Virus World

Common diabetes drug lowers SARS-CoV-2 levels, clinical trial finds Stephanie Soucheray, MA COVID-19 Thinglass/iStock Share Today, researchers from the University of Minnesota published evidence that the common diabetes drug metformin decreases the amount of SARS-CoV-2 in the body and helps reduce the risk of rebound symptoms if given early in the course of non-severe illness. The study, published in Clinical Infectious Diseases, suggests metformin may also help prevent long COVID. The researchers tested metformin against a placebo in 999 adults infected with COVID-19. More than 50% of the study enrollees were vaccinated, and treatment took place when the Omicron variant was the most dominant strain in the United States.

Study included those at standard-risk. Moreover, according to Carolyn Bramante, MD, principal investigator of the study and an assistant professor at the University of Minnesota, the study participants represented a standard- risk population, a group that currently lacks effective treatment options for the novel coronavirus. "This is not a high-risk population," Bramante told CIDRAP News. Instead, participants were 30 years or older, had a body mass index of 25 or higher (overweight), and did not require hospitalization for their COVID-19 infection. In several trials, Paxlovid has been shown to prevent deaths and hospitalization in high-risk, unvaccinated people, but standard-risk populations have not shown improvement in either time to resolution of symptoms or the incidence of hospitalization or death. Bramante said that these patient population demographics suggest metformin may be a clinical tool in outpatient medication that could be widely used. "The data support that someone would be justified if they prescribed it for outpatient treatment," she said.

Four-fold reduction in viral load by day 10. 

Participants were given a 14-day course of metformin, and participants collected nasal swabs on days 1, 5, and 10. Bramante said early treatment was key: Participants were enrolled within 3 days of a positive test, and if symptomatic, reported having symptoms for 7 or fewer days. The mean SARS-CoV-2 viral load was reduced 3.6-fold with metformin relative to placebo by day 10, the authors found, and those who received metformin were less likely to have a detectable viral load than placebo at days 5 or 10 (odds ratio [OR], 0.72; 95% confidence interval [CI], 0.55 to 0.94). Metformin reduced the odds of hospitalization or death through 28 days by 58%; emergency department visits, hospitalizations, and death through 14 days by 42%; and long COVID through 10 months by 42%. Viral rebound, defined as a higher viral load at day 10 than day 5, was less frequent with metformin (3.28%) than placebo (5.95%; OR, 0.68; 95% CI, 0.36 to 1.29). While the mechanism of action is not known, Bramante said metformin likely lowers inflammation and inhibits translation of the virus. In a commentary on the study, the authors write, "This study makes a strong case for a potential effect of metformin on COVID-19 virologic decay and prompts reevaluation of existing data in support of its use.

Research cited published (May 1, 2024) in Clin. Infect. Dis.:

https://doi.org/10.1093/cid/ciae159 

Significance

Abstract

The currently recommended five-day course of molnupiravir, an antiviral treatment, may not be long enough to treat COVID-19, according to a new paper involving UCL researchers. The study, published in Nature Communications, was conducted as part of PANORAMIC, an ongoing clinical trial evaluating potential treatments for COVID-19. In this virology sub-study, the researchers analyzed viral samples provided by 577 trial participants from across the U.K. who were randomly assigned to receive either a five-day course of molnupiravir or usual care without antiviral treatments. The researchers found that molunpiravir initially lowered patients' viral load more quickly than usual care, with 14% of molnupiravir patients having cleared the virus by day five, compared to only 2% of the usual care group. However, post-treatment the rate of viral decline in molnupiravir-treated participants significantly slowed. Nine days after treatments, only 48% of molnupiravir-treated patients had cleared the virus, compared to 56% of the patients receiving usual care. Furthermore, virus from these later samples contained more mutations than those seen in the usual care group. The researchers were able to grow some of these mutated viruses in the lab from samples taken up to nine days post-treatment, which suggests they could potentially be passed from patients who have taken molnupiravir to others. Lead author Professor Joseph Standing (UCL Great Ormond Street Institute of Child Health) said, "We know that molnupiravir works by introducing errors into the SARS-COV-2 virus—which causes COVID-19. Mutated variations of the virus often cannot replicate well and this is why we saw faster viral load decline.

"However, the fact the virus remains in patients after the five-day molnupiravir treatment course indicates the course is not long enough to clear the virus from the body. "It is possible that these patients could be spreading virus that has mutated and, if large numbers of patients are treated in this way, it is possible new variants, that help the virus evade the human immune system more effectively, may arise." The five-day course, say the authors, is not long enough to completely clear the virus. They suggest a longer course of treatment is trialed to see if this eliminates the virus from the body and limits the potential for patients to continue to spread the infection after the end of the treatment. The authors also looked at the body's immune response to the virus—specifically, the "spike protein" antibody levels after infection and treatment. They found that the group who had taken molnupiravir had 6,200 U/mL of antibodies after the treatment ended, compared to 8,400 U/mL in the group that received usual care. This could be because the treatment lowered the initial viral load, so the immune system didn't need to have such a strong response and produced fewer antibodies as a result. It potentially means molnupiravir-treated participants would be susceptible to re-infection sooner than the patients who received usual care. "These findings raise important questions about the impact of molnupiravir on patients' immunity," said Dr. Oliver van Hecke, Senior Clinical Research Fellow at the University of Oxford and co-author of the study. "Even if taking molnupiravir for longer fully gets rid of the virus, some patients might still develop weaker protection against catching it again in the future. "It would be useful to explore whether molnupiravir together with other antiviral drugs in combination better eliminates the virus, and ensure patients build up good immunity against it. This could help prevent treated patients from catching it again soon after and also reduce the chance of passing on mutated viral strains." These findings, say the authors, could help policymakers shape future antiviral treatment strategies and should inform future trials for COVID-19 treatments.

Published in Nat. Communications (Feb.23, 2024:

https://doi.org/10.1038/s41467-024-45641-0 

Reports have described SARS-CoV-2 rebound in COVID-19 patients treated with nirmatrelvir, a 3CL protease inhibitor. The cause remains a mystery, although drug resistance, re-infection, and lack of adequate immune responses have been excluded. We now present virologic findings that provide a clue to the cause of viral rebound, which occurs in ∼20% of the treated cases. The persistence of an intermediary form of infectious SARS-CoV-2 was experimentally documented in vitro after treatment with nirmatrelvir or another 3CL protease inhibitor, but not with a polymerase inhibitor, remdesivir.

This infectious intermediate decayed slowly with a half-life of ∼1 day, suggesting that its persistence could outlive the treatment course to re-ignited SARS-CoV-2 infection as the drug is eliminated. Additional studies are needed to define the nature of this viral intermediate, but our findings point to a particular direction for future investigation and offer a specific treatment recommendation that should be tested clinically.

Available in bioRxiV (Dec. 21, 2023):

 https://doi.org/10.1101/2023.12.20.572655 

April 4 (Reuters) - Gilead Sciences Inc (GILD.O) on Tuesday unveiled data from the first human study of its experimental oral COVID-19 antiviral, saying the results in healthy volunteers cleared the way for two large Phase III trials of the drug that have begun enrolling patients. The drug, obeldesivir and previously known as GS-5245, is designed to keep the coronavirus that causes COVID from replicating in the body and overwhelming a patient's immune system. Once metabolized, it works in the same way as Gilead's older intravenous COVID treatment Veklury (remdesivir), which targets virus replication through inhibition of the viral RNA polymerase. For standard risk patients, Gilead believes the new drug could help resolve symptoms earlier and is evaluating any association with symptoms of long COVID, Anu Osinusi, who oversees clinical research for hepatitis, respiratory and emerging viruses at Gilead, told Reuters. "The WHO still calls this a global health emergency ... We are not seeing a surge, but the numbers are holding steady," she said of the World Health Organization. The Phase I trial, which involved 70 healthy adults, showed that obeldesivir reached sufficient concentrations in the blood and supports taking it without regard to food, according to Gilead. Two obeldesivir patients reported headache, as did one placebo patient. No serious side effects were reported. The most common laboratory abnormality was grade 2 creatinine clearance decrease, which can be an indication of impaired kidney function and occurred in 31% of treated participants and 25% of placebo participants. Gilead has advanced obeldesivir into two late-stage global studies for treating non-hospitalized COVID patients. One trial is enrolling vaccinated people with at least two risk factors for developing serious COVID and unvaccinated patients with at least one risk factor. The other is enrolling COVID patients at standard risk of serious illness regardless of vaccination status.

Osinusi declined to comment on timing of results from the Phase III trials, noting that progress will depend on the course of the pandemic. The dosing regimen for both studies is a twice-daily tablet for five days, which would be a big advantage over currently available oral COVID antivirals if obeldesivir is proven to be effective. Pfizer Inc's (PFE.N) Paxlovid consists of three pills taken twice a day for five days, while Merck & Co's (MRK.N) Lagevrio is four capsules taken twice a day for five days. Paxlovid also can interact with a large number of medications, forcing patients to temporarily go off their other medicines or doctors to refrain from prescribing it for some. Lagevrio was shown in clinical trials to be less effective than Paxlovid in separate studies. Gilead's data is being presented later this month at the European Congress of Clinical Microbiology & Infectious Diseases in Copenhagen.

The antiviral ensitrelvir, which is not approved in the United States, shortens symptoms in people with mild COVID and might reduce risk of long COVID — but more data are needed. COVID-19 can inflict days of misery, even on people who do not develop serious illness. Now, trial data show that an antiviral called ensitrelvir shortens symptoms of mild to moderate COVID-19 by about a day — and is the first drug to make a statistically significant cut in the number of days people test positive for SARS-CoV-2. The drug’s manufacturer, Shionogi in Osaka, Japan, says the data also show that ensitrelvir has the potential to prevent long COVID. But scientists are sceptical about that claim and critical of the design of the clinical trial. The research was presented at the Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle, Washington, on 21 February, and has not yet been peer reviewed. Two oral antivirals are already widely used to treat COVID-19: Paxlovid (nirmatrelvir/ritonavir) and molnupiravir. Both target people who are at high risk of severe disease. But ensitrelvir was tested on people irrespective of their risk, which could have implications for its use in individuals at low risk. No drug has been conclusively shown to reduce the risk of long COVID, although preliminary evidence hints that Paxlovid might have this effect.

A pill for COVID cough

Organizers of the ensitrelvir trial investigated roughly 1,200 people, with the main goal of determining whether the drug could accelerate recovery. The results showed that participants who took 125-milligram ensitrelvir pills recovered from five specific symptoms — stuffy or runny nose, sore throat, cough, feeling hot or feverish and low energy or tiredness — about 24 hours earlier than did those in the control group. Participants who took the 125-milligram dose also tested negative for SARS-CoV-2 about 29 hours earlier than did those who took a placebo. According to Shionogi, the study was the first to show a statistically significant reduction in the time to a negative test result. A subset of participants were asked about their COVID-19 symptoms three and six months after trial enrolment as well as during their acute infection period. Those who reported two or more of the same symptoms at least twice in a row over this period were defined as having developed long COVID. Participants who had a relatively high number of symptoms during the illness's early stages had a 14% risk of developing long COVID if they took the antiviral, compared with a 26% risk for similar participants in the placebo group. This led Shionogi to conclude that participants who received ensitrelvir had a reduced risk of developing long COVID.

Doubts about design

But scientists who were not involved with the study point out that the trial was not specifically intended to investigate the risk of long COVID. That means that the pre-trial research plan didn’t describe any methods for analysing long COVID data. This means, for example, that it’s unclear whether Shionogi’s definition of long COVID was determined before the trial began, notes physician Eric Topol, director of the Scripps Research Translational Institute in San Diego, California. Because this was an exploratory phase of the study, it’s not possible to make any strong conclusions, he adds. Simon Portsmouth, head of clinical development at Shionogi in Florham Park, New Jersey, says that the company could not specify the plan for analysing long COVID data ahead of time because long COVID was less clearly defined in the past than now. He says that these results, although not definitive, will shape an ongoing trial evaluating ensitrelvir’s effect on COVID-19 symptoms. Scientists say it’s plausible that antivirals could prevent long COVID. One recent analysis found that people who took Paxlovid had a reduced risk of developing long COVID compared with those who took no antiviral drugs1. The study, published as a preprint, has not yet been peer reviewed. Study co-author Ziyad Al-Aly, chief of research and development at the VA St Louis Health Care System, in Missouri, says the ensitrelvir data make him more optimistic that attacking the virus early during an infection “seems to hold the key to reducing the risk of long COVID.” Topol agrees that the data that Shionogi have made public support the idea that antivirals protect against long COVID, at least when residual virus is involved in causing prolonged symptoms.

Published in Nature March 3, 2023:

https://doi.org/10.1038/d41586-023-00548-6 

Background

Methods

Findings

Interpretation

A gel that lines the respiratory tract prevented coronavirus infections in mice and monkeys, and may also work against any future new variants. An inhalable powder that coats the airways with a protective gel prevents coronavirus infections in mice and monkeys. It may be effective against any SARS-CoV-2 variant, including future ones that could evolve to evade existing vaccines. Vaccines have been critical for containing the covid-19 pandemic, but their efficacy may wane as the coronavirus that causes it mutates. Ke Cheng at North Carolina State University and his colleagues wondered if they could create a barrier for the airways that temporarily blocks the virus from causing infections. This could protect people against new variants while new vaccines are developed or old ones updated. First, they created a powder made of polymer and gelatin microparticles. When inhaled, this enters the mucus lining of the nasal passage and lungs, swelling to form a gel layer that blocks viral penetration. When tested in mice, the powder’s particles remained at high levels in their lungs for 8 hours, blocking the virus from causing an infection with up to 75 per cent efficiency, with no safety concerns.

Next, it was administered to six African green monkeys via an inhaler device. Eight hours later, the monkeys were inoculated with the original SARS-CoV-2 strain or its delta variant, introduced into the animals’ noses or into their lungs via a tube. Tests carried out several times over the next week revealed that the treated monkeys’ viral loads – the amount of virus in the body – were 50 to 300-fold lower than those of the animals in a control group that didn’t receive the gel before viral inoculation. The gel coating didn’t seem to impair breathing or cause any other side effects. The research team is seeking approval from the US Food and Drug Administration to test the gel in people. It could be inhaled using the same kind of device that people with asthma use when experiencing symptoms, says Cheng. If approved, the inhaled powder may provide short-term protection for people entering crowded places, such as supermarkets or aircraft, says Cheng. “Even with an N95 mask, the virus can sometimes find its way in, so this could be an extra layer of protection,” he says. In another part of the experiment, the team found the gel stopped mice from becoming infected with flu and pneumonia-causing viruses, suggesting that it could protect against a range of respiratory viruses with pandemic potential, says Cheng. Gary Anderson at the University of Melbourne, Australia, says inhaling the powder could create thick mucus in a person’s airways. “It’s likely to trigger a lot of coughing and that wouldn’t be well-tolerated,” he says. Instead, it might be better to take the powder nasally, he says.

Research published in Nature Materials (Feb. 9, 2023):

https://doi.org/10.1038/s41563-023-01475-7 

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 spread of SARS-CoV-2 and ongoing COVID-19 pandemic underscores the need for new treatments. Here we report that cannabidiol (CBD) inhibits infection of SARS-CoV-2 in cells and mice. CBD and its metabolite 7-OH-CBD, but not THC or other congeneric cannabinoids tested, potently block SARS-CoV-2 replication in lung epithelial cells. CBD acts after viral entry, inhibiting viral gene expression and reversing many effects of SARS-CoV-2 on host gene transcription. CBD inhibits SARS-CoV-2 replication in part by up-regulating the host IRE1α RNase endoplasmic reticulum (ER) stress response and interferon signaling pathways. In matched groups of human patients from the National COVID Cohort Collaborative, CBD (100 mg/ml oral solution per medical records) had a significant negative association with positive SARS-CoV-2 tests. This study highlights CBD as a potential preventative agent for early-stage SARS-CoV-2 infection and merits future clinical trials. We caution against use of non-medical formulations including edibles, inhalants or topicals as a preventative or treatment therapy at the present time.

Published in Science Advances (Jan. 20, 2022):

https://www.science.org/doi/epdf/10.1126/sciadv.abi6110

Pfizer Covid pills for symptoms may cause harmful reactions if taken with other prescription medications. As the omicron surge pummels a pandemic-weary nation, the first antiviral pills for Covid-19 promise desperately needed protection for people at risk of severe disease. However, many people prescribed Pfizer’s or Merck’s new medications will require careful monitoring by doctors and pharmacists, and the antivirals may not be safe for everyone, experts caution. The Food and Drug Administration authorized Pfizer’s Paxlovid for mild to moderate Covid in people as young as 12 who have underlying conditions that raise the risk of hospitalization and death from the coronavirus, such as heart disease or diabetes. However, one of the two drugs in the antiviral cocktail could cause severe or life-threatening interactions with widely used medications, including statins, blood thinners and some antidepressants. And the FDA does not recommend Paxlovid for people with severe kidney or liver disease.  Because of experts’ concerns about the potential side effects of Merck’s molnupiravir, the FDA has restricted its use to adults and only in scenarios in which other authorized treatments, including monoclonal antibodies, are inaccessible or are not “clinically appropriate.” The Paxlovid cocktail consists of two tablets of the antiviral nirmatrelvir and one tablet of ritonavir, a drug that has long been used as what is known as a boosting agent in HIV regimens. Ritonavir suppresses a key liver enzyme called CYP3A, which metabolizes many medications, including nirmatrelvir. In the case of Paxlovid treatment, ritonavir slows the body’s breakdown of the active antiviral and helps it remain at a therapeutic level for longer. The boosting effect was likely to have been crucial in driving Paxlovid’s high effectiveness in clinical trials. When Paxlovid is paired with other medications that are also metabolized by the CYP3A enzyme, the chief worry is that the ritonavir component may boost the co-administered drugs to toxic levels. Complicating matters, the drugs that pose interaction risks are widely prescribed to people at the greatest risk from Covid because of other health conditions.

The medications include, but are not limited to: blood thinners; anti-seizure medications; drugs for irregular heart rhythms, high blood pressure and high cholesterol; antidepressants and anti-anxiety medications; immunosuppressants; steroids (including inhalers); HIV treatments; and erectile dysfunction medications. “Some of these potential interactions are not trivial, and some pairings have to be avoided altogether,” said Peter Anderson, a professor of pharmaceutical sciences at the University of Colorado Anschutz Medical Campus. “Some are probably easily managed. But some we’re going to have to be very careful about.”  In its fact sheet about Paxlovid, the FDA has published a detailed list of medications that may interact harmfully with ritonavir, including those that should not be paired with the Covid antivirals. However, pharmacists stress that many of the drug interactions are manageable and that they should not preclude most people from taking Paxlovid. “Pharmacists are highly trained experts in medication safety and monitoring and are an excellent source of information and advice about interactions between medications and also supplements and herbal products,” said Emily Zadvorny, a clinical pharmacist who is the executive director of the Colorado Pharmacists Society. “They will help determine if a significant interaction exists and devise solutions to mitigate the interaction if possible.”  The good news is that health care providers have experience navigating ritonavir’s use among people with HIV — a group that often takes medications for other health conditions, in addition to antiretroviral therapy.  Dr. William Werbel, an assistant professor of medicine at Johns Hopkins University who specializes in transplant infectious diseases, advised people at high risk of Covid-19 complications to talk to their health care providers, as well as a savvy pharmacist, about changes they could make to their drug regimens should they need Paxlovid — even before they become infected with the virus.

Anyone seeking Paxlovid, which must be prescribed within five days of the first symptoms, should be sure to let their prescribers and pharmacists know the complete lists of other medications and over-the-counter supplements they are taking, Anderson said. Some medications, such as particular statins, are most likely safe to stop taking during treatment with the Covid pills, Anderson said. For example, it might be better to stay on certain blood thinners but to lower the doses. Some heart rhythm drugs cannot be taken with Paxlovid. Conversely, some anti-seizure medications can boost liver enzymes’ metabolic action and thus lower the body’s Paxlovid levels, as can the herbal supplement St. John’s Wort. The FDA warned that they should not be combined with Paxlovid. Because the Paxlovid treatment is brief — 30 pills, taken as three pills twice a day for five days — experts are hopeful that the risk of adverse interactions with other medications is low. “Five days of interactions is not a big deal for the majority of drugs,” said Jason Gallagher, a clinical pharmacy specialist in infectious diseases at Temple University Hospital in Philadelphia. If a drug’s potential interaction with Paxlovid poses too much of a risk, Anderson said, a safe and effective alternative Covid-19 therapy would be GlaxoSmithKline’s sotrovimab — the sole authorized monoclonal antibody treatment that research indicates reliably neutralizes the omicron variant of the virus. Otherwise, the antiviral molnupiravir is an option, albeit one with a much lower efficacy than either Paxlovid or sotrovimab.  Even with the concerns about taking Paxlovid with other prescription medications, experts are excited about the drug's potential. “Paxlovid is a breakthrough drug,” Anderson said. “This could make a real difference in the pandemic by making an effective Covid treatment available to many people.”

FDA List of drugs interferingn with Paxlovid (Dec. 22, 2021):

https://www.fda.gov/media/155050/download 

The ongoing evolution of SARS-CoV-2 to evade vaccines and therapeutics underlines the need for innovative therapies with high genetic barriers to resistance. Therefore, there is pronounced interest in identifying new pharmacological targets in the SARS-CoV-2 viral life cycle. The small molecule PAV-104, identified through a cell-free protein synthesis and assembly screen, was recently shown to target host protein assembly machinery in a manner specific to viral assembly. In this study, we investigate the capacity of PAV-104 to inhibit SARS-CoV-2 replication in human airway epithelial cells (AECs). We show that PAV-104 inhibits >99% of infection with diverse SARS-CoV-2 variants in immortalized AECs, and in primary human AECs cultured at the air-liquid interface (ALI) to represent the lung microenvironment in vivo.

Our data demonstrate that PAV-104 inhibits SARS-CoV-2 production without affecting viral entry, mRNA transcription, or protein synthesis. PAV-104 interacts with SARS-CoV-2 nucleocapsid (N) and interferes with its oligomerization, blocking particle assembly. Transcriptomic analysis reveals that PAV-104 reverses SARS-CoV-2 induction of the type-I interferon response and the maturation of nucleoprotein signaling pathway known to support coronavirus replication. Our findings suggest that PAV-104 is a promising therapeutic candidate for COVID-19 with a mechanism of action that is distinct from existing clinical management approaches. PAV-104, a small molecule, potently inhibits SARS-CoV-2 replication in human airway epithelial cells by disrupting viral particle assembly and release. These findings suggest that PAV-104 holds significant promise as a therapeutic for COVID-19.

Published (April 22, 2024):

https://doi.org/10.1038/s42003-024-06130-8 

Immunocompromised patients often fail to raise protective vaccine-induced immunity against the global emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. Although monoclonal antibodies have been authorized for clinical use, most have lost their ability to potently neutralize the evolving Omicron subvariants. Thus, there is an urgent need for treatment strategies that can provide protection against these and emerging SARS-CoV-2 variants to prevent the development of severe coronavirus disease 2019.

Here, we report on the design and characterization of a long-acting viral entry-blocking angiotensin-converting enzyme 2 (ACE2) dimeric fusion molecule. Specifically, a soluble truncated human dimeric ACE2 variant, engineered for improved binding to the receptor-binding domain of SARS-CoV-2, was fused with human albumin tailored for favorable engagement of the neonatal fragment crystallizable receptor (FcRn), which resulted in enhanced plasma half-life and allowed for needle-free transmucosal delivery upon nasal administration in human FcRn-expressing transgenic mice. Importantly, the dimeric ACE2-fused albumin demonstrated potent neutralization of SARS-CoV-2 immune escape variants.

Published in P.N.A.S (December 2023):

https://doi.org/10.1093/pnasnexus/pgad403

Background

Methods

Findings

Interpretation

Background: Post-acute sequelae of COVID, termed “Long COVID”, is an emerging chronic illness potentially affecting ~10% of those with COVID-19. We sought to determine if outpatient treatment with metformin, ivermectin, or fluvoxamine could prevent Long COVID. 

Methods: COVID-OUT (NCT04510194) was a decentralized, multi-site trial in the United States testing three medications (metformin, ivermectin, fluvoxamine) using a 2x3 parallel treatment factorial randomized assignment to efficiently share placebo controls. Participants, investigators, care providers, and outcomes assessors were masked to randomized treatment assignment. Inclusion criteria included: age 30 to 85 years with overweight or obesity, symptoms <7 days, enrolled within <=3 days of documented SARS-CoV-2 infection. Long COVID diagnosis from a medical provider was a pre-specified secondary outcome assessed by monthly surveys through 300 days after randomization and confirmed in medical records. 

Findings: Of 1323 randomized trial participants, 1125 consented for long-term follow up, and 95.1% completed >9 months of follow up. The median age was 45 years (IQR, 37 to 54), and 56% were female (7% pregnant). The median BMI was 30 kg/m2 (IQR, 27 to 34). Overall, 8.4% reported a medical provider diagnosed them with Long COVID; cumulative incidence: 6.3% with metformin and 10.6% with matched placebo. The hazard ratio (HR) for metformin preventing Long COVID was 0.58 (95%CI, 0.38 to 0.88; P=0·009) versus placebo. The metformin effect was consistent across subgroups, including viral variants. When metformin was started within <4 days of symptom onset, the HR for Long COVID was 0.37 (95%CI, 0.15 to 0.95).  No statistical difference in Long COVID occurred in those randomized to either ivermectin (HR=0.99; 95%CI, 0.59 to 1.64) or fluvoxamine (HR=1.36; 95%CI, 0.78 to 2.34).

Interpretations: A 42% relative decrease and 4.3% absolute decrease in the Long COVID incidence occurred in participants who received early outpatient COVID-19 treatment with metformin compared to exact-matching placebo.

Trial Registration: ClinicalTrials.gov: NCT04510194.

Preprint available at the Lancet (March 6, 2023):

https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4375620 

Believed to be the world’s first COVID-19 therapeutic created by generative AI, the drug will soon begin clinical trials, the Canadian-founded company announced. For the first time ever, a COVID-19 drug entirely designed by generative AI has been approved for human use and will soon begin clinical trials in China, the Canadian-founded company announced Thursday. The drug, named ISM3312, was discovered in a matter of months by multinational biotechnology company Insilico Medicine. Believed to be the world’s first COVID-19 therapeutic created by generative AI, one of the company’s CEOs claims the drug is already “as perfect as it can get,” according to initial tests. “I just don’t think it’s possible to make a better one, period,” said Alex Zhavoronkov, the Canadian founder and co-CEO of Insilico Medicine, told the Star. “The molecule is so stable... it is an absolutely novel molecule not found in any of the libraries” of known therapeutics. ISM3312 showed great promise during preclinical studies done on mice and isolated cells, able to significantly lower viral load in lung tissue and reduce lung inflammation. It can be taken orally or inhaled, is effective even at low doses and potentially has few side effects, the company said in a release. “If your molecule is very tolerable, and if you make very little of it available in the body and it still works, it’s perfect, right?” Zhavoronkov said.

ISM3312 works by inhibiting a protein called 3CL protease — a critical factor in viral replication and a popular target for anti-COVID drugs. Unlike similar therapeutics, however, Zhavoronkov said his drug works on a very broad spectrum — showing efficacy not only against all current COVID variants, but also coronaviruses other than SARS-CoV-2. As such, it may possess the ability to resist future mutations, providing a solution to drug-resistant strains, he continued. “You can also use it potentially for prevention,” Zhavoronkov said — because the 3CL protease target is only present in viruses, it should be safe to take when otherwise healthy. The company started work on the drug in early 2020, back near the start of the pandemic. They began by slotting the 3D structure of 3CL protease into one of their in-house AI programs; within a matter of days, the model was able to generate about 20 different potential drug candidates from scratch. In contrast, traditional drug discovery pipelines can take years or even decades to find one suitable therapeutic. “The beauty of generative AI (in drug discovery) is instead of searching for a needle in a haystack, it generates a bunch of perfect needles for you,” Zhavoronkov said. “Then you just have to choose from those perfect needles — if you want the longer one or the one that is more stable.” By February of 2020, Insilico had published their first set of drug candidates online; by April, they’d filed a related patent application. But it wouldn’t be until recently that they’d receive approval to start clinical trials. “Unfortunately, at that time, you probably remember everybody was running around with their heads on fire, right?” Zhavoronkov said.

Insilico, still a relatively small company at the time, had difficulty finding a partner interested in their product. “Some big pharmas thought that COVID was going to go away very quickly, some big pharmas thought vaccines will solve the problem and some big pharmas didn’t even believe there was a pandemic for a while,” he continued. “And at that time we were not exactly very well funded.” The project was further stalled in 2021 due to the limited availability of COVID-19 viruses for use in testing, with governments and big pharmaceutical companies given priority. Insilico used the delay to refine and improve on their drug candidates, eventually narrowing the list down to just one: ISM3312. While frustrating, Zhavoronkov admitted the delay inadvertently led to the discovery of his “perfect” drug and its subsequent approval for human use by the China National Medical Products Administration. That said, had all the resources been available at the start, Zhavoronkov said “I can probably do it all again in under a year.” The company hasn’t given a start date or timeline for the clinical trials, though it promises to start “soon.” “There remains an urgent need for conducting well-designed clinical trials for scientific evaluation of potential COVID-19 therapies such as ISM3312,” said Dr. Sujata Rao, Insilico’s senior vice-president and head of clinical development, in a release. “We are committed to exploring ongoing unmet medical needs to include subgroups under-represented in COVID-19 trials as well as in patients who may have variants that are more resistant to antiviral drugs.” Insilico isn’t the only company utilizing AI to treat COVID-19, but they may be the furthest along. For example, company Exscientia AI limited is currently in the discovery phase of a new COVID drug using a different AI system, in a project wholly backed by the Bill and Melinda Gates Foundation. Given the promise of their new drug, Zhavoronkov said it may be a “very long time,” if ever, before Insilico looks at making another COVID-19 therapeutic. “It might make sense developing maybe one more drug for COVID, also AI generated. But that would come much later — it will take a while for resistance to develop against mine.”

In a recent study published in The New England Journal of Medicine, researchers used the TOGETHER platform trial protocol to perform a phase III randomized controlled trial (RCT) to evaluate the effectiveness of pegylated interferon (IFN) lambda (λ) therapy in outpatients with coronavirus disease 2019 (COVID-19) in Canada and Brazil. They implemented this trial between June 24, 2021, and February 7, 2022. The TOGETHER platform trial evaluated 12 different therapeutic interventions against COVID-19 since its commencement in June 2020.

Background

Type III IFNs represent the first line of defense in upper respiratory tract (URT) infections, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, SARS-CoV-2 elicits weak expression of type III IFNs. Thus, COVID-19 treatment with an exogenous source, such as pegylated IFN λ, could trigger broad-spectrum antiviral immunity to help treat SARS-CoV-2 infection at an early stage. Two phase II studies have characterized the influence of pegylated interferon lambda treatment on SARS-CoV-2 viral load. Likewise, over 20 clinical trials covering over 4,000 patients with multiple diseases, including hepatitis B, C, and D, and COVID-19, have shown the safety and side effects of pegylated interferon lambda.

About the study

In the present study, researchers screened patients attending the trial outpatient care clinics to identify adults ≥ 18 years who presented with COVID-19 within seven days of symptom onset or met the high-risk criterion for proceeding to COVID-19 (e.g., older age, type II diabetes, obesity). All patients who met the eligibility criteria provided written informed consent, and trial personnel performed a SARS-CoV-2 rapid antigen test. Prior to randomization, trial personnel gathered each patient's sociodemographic characteristics, pre-existing health conditions, and the World Health Organization (WHO) clinical progression scale for COVID-19. A pharmacist randomized all participants using a block randomization procedure at a trial facility, stratifying participants in age-based groups (less than or greater than 50 years) for the administration of pegylated interferon lambda (study group) or placebo. The treating physicians and other staff involved in the trial remained blinded to the randomized assignments. The primary study outcome was hospitalization due to the progression of COVID-19 or an emergency department (ED) visit within 28 days after randomization. Likewise, they assessed secondary outcomes within 28 days after randomization, which covered SARS-CoV-2 clearance, time lapse since randomization to COVID-19-related hospitalization or death, days spent in hospital or intensive care unit (ICU) with mechanical ventilation, and adverse reactions to treatment or placebo. They recorded adverse events as they occurred and other data on prespecified days. The team performed virological assessments virtually on days three and seven after randomization using mid-turbinate nasal swabs. The data and safety monitoring committee assessed the safety and efficacy of pegylated interferon lambda therapy vs. placebo based on set thresholds in the statistical plan. They ceased enrolling patients into the study group as soon as they met the prespecified threshold for efficacy. The researchers applied a Bayesian framework to all statistical analyses to present the supremacy of interferon over placebo concerning the primary and the safety outcomes.

Results

Of 2,617 patients recruited in the trial, 933 and 1,018 were randomized to receive interferon treatment and placebo, respectively. The average age of the trial patients was 43 years, and 57.1% were women. Concerning primary outcome, both intention-to-treat and modified intention-to-treat populations yielded similar results. A primary outcome event ensued in 25/931 patients in the interferon lambda group and 57/1018 of the placebo group, with a relative risk (RR) of 0.49 and 95% Bayesian credible interval (CI) in the former. For the latter, it occurred in 23/929 and 55/1018 patients in the interferon and placebo groups, respectively, with RR of 0.47; 95% Bayesian CI. The most frequent primary-outcome event was hospitalization, which occurred in a median of five days post-randomization and comprised 74% of all events in the intention-to-treat population. The effect of interferon treatment increased among patients who had received it within three days of symptom onset. Accordingly, only 11/567 and 28/590 patients in the interferon and placebo groups experienced a primary event, with RR of 0.42; 95% Bayesian CI.

Conclusions

This phase III trial demonstrated that a single subcutaneous dose of pegylated interferon lambda administered within a week of the onset of symptoms reduced the risk of a primary outcome event (hospitalization) by more than 50%. It also reduced the time to COVID-19-related hospitalization or death by 41%, hazard ratio (HR) equal to 0.59, 95% Bayesian CI. Among patients who received the treatment within three days after symptom onset, it further reduced to 65%, RR equals 0.42; 95% Bayesian CI. Intriguingly, among the patients with a baseline viral load >192 million copies per milliliter (high), interferon treatment showed its effect at day 7 only. The median log10 decline in viral loads was 8.29 in the interferon group and 5.16 in the placebo group; the same for hospitalized patients was 7.19 and 3.16 in the interferon and placebo groups, respectively. To summarize, this large-scale trial involving most COVID-19 vaccinated outpatients with symptomatic COVID-19 showed that a single dose of pegylated interferon lambda reduced the incidence of hospitalization or an ED visit due to COVID-19 regardless of infecting SARS-CoV-2 variant. Thus, this treatment regimen could play a vital role in response to COVID-19.

Published in NEJM (Feb. 9, 2023):

https://www.nejm.org/doi/full/10.1056/NEJMoa2209760   

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.