan Govindarajan, Venkata Udumula and Michael G. Natchus of Emory Institute for Drug Development at Emory University; Kaori Sakamoto of the College of Veterinary Medicine at the University of Georgia; Joseph Patti of Aviragen Therapeutics Inc. (now at JP Biotech Advisors Inc.); and John Vernachio of Aviragen Therapeutics Inc. The study was funded by the National Institutes of Health.

The omicron (B.1.1.529) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is responsible for coronavirus disease 2019 (Covid-19), has spread rapidly around the world and has already become the predominant variant circulating in many countries. As of February 2022, omicron variants have been divided into four distinct sublineages: BA.1, BA.1.1, BA.2, and BA.3.1 Most circulating omicron variants belong to sublineage BA.1; however, in Denmark, India, and the Philippines, the sublineage BA.2 is now becoming dominant.

As compared with the Wuhan/Hu-1/2019 reference strain, the sublineage BA.2 of the omicron variant has 16 amino acid substitutions in the receptor-binding domain of the spike (S) protein of SARS-CoV-2,2 which is the primary target for monoclonal antibody–based therapy. The BA.2 and BA.1 variants share 12 of these 16 substitutions; however, BA.2 has four substitutions in the receptor-binding domain (i.e., S371F, T376A, D405N, and R408S) that differ from those in BA.1. These findings suggest that there may be differences in the effectiveness of monoclonal antibodies against these different omicron sublineages. Accordingly, we examined the neutralizing ability of therapeutic monoclonal antibodies that have been approved by the Food and Drug Administration, individually and in combination, against the omicron BA.2 subvariant hCoV-19/Japan/UT-NCD1288-2N/2022 (omicron/BA.2; NCD1288), which was isolated from a traveler who arrived in Japan from India. Whole-genome sequencing analysis of the NCD1288 virus stock confirmed that it had the 16 substitutions that are characteristic of the omicron variant in the receptor-binding domain of the S protein, as compared with the Wuhan/Hu-1/2019 reference strain...

The susceptibilities of omicron/BA.2 (NCD1288) to remdesivir, molnupiravir, and nirmatrelvir were similar to those of the ancestral strain and other variants of concern (i.e., 50% inhibitory concentration values for these three agents that differed by factors of 2.5 to 4.5, 0.7 to 1.6, and 1.5 to 3.3, respectively) (Table 1).3 Clinical studies are warranted to determine whether these antiviral therapies are indeed effective against omicron/BA.2 infections. Our data indicate that some therapeutic monoclonal antibodies (REGN10987–REGN10933, COV2-2196–COV2-2130, and S309) have lower neutralizing activity against omicron/BA.2 than against earlier variant strains.

Published in NEJM (March 9, 2022):

https://doi.org/10.1056/NEJMc2201933 

The first crop of antivirals against SARS-CoV-2 is promising. But new drugs will be needed to counter the looming threat of resistance.  The roll-out of COVID-19 vaccines at the beginning of 2021 marked a key turning point in the fight against the global pandemic. Another major milestone arrived at the end of the year, with the approval of two oral antiviral treatments — molnupiravir and Paxlovid — that promise to reduce the number of COVID-19 hospitalizations and deaths. But as these pills slowly make their way into pharmacies worldwide, researchers are already looking ahead to the drugs that could supersede them. “These are our first-generation antivirals against coronaviruses,” says Sara Cherry, an immunologist at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia. Our experience with antivirals against other diseases, like hepatitis C and HIV, proves that “we can do better and better over time”, she adds.  Clinical-trial data showed that molnupiravir, developed by the pharmaceutical firm Merck, based in Kenilworth, New Jersey, and the biotechnology company Ridgeback Biotherapeutics in Miami, Florida, cut hospitalizations and deaths by 30%, compared with people who took placebos. Meanwhile, Paxlovid (nirmatrelvir and ritonavir), made by Pfizer, based in New York City, cut hospitalizations and deaths by 89%. UK regulators approved molnupiravir in November and Paxlovid in December, and US regulators granted emergency authorizations for both drugs in December. Other countries have followed suit with their own approvals, and many are negotiating with the drug makers to buy courses of the drugs or to manufacture their own generic versions. For now, the pills are in short supply. Drug makers are still scaling up production of the antivirals, which are in huge demand to treat the highly transmissible Omicron variant. But when they become more widely available — and if their clinical-trial data is borne out in the real world — the pills will become vital tools to prevent people from becoming seriously ill with COVID-19, says Cherry. It’s too soon to tell whether SARS-CoV-2 is likely to develop any resistance to these first-generation antivirals, says Tim Sheahan, a coronavirologist at the University of North Carolina at Chapel Hill. Although its sky-high rate of replication is a breeding ground for mutations, he says, the virus also causes acute infections that offer relatively little time for resistance-causing mutations to accumulate. But the threat of resistance is particularly severe for ‘monotherapies’ such as molnupiravir and Paxlovid that each target only one part of the virus. That’s why it’s imperative to develop new antivirals aimed at different targets, or ones that can be combined into a single treatment to attack the virus on multiple fronts, says Sheahan. 

A race against resistance

Successful antivirals have typically targeted two key pieces of a virus’s biological machinery, a polymerase and a protease, both of which are essential for viral replication. The current COVID pills are no exception: Paxlovid inhibits SARS-CoV-2’s main protease, whereas molnupiravir tricks its RNA polymerase into incorporating part of the drug into the virus’s RNA, creating so many errors that it cannot survive. A third drug — remdesivir, developed by Gilead, based in Foster City, California — inhibits RNA polymerase, but treatment is expensive and currently requires intravenous infusions over three consecutive days, making it inaccessible to many people.  Unfortunately, molnupiravir’s mode of attack means that it might not be wise to include it in a combination therapy, says Luis Schang, a virologist at Cornell University in Ithaca, New York. If the treatment does not completely wipe out the virus in a patient, some of the RNA errors it creates might inadvertently give the virus resistance against the other drug in the combination. That’s why it’s a key priority for researchers to find an accessible drug that effectively blocks the virus’s RNA polymerase, he says, which could be used in partnership with a protease inhibitor such as Paxlovid. One option may be an oral version of remdesivir, which Gilead is currently testing. Other antiviral drug candidates are slowly working their way through the clinical-trial pipeline, says Carl Dieffenbach, director of the division of AIDS at the US National Institute of Allergy and Infectious Diseases (NIAID). He says that one promising candidate is a protease inhibitor, developed by Shionogi & Company, based in Osaka, Japan, and Hokkaido University in Japan, that is currently in phase II/III clinical trials in Asia. The candidate targets the same protease as Paxlovid but would only require patients to take a single pill each day.  That simpler regimen could help to avert the rise of resistance, Cherry says. Unfinished treatments can hasten drug resistance by allowing the virus to develop defences against the drug while it continues multiplying and wreaking havoc in the body. Both molnupiravir and Paxlovid consist of several pills that must be taken twice a day for five consecutive days. “The second you have people taking something multiple times a day when they’re sick is when you have issues with compliance,” Cherry says.

Target practice

Researchers should also develop treatments that target other parts of the virus, Schang says. “This time we got lucky with a virus that encodes both a polymerase and a protease, and here we are two years later with only a suboptimal arsenal,” he says. “We really have to identify and validate new targets for antivirals so that when the next [pandemic] happens, we have a much broader pipeline to choose from.”  Other potential targets include a different protease in SARS-CoV-2 called PLpro, and an enzyme called methyltransferase that stabilizes the virus’s RNA, says Matt Hall, the director of the early translation branch at the US National Center for Advancing Translational Sciences (NCATS). Clear Creek Bio, a biotechnology firm based in Cambridge, Massachusetts, announced on 6 January that it will collaborate with NCATS to develop an oral drug targeting the PLpro enzyme. Dieffenbach says that researchers would ideally like to identify targets that are common to entire families of viruses and inhibit them with a single drug. That would potentially allow public-health officials to rapidly deploy an effective antiviral the next time a novel virus with pandemic potential emerges. Developing such broad-spectrum drugs will take significant public and private investment, and the cooperation of pharmaceutical companies, says Hall. Calls for such efforts were not heeded in the wake of the 2003 SARS-CoV outbreak, he adds, but the latest pandemic has underlined the need for action. Last year, the United States appropriated US$1.2 billion to NIAID to launch the Antiviral Drug Discovery Centers for Pathogens of Pandemic Concern, which will fund basic research on developing antivirals for seven virus families. Hall says this gives him hope that antiviral research will continue even as the COVID-19 pandemic wanes. But all antivirals face an inherent limitation, says Dieffenbach: they must be taken within days of infection to stop a virus from proliferating. Antivirals are only effective if people acknowledge that they might be ill, and can access tests that provide a timely diagnosis. “We can build the best drugs in the world, but if people don’t understand that they have to get on board quickly, they’re not going to do any good,” says Dieffenbach. “Pills do not take themselves.”

Published in Nature (Jan. 22, 2022):

https://doi.org/10.1038/d41586-022-00112-8 

Atea Pharmaceuticals said Tuesday that its antiviral pill for Covid-19 failed to combat the virus in a mid-stage trial, leading the company to delay its pivotal study by a year.  The disappointing news follows a far more hopeful October update from Merck, whose similar antiviral reduced the chances that patients newly diagnosed with Covid-19 would be hospitalized by about 50% in a Phase 3 study. There is a desperate need for treatments for early Covid that can be taken as pills. Current treatments, such as remdesivir and monoclonal antibodies, are generally given intravenously or as injections, and are difficult to distribute to large numbers of people. The hope is that pills to treat Covid could be given widely in order to prevent infected people from progressing to severe disease, hospitalization, or death. Atea, partnered with global drug maker Roche, said its drug, AT-527, failed to beat placebo at reducing the amount of measurable virus in patients with mild or moderate Covid-19, missing the primary endpoint of a 100-patient trial. As a result, Atea and Roche are rethinking their Phase 3 trial. That study, designed to enroll up to 1,400 patients, has a primary endpoint of reducing the time it takes patients to recover from Covid-19 and secondary goals including preventing hospitalization. In light of the Phase 2 results, Atea and Roche are now considering whether to change the primary endpoint and target population. Data from that study, once expected this year, are now slated for the second half of 2022, Atea said.

AT-527 works similarly to Merck’s drug, molnupiravir, and was widely expected to succeed in clinical development. The problem might have been trial design. While Merck deliberately excluded patients who had been vaccinated for Covid-19, Atea did not, which might have skewed the results, according to the company. Merck also recruited only patients who had at least one risk factor for severe Covid-19, such as obesity or heart disease, while Atea required only a positive test and mild symptoms.  In a subgroup of patients at high risk for severe Covid-19, AT-527 outperformed placebo at reducing virus levels over seven days, Atea said, which could inform the company’s changes to its Phase 3 trial. “Based on what we know now, this actually is not surprising, as other direct-acting antivirals, including molnupiravir, have shown similar outcomes in the mild-to-moderate outpatient population,” Atea CEO Jean-Pierre Sommadossi said on a conference call with analysts Tuesday. “What is reassuring is that viral reduction … was observed in high-risk patients with underlying health conditions.” The news is a bitter disappointment for Atea, which has spent the past 18 months touting the potential of AT-527, developed as a treatment for hepatitis C, to change the course of the Covid-19 pandemic. The company, which commanded a market value of about $3.4 billion as of Monday, fell 70% in premarket trading on Tuesday. Merck, partnered with Ridgeback Biotherapeutics, is seeking an emergency use authorization for its Covid-19 antiviral and will make its case to a panel of Food and Drug Administration advisers on Nov. 30. Results for another potential oral Covid-19 treatment, from Pfizer, are expected by the end of the year.

Atea Pharmaceuticals Press Release (Oct. 29, 2021): 

https://ir.ateapharma.com/news-releases/news-release-details/atea-pharmaceuticals-provides-update-and-topline-results-phase-2 

Thanks to the American Rescue Plan, the Biden Administration is investing more than $3 billion to accelerate the discovery, development and manufacturing of antiviral medicines as part of the Biden Administration’s whole-of-government strategy to develop the next generation of COVID-19 treatments. Through collaboration within the U.S. Department of Health and Human Services (HHS), including the National Institutes of Health (NIH) and its National Institute of Allergy and Infectious Diseases (NIAID), and the Biomedical Advanced Research and Development Authority (BARDA), part of the HHS Office of the Assistant Secretary for Preparedness and Response (ASPR), this plan – called the Antiviral Program for Pandemics – will respond to the urgent need for antivirals to treat COVID-19 by spurring the availability of medicines to prevent serious illness and save lives. It also will build sustainable platforms for discovery and development of antivirals for other viruses with pandemic potential, helping better prepare the nation to face future viral threats. Even as hundreds of millions of Americans get vaccinated against COVID-19 and cases, hospitalizations and death rates fall, the Biden Administration remains committed to identifying effective treatment options that can prevent people diagnosed with COVID-19 from progressing to serious illness and death. Highly effective oral antiviral medicines that can be taken at home early in the course of infection, similar to antiviral treatment for influenza, would save lives both here and abroad and prevent overwhelming surges in hospitalizations. This plan will support research to identify and accelerate availability of breakthrough treatment options to ensure the public has access to viable medicines.

“New antivirals that prevent serious COVID-19 illness and death, especially oral drugs that could be taken at home early in the course of disease, would be powerful tools for battling the pandemic and saving lives,” said Dr. Anthony Fauci, chief medical adviser to the President and NIAID Director. “Through multidisciplinary collaborations among leading scientists in academia and industry, this investment from the American Rescue Plan to create the Antiviral Program for Pandemics will help inspire medical innovation and build on the extraordinary success we have seen in developing the COVID-19 vaccines.” This plan accelerates and expands the Administration’s ongoing efforts to support clinical trials to test prioritized drug candidates for COVID-19 and to support the advanced development of promising therapies. Working through an unprecedented public-private partnership called ACTIV (Accelerating COVID-19 Therapeutics and Vaccines), 19 therapeutic agents have been prioritized for testing in rigorous clinical trials for outpatients and inpatients with COVID-19. Having additional FDA-authorized antiviral medicines available within a year would be a major breakthrough in ongoing efforts to combat COVID-19 and protect the public, which is why last week the Administration announced it would procure more than 1.5 million regimens of a Merck investigational antiviral treatment, should it receive emergency use authorization. “With the President’s leadership, this Administration has vaccinated millions of people. Even with very effective vaccines, some people may remain vulnerable to the virus, including people who are immunosuppressed or who are unvaccinated,” said Dr. David Kessler, Chief Science Officer for the Biden Administration’s COVID-19 Response. “An easily administered oral antiviral drug would be an important part of our therapeutic arsenal that would complement the great success of our vaccine efforts. Our Administration is going to harness the power of American ingenuity to spur the creation and development of these drugs that can save lives both here in the United States and around the world.”

“The remarkable and rapid development of vaccines and testing technology has shown how agile scientific discovery can be when we combine the resources of public agencies, private entities, and our nation’s most brilliant and creative minds,” said Dr. Francis S. Collins, NIH Director. “We will leverage these same strengths as we construct a platform for the discovery and development of effective antivirals that will help us defeat COVID-19 and better prepare us for potential future viral pathogens.” As part of the plan announced today, the NIH will evaluate, prioritize and advance antiviral candidates to Phase 2 clinical trials, using current and expanded contract resources and the NIH’s National Center for Advancing Translational Sciences laboratories to de-risk early stage development with sponsors and guide candidates along development paths. The plan provides more than $300 million for research and lab support, nearly $1 billion for preclinical and clinical evaluation, and nearly $700 million for development and manufacturing through NIAID and BARDA. “This plan builds on the long, successful partnership between BARDA and NIH to develop vaccines, therapeutics and diagnostics, from combatting Ebola, anthrax and smallpox, to now tackling COVID-19,” said BARDA Director Gary Disbrow, Ph.D. “Throughout this public health emergency, we have worked with industry to develop treatments to reduce severe illness, hospitalizations, and deaths, and this proposal will help us go even further to accelerate and deliver more safe and effective treatments that are easy to administer.” Additionally, the plan allocates up to $1.2 billion to support the creation of collaborative drug discovery groups called Antiviral Drug Discovery (AViDD) Centers for Pathogens of Pandemic Concern that will harness the creativity of the biomedical research community and drive innovative antiviral drug discovery and development. These centers will create platforms that will initially target coronaviruses, and then could be expanded to other viruses with pandemic potential – helping to better prepare the nation for future viral threats.

The last time the world needed an antiviral medicine as quickly as possible, Daria Hazuda, vice president of infectious disease and vaccine discovery research at Merck, answered the call. Around 150,000 Americans were infected with HIV each year when rates peaked in the mid-1980s, and by the year 2000 nearly 500,000 people had died of AIDS in the U.S. Hazuda’s research at the time focused on HIV’s ability to insert its genetic material into the the human genome. Her lab developed a novel way to target that process with a drug called raltegravir, which was approved for use in 2007 and is still used today.  Now, she hopes to develop a drug for COVID-19 — at a substantially faster pace.  While most of the world’s attention is currently laser focused on getting vaccines to more people to stem the spread of the coronavirus, there’s also significant pressure on scientists to find a cure.  Doctors have some medications they can use to treat the effects of COVID-19, but developing a drug that targets the virus itself is a complex and costly procedure. More than a year into the pandemic only one antiviral treatment — remdesivir — is currently recommended for use in the U.S., and experts say it is not nearly effective enough. “Vaccine manufacturers are making next generation vaccines to try and stay one step ahead, but it is unpredictable. So you need other interventions to address the potential evolution of the virus,” Hazuda said. She and her team, along with researchers at Miami-based Ridgeback Biotherapeutics, worked seven days a week in the spring of 2020 to find a possible treatment for COVID-19 and prepare for the clinical trials necessary to prove its safety and effectiveness. Their drug, molnupiravir, is one of two powerful medicines to treat COVID-19 that are nearing the end of clinical testing.  “The day started really early and ended really late at night,” Hazuda said. “But there was a tremendous sense of mission. Everybody wanted to help even though they were exhausted. There was so much we all had to do.” Scientists are hopeful that new drugs designed to stop the virus’ deadly reproduction could reduce hospitalizations and deaths from COVID-19. The drugs offer hope and a contingency plan for unvaccinated individuals, particularly in low-income countries lagging far behind in the race to vaccinate. 

Chasing a moving target

Viruses mutate constantly, making it challenging to find a medicine that will not just work, but continue to work as the virus morphs. Mutations can change the shape of viruses’ proteins and thereby make them resistant to drugs. The hunt for effective antivirals is largely a hunt for a “conserved target,” such as a protein that rarely changes its shape even as the virus mutates.  Since scientists shared the sequenced genome of the novel coronavirus in January 2020 — detailing the specific genetic information and proteins of the virus — researchers have worked at breakneck speed to find a targeted medicine. Hazuda’s experience with HIV and Hepatitis C helped her team quickly rule out targets in the SARS-CoV-2 structure that were likely to change as the virus mutated and focus instead on “very highly conserved targets to minimize the potential of developing resistance,” she said.  Antiviral medications often target a virus during the process of replication, when it uses our cells’ resources to make copies of itself — leading to cell damage and the release of more virus. By early March of last year, Hazuda had narrowed her search to compounds aimed at proteins that could copy the virus’s genetic material. Her team came across a pre-clinical publication from an Emory University scientist on molnupiravir, a compound initially developed for influenza and other viruses. Research suggested the compound could make it harder for the virus to replicate itself by interrupting the RNA polymerase enzyme, which acts like a copy machine for the viral genome. In various academic labs, molnupiravir has demonstrated activity against flu and many different types of coronavirus, including MERS and the common cold.  “We were very interested in finding an agent that would have the potential to be not only active against CoV-2, but potential future outbreaks or pandemics caused by other coronaviruses,” Hazuda said. Because Ridgeback Biotherapeutics had the rights to molnupiravir, Merck began collaborating with the smaller pharmaceutical company to test the safety of the compound and prepare it for clinical studies.  The idea is that molnupiravir could be taken as an oral pill by symptomatic patients who test positive for COVID-19, before their illness is severe enough to require going to a hospital. The hope is that it can stop the virus in its tracks, before it can replicate uncontrollably and cause a person to become more sick. One phase 2 clinical study showed that molnupiravir is unlikely to significantly change the illness of those people who are hospitalized with COVID-19, but Hazuda is hopeful that phase 3 trials — expected to conclude by the end of the year — will demonstrate its effectiveness as a treatment that can be used outside of the hospital for people with mild to moderate cases.

Adolfo Garcia-Sastre, the director of the Global Health and Emerging Pathogens Institute at Icahn School of Medicine at Mount Sinai, also spent the spring of 2020 looking for a medication that could thwart the coronavirus’ lifecycle, but at a different stage. He sought a drug that influences the human proteins that the virus uses to build its components.  Because viruses hijack human cells and use their proteins (called factors) and other materials for their own purpose, identifying the factors they rely on can be a first step toward halting their actions.  Garcia-Sastre’s collaborators at the Quantitative Biosciences Institute at the University of California, San Francisco, identified more than 300 human factors most likely to make an impact on viral replication. Then, his lab tested around 90 drugs that are known to affect these factors. They landed on plitidepsin, an injectable medicine developed by Spain’s PharmaMar and used in patients with multiple myeloma, a type of blood cancer. It was shown to interfere with the function of a human factor called eEF1A, which the virus uses in the assembly of  its proteins. So far, plitidepsin seems to overcome some of the difficulties in finding a drug that targets virus replication. One is that often their effectiveness in the lab or in animal testing doesn’t carry over to humans. Another is toxicity: The concentrations required can cause undesired effects in human cells. Plitidepsin passed the critical phase 1 clinical trial conducted in Spain, showing that toxicity is not a barrier to use. The ongoing phase 3 clinical trial will show whether plitidepsin decreased days of hospitalization for COVID-19 patients.  The study, expected to be completed in August, will compare plitidepsin’s effectiveness to remdesivir, the current standard of care, which also works by inhibiting replication and can shorten hospitalization for COVID-19 patients by four days, on average. Where remdesivir has fallen short on decreasing the deadliness of the virus, Garcia-Sastre hopes plitidepsin will demonstrate live-saving potential.

The cost of discovery

While doctors have blood thinners and steroids to treat the symptoms of a raging COVID-19 illness, developing a new medicine that specifically targets the virus itself can take many years, explained Bhaven Sampat, an economist and associate professor at the Department of Health Policy and Management at the Mailman School of Public Health at Columbia University.  By repurposing an existing medicine and using already-developed compounds, both Garcia-Sastre and Hazuda shaved precious time off the drug development process. Piggybacking off already identified candidates also helps sidestep some of the cost spent on basic research. “That’s particularly useful because you don’t have to reinvent the wheel in a way,” Sampat said. Remdesivir, so far the only antiviral approved for COVID-19, benefited from the same leg up. Developed nearly a decade ago and shown effective against other coronaviruses including Ebola, SARS and MERS, it was fast tracked for use against COVID-19 and greenlit by the FDA in October 2020.  Another existing drug, ivermectin, may also have potential against SARS-CoV-2. A May meta-analysis suggests it could speed recovery and reduce mortality from COVID-19. The idea is controversial; some experts are unconvinced while proponents are eager to put it to use as a cheap, effective treatment. The anti-parasitic, developed by Merck in the 1980s, is no longer under patent. The company has contended there is not sufficient evidence for its use against COVID. Merck declined to respond to PBS NewHour’s request for comment. Developing a new drug oftentimes costs more than $1 billion dollars, a financial and technological burden typically shared by federally and grant-supported research labs (often at universities), which do basic research to identify drug candidates, and pharmaceutical companies, which bring medicines through expensive clinical trials to market.....

In two preclinical models of COVID-19, plitidepsin showed a 100-fold reduction in viral replication in the lungs and demonstrated an ability to reduce lung inflammation. Scientists at UC San Francisco’s Quantitative Bioscience Institute (QBI) and the Icahn School of Medicine at Mt. Sinai (ISMMS) in New York have shown that plitidepsin (Aplidin), a drug approved by the Australian Regulatory Agency for the treatment of multiple myeloma, has potent antiviral activity against SARS-CoV-2, the virus that causes COVID-19. In laboratory experiments reported in Science on Jan. 25, plitidepsin, a compound originally discovered in a Mediterranean sea squirt, was 27.5-fold more potent against SARS-CoV-2 than remdesivir, a drug that received FDA emergency use authorization in 2020 for the treatment of COVID-19. In addition, in two preclinical models of COVID-19, plitidepsin showed a 100-fold reduction in viral replication in the lungs and demonstrated an ability to reduce lung inflammation.  The studies were led by the laboratories of Nevan Krogan, PhD, director of the QBI, part of the UCSF School of Pharmacy, and Adolfo García-Sastre, PhD, professor of microbiology and director of the Global Health and Emerging Pathogens Institute at ISMMS.

In 2020, in response to the COVID-19 pandemic, Krogan, also a senior investigator at Gladstone Institutes, brought many UCSF labs together in the QBI Coronavirus Research Consortium (QCRG), which played a major role in the new research. In a separate publication posted to the bioRxiv preprint server, the UCSF and ISMMS researchers, in collaboration with Greg Towers, PhD, and Clare Jolly, PhD, of University College London, show that plitidepsin has antiviral activity against the recently identified B.1.1.7 variant of SARS-CoV-2 which is comparable to the drug’s activity against the original SARS-CoV-2 strain. Additionally, they found plitidepsin to be about 100 times more potent than remdesivir in human epithelial cells.    “From the start, our scientific investigations with the QCRG were to research where and how the SARS-CoV-2 virus was co-opting its human host to thrive, survive and become deadly,” said Krogan. “That research led us to a biologic pathway, the eukaryotic translation machinery, where inhibition of the pathway showed significant antiviral activity in cell culture. One of the promising agents that arose from our screen of drugs that inhibit this pathway was plitidepsin. Our preclinical data showing increased potency compared to remdesivir, and in conjunction with recent early clinical data showing promise in COVID-19 patients, as reported by the drug’s manufacturer, suggest plitidepsin should be further evaluated as a COVID-19 therapy.” García-Sastre said, “The ongoing COVID-19 pandemic has created an immediate need for antiviral therapeutics that can be moved into the clinic urgently. This led us to screen clinically approved drugs with established safety profiles. Our previous study of the SARS-CoV-2’s interactions with human host cells led us to  a protein  known as eEF1A, which is involved in translating mRNA into proteins, as a potential druggable target to inhibit SARS-CoV-2 replication.” 

The studies were conducted in close collaboration with PharmaMar, a Spanish pharmaceutical  company that first isolated plitidepsin (trade name Aplidin) from a sea organism known as Aplidium albicans. “Plitidepsin is an extremely potent inhibitor of SARS-CoV-2, but its most important strength is that it targets a host protein rather than a viral protein,” said Kris White, PhD, assistant professor of microbiology at ISMMS, first author of the Science paper. “This means that if plitidepsin is successful in the treatment of COVID-19, the SARS-CoV-2 virus will be unable to gain resistance against it through mutation, which is a major concern with the spread of the new U.K. and South African variants.” Krogan said the work is further validation of the QCRG’s focus on host proteins as a strategy to fight COVID-19 and other viral diseases. “It is host mechanisms that permit the SART-CoV-2 virus to wreak havoc,” Krogan said. “By targeting host factors that enable or facilitate disease, we have the potential to have a more far-reaching impact in drug development. In this case, SARS-CoV-2 and its mutant strains, and possibly other viruses that leverage the same pathway, may also be susceptible to the same therapeutic agents that inhibit this virus–host interaction.”

Cited Publications in Science (Jan. 25, 2021):

https://science.sciencemag.org/content/early/2021/01/22/science.abf4058 

bioRxix (Jan. 24, 2021):

https://doi.org/10.1101/2021.01.24.427991

Just two days after announcing its R&D chief was stepping down, Gilead Sciences has announced it will be buying up a few of Novartis’ unwanted early-stage infection assets. The West Coast Big Biotech, which has been shuffling its execs over the past few weeks, today licensed three preclinical antiviral programs from Novartis including investigational agents with the potential to treat human rhinovirus, influenza and herpes.

For its part, Novartis gets an undisclosed upfront payment, with biobucks worth $291 million as well as royalties on annual net sales. “Today’s announcement builds on Gilead’s heritage in antiviral research and development. We look forward to applying this expertise to advance the development of potential new treatments for viruses with limited therapeutic options,” said John McHutchison, M.D., Gilead’s outgoing chief scientific officer and head of R&D. 

Gilead has been pivoting toward cancer in recent years, most notably though its $12 billion buyout of Kite Pharma and its CAR-T drugs, but anti-infectives against hepatitis C and HIV remain the base of the company and seemingly still an important part of its future.

Over four years have passed since the beginning of the COVID-19 pandemic. The scientific response has been rapid and effective, with many therapeutic monoclonal antibodies and small molecules developed for clinical use. However, given the ability for viruses to become resistant to antivirals, it is perhaps no surprise that the field has identified resistance to nearly all of these compounds. Here, we provide a comprehensive review of the resistance profile for each of these therapeutics. We hope that this resource provides an atlas for mutations to be aware of for each agent, particularly as a springboard for considerations for the next generation of antivirals. Finally, we discuss the outlook and thoughts for moving forward in how we continue to manage this, and the next, pandemic.

Published (April 18, 2024):

https://doi.org/10.1016/j.chembiol.2024.03.008

Highlights

Summary

The Antiviral Program for Pandemics (APP) team, along with experts from across the National Institutes of Health (NIH) and Biomedical Advanced Research and Development Authority (BARDA), has drafted Target Product Profiles (TPPs) for potential direct-acting antiviral therapeutics candidates targeting several key viruses of pandemic potential.  These TPPs should be considered ‘living documents’ that are never final but may be useful starting points for consideration by therapeutics developers who are drafting TPPs for their specific candidates.  Also, the example TPPs are not intended to provide details about product requirements for funding or other support from USG or other funders.  Instead, these sample TPPs are being provided as tools for scientists working toward therapeutics product development of direct-acting antivirals for use in potential future outbreaks or pandemics. We are happy to receive feedback on these sample TPPs and may make updates/revisions or add TPPs for additional clinical indications in the future, so please monitor this page for updates and send any feedback to APPSubmissions@mail.nih.gov

A trial of a Chinese-developed derivative of remdesevir showed comparable efficacy to Paxlovid in a study published in NEJM. When H. Eric Xu fell sick and tested positive with Covid this month, he took pills of his own invention. Paxlovid, the primary oral antiviral available in the U.S., is in short supply in China. But Xu, a prominent biochemist at the Chinese Academy of Sciences, had helped devise his own in 2021 and, as the drug’s inventor, could legally take it even as it went through clinical trials.  His symptoms were alleviated, and he wasn’t alone. In an 822-patient clinical trial published Wednesday in the New England Journal of Medicine, Xu’s antiviral, VV116, appeared just as effective as Paxlovid at easing patient’s symptoms. Newly diagnosed patients who took VV116 recovered after a median of 4 days, compared with 5 days for Paxlovid, though experts caution that the study was not large enough to say one was better than the other. The drug is being developed by Chinese drugmakers Junshi Biosciences and Vigonvita Life Science. The results could lend Chinese authorities and physicians a new tool as they try to keep a burgeoning outbreak at bay, while eventually adding another antiviral to the world’s arsenal. “I hope the publication of these results will get approval much quicker,” Xu said in an interview. Quicker, however, may not be quick enough. The virus has spread rapidly in China since authorities lifted many of the country’s strict mitigation measures in response to protests over its zero-Covid policies. “It will take time to manufacture,” he added. “I think the pandemic will pass.” Although promising, the data may not in fact be enough to win over regulators and other researchers, particularly in countries where alternatives are available.  Part of the problem is the study’s main metric.

While the FDA has previously approved antivirals, such as the flu drugs Xofluza and Tamiflu, that are shown to alleviate symptoms faster than alternatives, the primary endpoint of U.S. trials of antivirals to treat Covid has been their effectiveness in preventing hospitalization or death. It isn’t actually clear how quickly Paxlovid — the drug VV116 was compared to — alleviates symptoms in all patients.  Pfizer presented data at ID Week, an annual infectious disease conference, this year showing high-risk unvaccinated patients who took Paxlovid recovered faster than patients on placebo, said Davey Smith, an infectious disease physician at University of California-San Diego. But the company acknowledged this year that vaccinated, standard-risk patients who received Paxlovid didn’t recover significantly faster than placebo in a separate trial.  The VV116 study contained a mix of vaccinated and unvaccinated patients, randomized to receive VV116 or Paxlovid. The majority — around 75% — had received at least a primary vaccine course. It was also smaller than typical non-inferiority studies, in which  researchers try to show a new drug is just as good as an existing one, said Smith. Usually, these studies have thousands of patients.  "Our FDA would probably not go for this being an approved drug, based on this endpoint,” Smith said. David Perlin, who develops new anti-infectives as chief scientist at the Center of Discovery and Innovation in New Jersey, said VV116 appeared to be a “good addition” and little different than the approved antiviral molnupiravir, which has a similar mechanism of action.  But he agreed there wasn’t enough data for U.S. authorities.  “With 800 participants, I’m not sure the FDA is going to extract enough of the adverse events you would want to look for,” he said. 

The drug itself has attracted broad interest. It is a derivative of Gilead’s remdesivir, the first antiviral authorized for Covid-19 in May, 2020. Xu said he and a team of researchers, including collaborators at the Wuhan Institute of Virology, took remdesivir’s “parent” molecule, called GS-441524, and spent six months modifying it, until they struck upon a version that could neutralize the virus throughout the body, without causing toxicity.  In early 2020, a pair of researchers called on Gilead to develop GS-441524 itself as a pill for Covid. In public statements and emails to the researchers, Gilead claimed it wouldn’t be effective or safe. And it would take longer to develop, because, unlike remdesivir, it had never been tested in humans. But the researchers argued that Gilead preferred remdesivir because it had a longer patent life.  Those scientists now see VV116’s results as vindication. “As for whether an effective pill could have been available far earlier in the pandemic if Gilead did develop GS-441524: The answer is yes” said Victoria Yan, one of the researchers and a graduate student at MD Anderson Cancer Center, in an email.  Xu argued it’s likely GS-441524 would have worked to some degree, but that changes his team made ensured it was potent in the body. Yan agreed that one of the changes did help.  Gilead reiterated in an email that the company didn’t develop GS-441524 because of concerns about “technical feasibility.” The company announced in January it is working on an oral antiviral, based off of GS-441524, which is now in Phase 3. It’s among a small handful of efforts, including VV116, to develop antiviral pills that are as effective as Paxlovid but don’t come with the same drug-to-drug interactions that prevent some of the highest risk patients from taking Pfizer’s drug.  These efforts could also make antivirals more available across the globe. Although molnupiravir, a less effective drug, is now widely available, access to Paxlovid has been “pretty limited,” said Julien Potet, a policy advisor to Doctors Without Borders.  That could be because Pfizer started striking agreements with generic manufacturers later than Merck, molnupiravir’s developer, and Paxlovid is more complex to make, Potet said.    “If reasonably priced, [VV116] could make a major difference,” he added in an email.

The trials to make these new drugs available in the U.S. will have to look different than the one Junshi ran. Currently, U.S. researchers can’t easily run non-inferiority studies against Paxlovid. Because the drug is under emergency use authorization, researchers can only get it from Pfizer, but academics have so far struggled to access the drug for outside trials. As part of the team of researchers working on National Institutes of Health trials for Covid, Smith said he tried and failed to get Paxlovid for a non-inferiority study. “You could not run this non-inferiority trial here,” he said.  Companies developing new Covid antivirals have complained to federal officials that it has become impossible to run studies, said one government scientist involved in such talks, who spoke on condition of anonymity to discuss confidential deliberations. The FDA has asked them to compare their experimental drug to standard-of-care, but Pfizer refused to provide Paxlovid for the studies. “I’ve heard multiple times from multiple drug companies,” the researcher said. Drugmakers have had to go to other countries where regulations or the standard-of-care are different, the scientist said, and then hope they can convince the FDA to accept the data. Gilead, for example, currently lists three study sites for its Phase 3 trial. Two are in Canada. One is in Romania.  Pfizer, in a statement, said it “is prioritizing”  Paxlovid for “patients at high risk for severe COVID-19 through governments and government-funded research organizations” and that, while it has received many research requests, “unfortunately, it is impossible to support them all.” “We evaluate each proposal, selecting those with strongest scientific basis, the greatest likelihood of generating data important to patients and physicians, the intention to generate new data that is not already being collected through different means, and the ability of the requesting organization to protect the welfare of patients participating in research studies,” they said. 

The story has been updated to correct a name and to include a comment from Gilead. 

The country’s drug regulator has granted conditional authorization for an HIV drug to be used to treat COVID-19.  China’s drug regulator granted conditional approval on Monday for an HIV drug to be used to treat COVID-19. The drug, Azvudine, developed by Chinese drugmaker Genuine Biotech, is the first oral antiviral for the disease made in China. Genuine Biotech, headquartered in Pingdingshan, applied for regulatory approval earlier this month. In an announcement, the company said that 40% of people with COVID-19 who were given Azvudine for a week in a phase III clinical trial showed “improved clinical symptoms”, compared with 11% of those given a placebo. However, detailed data from the trial, including whether the treatment reduced the risk of hospitalization or death, have not been released. Although drug-efficacy data are lacking, Jun Wang, a pharmacologist at Rutgers University in New Brunswick, New Jersey, says because Azvudine is already approved in China as an HIV treatment, it should have abundant safety data, which would have fast-tracked its application. Genuine Biotech will need to submit more post-marketing data in order for the drug to receive full approval. Most antivirals target two SARS-CoV-2 proteins that are essential for replication, a polymerase and a protease. Azvudine tricks the virus’s polymerase into incorporating the drug into its RNA, which stops the virus from replicating1. In China and globally, the demand for COVID-19 therapies is enormous, says Sheng Ding, a pharmaceutical chemist at Tsinghua University in Beijing. Until the Azvudine authorization, China had approved only one oral antiviral to treat the disease, Paxlovid, developed by Pfizer in New York City. It is highly effective — it reduces the risk of hospitalization and death by nearly 89% — but supplies in China are limited. “The market will have room for several more drugs that may not outperform Paxlovid, but allow more people to access effective therapies,” adds Ding. Another Chinese-made oral antiviral, VV116, is in the final stages of development, and another dozen are in various stages of development.

Published in Nature  (July 26, 2022):

https://doi.org/10.1038/d41586-022-02050-x