Virus World

Introduction

Background

Methods

Findings

Interpretation

Merck & Co.’s molnupiravir appears to be speeding evolution of SARS-CoV-2. A widely used COVID-19 drug may be driving the appearance of new SARS-CoV-2 variants, sparking concerns it could prolong and even reinvigorate the pandemic. The drug, molnupiravir, produced by Merck & Co., is designed to kill the virus by inducing mutations in the viral genome. A survey of viral genomes reported in a new preprint, however, suggests some people treated with the drug generate novel viruses that not only remain viable, but spread. “It’s very clear that viable mutant viruses can survive [molnupiravir treatment] and compete [with existing variants],” says virologist William Haseltine, chair of ACCESS Health International, who has repeatedly raised concerns about the drug. “I think we are courting disaster.” But a Merck spokesperson disputes that the drug has led to the emergence of widely circulating variants, and some researchers downplayed the significance of molnupiravir-caused mutations. “Right now, it’s much ado about nothing,” says Raymond Schinazi, a medicinal chemist at the Emory University School of Medicine, noting that with SARS-CoV-2 infecting millions of people worldwide, the virus is naturally mutating at a fast clip. Authorized in the United Kingdom and the United States in late 2021, molnupiravir was the first oral antiviral approved anywhere to fight COVID-19. It has since been authorized in dozens of other countries. In 2022, Merck estimated global sales of the compound at more than $5 billion. Though that is well below the $18.9 billion in 2022 sales for Paxlovid, another oral SARS-CoV-2 antiviral, molnupiravir remains widely popular in certain countries. From the start, however, Haseltine and others worried about the drug’s mechanism, which involves introducing so many mutations into the viral genome that it can no longer reproduce. One concern was that the drug might mutate not just the coronavirus, but the DNA of people receiving it—a side effect that has not been seen so far. Another was that mutated virus would survive and propagate—and perhaps turn out to be more transmissible or virulent than before.

Before the U.S. Food and Drug Administration authorized the drug, a Merck spokesperson called the worry “an interesting hypothetical concern.” Nevertheless, researchers and citizen scientists from around the globe began to scan SARS-CoV-2 genome sequences deposited in the international GISAID database, looking for the kinds of mutations expected to be caused by molnupiravir. Rather than inducing random changes in the virus’ RNA genome, the drug is more likely to cause specific nucleic acid substitutions, with guanine switching to adenine and cytosine to uracil. One virus hunter, Ryan Hisner, a middle school science and math teacher in Monroe, Indiana, started to catalog suspect variants in August 2022 and quickly identified dozens of sequences that showed clusters of those hallmark substitutions. Hisner raised his concerns with researchers on Twitter and ultimately teamed up with Thomas Peacock, a virologist from Imperial College London. With other colleagues, the pair systematically reviewed more than 13 million SARS-CoV-2 sequences in GISAID and analyzed those with clusters of more than 20 mutations. In a preprint posted on 27 January, they report that a large subset showed the hallmark substitutions; all dated from 2022, after molnupiravir began to be widely used. These signature clusters, the researchers found, were up to 100 times more common in countries where molnupiravir was widely used, including the United States, Australia, and the United Kingdom, than in countries such as France and Canada where it was not. Tracking the dates and locations of the sequences showed some of the mutated strains were spreading in the community. “Clearly something is happening here,” Peacock says. Whether the changes will lead to variants that are more pathogenic or transmissible is unclear, the researchers say. “We are not coming to a conclusion about risk,” says team member Theo Sanderson, a geneticist at the Francis Crick Institute. Haseltine, however, likens the danger to keeping a pet lion. “Just because it didn’t bite you yesterday doesn’t mean it won’t bite you today,” he says. The Merck spokesperson says the link between the mutations and the drug is unproved. “There is no evidence that any antiviral agent has contributed to the emergence of circulating variants,” she says.

But the new result comes on the heels of two others that could change the risk-benefit calculus for the drug. In one, researchers in Australia found evidence that molnupiravir treatment may be leading to new variants in immunocompromised patients. Because these patients’ immune systems have trouble clearing the virus, viral variants can accrue large numbers of mutations, possibly causing big leaps in viral behavior that can then be passed to others. (Researchers have speculated that Omicron and other SARS-CoV-2 variants evolved naturally in immunocompromised people.) Repeatedly sequencing SARS-CoV-2 genomes from nine patients, five of whom received the drug and four who did not, the researchers found that molnupiravir-treated individuals harbored an average of 30 new variants each within 10 days of the initial dose, far more than the untreated patients. “Our study demonstrates that this commonly used antiviral can ‘supercharge’ viral evolution in immunocompromised patients, potentially generating new variants and prolonging the pandemic,” the authors wrote in a 22 December 2022 preprint. A second report, which appeared on 28 January in The Lancet, suggests that, at least among people who have been vaccinated against COVID-19, molnupiravir offers limited benefits. The study tracked 26,411 vaccinated participants in the United Kingdom’s PANORAMIC clinical trial, roughly half of whom were given the drug. It did reduce symptom severity and improve patient recovery times, but the researchers found it did not lower the frequency of COVID-19–associated hospitalizations or deaths among high-risk adults. The new U.K. and Australian studies don’t prove molnupiravir is causing the emergence of dangerous new SARS-CoV-2 variants, says Ravindra Gupta, a clinical microbiologist at the University of Cambridge. But he argues the drug’s limited benefit suggests it’s no longer worth the risk. “Taken together, these results do call into question whether molnupiravir should be used.”

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 

A panel of experts advising the Food and Drug Administration voted narrowly in favor of emergency use authorization of an antiviral pill from Merck and Ridgeback Biotherapeutics to treat COVID-19. The vote was 13 for and 10 against authorization. The FDA isn't obligated to follow the recommendations of its advisers but typically does. If the agency authorizes use of the drug, called molnupiravir, it would be the first oral antiviral treatment for COVID-19 that could be taken at home. A second oral medicine from Pfizer, called Paxlovid, is also being considered for authorization by the FDA. The Merck drug is taken twice a day for five days and works by causing a cascade of disabling mutations in the SARS-CoV-2 coronavirus during replication. The drug is intended for use by people with mild to moderate illness and who are at high risk of developing severe COVID-19. It is supposed to be taken within five days of symptoms.  An interim analysis of a clinical study of the drug found that molnupiravir cut the risk of hospitalization or death in half. Among people who got the drug, 7.1% ended up in the hospital or died, compared with 14.1% who got the placebo. However, the final study analysis released Friday showed only a 30% reduction in the risk of hospitalization or death.  An FDA summary showed that in the second half of the study, patients in the group treated with the drug were more likely to be hospitalized or to die than those who got the placebo. The drug's protection against death seen in the first half of the study didn't hold up in the second half.

When asked about this discrepancy by committee chairperson Dr. Lindsey Baden, Dr. Nicholas Kartsonis, a Merck senior vice president, said, "I don't have a satisfying answer to your question." The ability of the medicine to cause mutations beyond the virus, as seen in some lab and animal tests, raised some safety issues that were discussed at length during the daylong meeting. The possibility of birth defects weighed on the panel, and there were reservations about prescribing the drug for pregnant people. But the drug could also carry some benefits for them. "I don't think you can ethically say it's OK to give this drug in pregnancy, obviously," said Dr. Janet Cragan of the Centers for Disease Control and Prevention during the deliberations. "But at the same time, I'm not sure you can ethically tell a pregnant woman who has COVID-19 that she can't have the drug if she's decided that's what she needs." There were also concerns about whether the drug could cause harmful mutations in the spike protein of the virus, which is the target of COVID-19 vaccines in wide use around the world. During the panel's discussion, John Coffin, a virologist at Tufts University, said that an elevated random mutation rate like the one seen with molnupiravir is a relatively small factor in development of viral variants of concern. Several panelists called for additional study of the medicine in people with compromised immune systems in order to look for changes in the virus after they were treated with the drug.

Data package evaluated in the Nov. 30, 2021 meeting is available at:

https://www.fda.gov/media/154418/download 

EMA’s human medicines committee (CHMP) has issued advice on the use of Lagevrio (also known as molnupiravir or MK 4482) for the treatment of COVID-19. The medicine, which is currently not authorised in the EU, can be used to treat adults with COVID-19 who do not require supplemental oxygen and who are at increased risk of developing severe COVID-19. Lagevrio should be administered as soon as possible after diagnosis of COVID-19 and within 5 days of the start of symptoms. The medicine, which is available as capsules, should be taken twice a day for 5 days. EMA issued this advice to support national authorities who may decide on possible early use of the medicine prior to marketing authorisation, for example in emergency use settings, in light of rising rates of infection and deaths due to COVID-19 across the EU.

The advice follows a review of data, including data on the medicine’s quality and results from completed and ongoing studies. Interim results from the main study in non-hospitalised, unvaccinated patients with at least one underlying condition putting them at risk of severe COVID-19 were assessed as part of this advice. Lagevrio, when given at a dose of 800 mg twice a day, reduced the risk of hospitalisation and death when treatment started within 5 days of the start of symptoms. About one month after treatment started 7.3% of patients (28 out of 385) who took Lagevrio compared with 14.1% (53 out of 377) of patients who took placebo (a dummy treatment) had been hospitalised or had died; none of the patients in the Lagevrio group died compared with eight patients in the placebo group. In terms of safety, the most common side effects reported during treatment and within 14 days after the last dose of Lagevrio were diarrhoea, nausea, dizziness and headache, all of which were either mild or moderate.

Lagevrio is not recommended during pregnancy and in women who can become pregnant and are not using effective contraception. Women who can become pregnant must use effective contraception during treatment and for 4 days after the last dose of Lagevrio. Breastfeeding should be interrupted during treatment and for 4 days after treatment. These recommendations are given as laboratory studies in animals have shown that high doses of Lagevrio can impact the growth and development of the foetus. EMA’s proposed conditions of use are published on the EMA website. The Agency’s advice can now be used to support national recommendations on the possible use of the medicine before marketing authorisation. In parallel, a more comprehensive rolling review is ongoing ahead of a possible application for a marketing authorisation. EMA will further communicate on the progress of this review.

More about the medicine

Lagevrio is an oral antiviral medicine that reduces the ability of SARS-CoV-2 (the virus that causes COVID-19) to multiply in the body. It does this by increasing the number of alterations (mutations) in the virus’ genetic material (known as RNA) in a way that impairs the ability of SARS-CoV-2 to multiply.

Lagevrio is being developed by Merck Sharp & Dohme in collaboration with Ridgeback Biotherapeutics.

More about the procedure

EMA’s Executive Director requested the review under Article 5(3) of Regulation 726/2004 following preliminary discussions with EMA’s COVID-19 pandemic task force (COVID-ETF), which brings together experts from across the European medicines regulatory network, and with the Heads of Medicines Agencies (HMA). The review has been carried out by EMA’s Committee for Medicinal Products for Human Use (CHMP), which is responsible for questions concerning medicines for human use. The Committee’s scientific opinion can now be used by the EU Member States when making decisions on the use of this medicine at national level prior to marketing authorisation.

The UK Medicines and Healthcare Products Regulatory Agency said Thursday it had authorized Merck and Ridgeback Biotherapeutics' oral antiviral, molnupiravir, to treat mild-to-moderate Covid-19 in adults at risk for severe illness. It is the world's first oral antiviral to be authorized anywhere for the treatment of Covid-19. The drug comes in capsule form and will be known as Lagevrio. The companies have sought US Food and Drug Administration emergency use authorization for the drug, and the FDA said it will convene its Antimicrobial Drugs Advisory Committee on November 30 to discuss molnupiravir's ability to treat mild-to-moderate Covid-19 in adults who are at high risk for severe disease, including hospitalization or death. Merck and Ridgeback also say the European Medicines Agency has initiated a rolling review of its marketing application.  Merck announced last month that the capsule reduced the risk of hospitalization or death from Covid-19 by half. "At the interim analysis, molnupiravir reduced the risk of hospitalization or death by approximately 50%; 7.3% of patients who received molnupiravir were either hospitalized or died through Day 29 following randomization (28/385), compared with 14.1% of placebo treated patients (53,377)," the company said in a news release in October. "Through Day 29, no deaths were reported in patients who received molnupiravir, as compared to 8 deaths in patients who received placebo." The data has not yet been peer-reviewed or published, but spurred excitement about a potentially easy, accessible treatment for Covid-19.

The Bill & Melinda Gates Foundation is committing up to $120 million to accelerate production of generic versions of Merck's Covid-19 drug. A s concern mounts over access to Covid-19 remedies, the Bill & Melinda Gates Foundation is committing up to $120 million to accelerate production of generic versions of an experimental Merck (MRK) pill to treat Covid-19 that would be available to dozens of low-income countries. But the effort was greeted with mixed reactions by patient advocates. The Gates Foundation plans to provide different types of incentives so that eight generic manufacturers, all of which have already signed voluntary licensing deals with Merck, will be positioned to produce a sufficient quantity of the drug, called molnupiravir, as quickly as possible. The goal is to convince the generic companies to ready their facilities rather than wait to gauge demand for the pill — which early data suggests could reduce hospitalizations and deaths — before ramping up. “They have the capacity. They can do this,” Trevor Mundel, president of global health at the Gates Foundation. “This is an incentive for them to do it earlier rather than wait to see what the market is like… They want to see (if there will be) enough volume. They (may) want to see who will pay at the end of the day. We don’t want to them to wait.”  Notably, the Gates Foundation will offer volume guarantees over a specified period of time, so the generic manufacturers have confidence their production investments will return acceptable profit margins. So far, the foundation has also awarded $2.4 million in grants to help the generic companies more quickly apply to the World Health Organization for manufacturing prequalification.

As of now, the Gates Foundation has agreed to provide up to approximately $1.9 billion to underwrite various efforts to combat Covid-19. These include the COVAX vaccine distribution program – which is overseen by the WHO, the GAVI vaccine alliance and the Coalition for Epidemic Preparedness Innovations – and guarantees to support at-risk manufacturing of monoclonal antibody treatments for low- and middle-income countries.  This latest move comes after Merck reached a deal with large generic makers such as Cipla, Dr. Reddy’s Laboratories, and Sun Pharmaceuticals to supply its pill to more than 100 low-to-middle-income countries. For the moment, though, it is not clear how many pills each company will produce, the production costs the companies will incur, or the pricing. The Merck pill has generated excitement because top-line study results indicated it reduced both hospitalization and death compared to a placebo by 50%. In the placebo group, 53 patients, or 14.1%, were hospitalized or died. For those who received the drug, 28, or 7.3%, were hospitalized or died. The data from the study were made public in a press release and have not yet been peer-reviewed. The findings set off another wave of anxiety, however, over inequitable access to Covid-19 medical products. Last year, wealthy countries quickly reached deals with vaccine makers, leaving low and middle-income countries to largely rely on the World Health Organization to organize programs to purchase and distribute vaccines. So far, the effort has fallen short.

As a result, there has been consistent pressure on the vaccine makers to share their intellectual property and other know-how so that generic manufacturers could more readily produce Covid-19 vaccines and make them available at lower costs to poorer countries. Pope Francis, for instance, urged the vaccine makers to do so in remarks earlier this week. By striking the voluntary licensing agreements, Merck is hoping to avoid a similar fate. But the company, which developed the pill along with Ridgeback Biotherapeutics, has not indicated any plans to share its intellectual property. However, Merck has said it is in discussions with the Medicines Patent Pool, a United Nations-sponsored organization, to explore the potential for additional licenses. Consequently, the specter of inequitable access has surfaced. ‘While any initiative to accelerate production and access, especially on the African continent and low income countries, is welcome, the Gates Foundation investment is incomplete. Vaccine and treatment apartheid affect all low and middle-income countries today due to intellectual property barriers,” said Rohit Malpani, a former director of policy and analysis at Doctors Without Borders and now a board member at UNITAID, which backs the Medicines Patent Pool. “It is necessary also to tackle these patent barriers to ensure access to these medicines. The Gates Foundation should be throwing it’s considerable power and influence behind a waiver of intellectual property rules at the World Trade Organization, as well as pressuring Merck to expand the voluntary license to include all countries.” The concern has been further fueled by uncertainty over pricing. The U.S. government signed a $1.2 billion deal to purchase 1.7 million doses. That works out to a $712 unit cost for a five-day treatment course, according to the contract. The company has indicated there are plans to produce 10 million doses by the end of this year and 20 million doses in 2022......

The drug maker will seek authorization for molnupiravir, the first drug of its kind for Covid. Experts said such pills could be a powerful tool against the virus.  The drug maker Merck said on Friday that it would seek authorization for the first antiviral pill for Covid after its drug, known as molnupiravir, was shown in a clinical trial to cut the risk of hospitalization or death in half when given to high-risk people early in their infections. The treatment could become the first in a wave of antiviral pill products, which experts say could offer a powerful new tool in efforts to tame the pandemic, as they could reach more people than the antibody treatments that are being widely used in the United States for similar patients. “I think it will translate into many thousands of lives being saved worldwide, where there’s less access to monoclonal antibodies, and in this country, too,” said Dr. Robert Shafer, an infectious disease specialist and expert on antiviral therapy at Stanford University. Late-stage study results of two other antiviral pills, one developed by Pfizer and the other by Atea Pharmaceuticals and Roche, are expected within the next few months.  The Merck drug, which is designed to stop the coronavirus from replicating, is to be taken as four capsules twice a day for five days.

Merck said an independent board of experts monitoring its study data had recommended that its trial be stopped early because the drug’s benefit to patients had proved so convincing. The company said that the Food and Drug Administration had agreed with that decision.  For the research, the monitors looked at data through early August, when the study had enrolled 775 volunteers in the United States and overseas. For volunteers who received the drug, their risk of being hospitalized or dying fell 50 percent, without any concerning side effects, compared with those who received placebo pills, Merck said in a news release announcing the findings. Seven percent of volunteers in the group that received the drug were hospitalized, and none of them died, compared with a 14 percent rate of hospitalization and death — including eight deaths — in the group that received the placebo. The Merck pill’s efficacy was lower than that of monoclonal antibody treatments, which mimic antibodies that the immune system generates naturally when fighting the virus. Those drugs have been in high demand recently, but they are expensive, are typically given intravenously, and have proved cumbersome and labor-intensive for hospitals and clinics to administer. Studies have shown that they reduce hospitalizations and deaths 70 to 85 percent in similar high-risk Covid patients. 

Still, Angela Rasmussen, a virologist and research scientist at the Vaccine and Infectious Disease Organization at the University of Saskatchewan, said that antiviral pills could have a greater impact by virtue of reaching more people. “If that holds up at the population scale,” she said, “that is going to translate to an objectively larger number of lives saved potentially with this drug,” adding that, “Maybe it isn’t doing the same numbers as the monoclonal antibodies, but it’s still going to be huge.” The federal government has placed advance orders for 1.7 million courses of Merck’s drug, at a price of about $700 per patient. That is about one-third of the current cost of a monoclonal antibody treatment. Merck — which is developing the pill with its partner, Ridgeback Biotherapeutics of Miami — has not said which patients it plans to ask the F.D.A. to approve the drug for. It may be initially approved for the limited group of patients who are eligible to receive monoclonal antibody treatments: possibly older people and those with medical conditions that put them at high risk for bad outcomes from Covid. But experts said they expected that the drug might eventually be used more widely, in many people who test positive for the virus. If authorized, Merck’s drug would be the second antiviral treatment for Covid. The first, remdesivir, must be infused and has lost favor among clinicians as studies have suggested that it offers only modest benefit for Covid patients.

KENILWORTH, N.J.--(BUSINESS WIRE)--Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced it has entered into a procurement agreement with the United States government for molnupiravir (MK-4482). Molnupiravir is currently being evaluated in a Phase 3 clinical trial, the MOVe-OUT study, for the treatment of non-hospitalized patients with laboratory-confirmed COVID-19 and at least one risk factor associated with poor disease outcomes. Merck is developing molnupiravir in collaboration with Ridgeback Biotherapeutics. “Merck is pleased to collaborate with the U.S. government on this new agreement that will provide Americans with COVID-19 access to molnupiravir – an investigational oral therapy being studied for outpatient use early in the course of disease – if it is authorized or approved,” said Rob Davis, president, Merck. “In addition to this agreement with the U.S. government, we are actively engaged in numerous efforts to make molnupiravir available globally to fulfill Merck’s commitment to widespread access.” Through the agreement, if molnupiravir receives Emergency Use Authorization (EUA) or approval by the U.S. Food and Drug Administration (FDA), Merck will receive approximately $1.2 billion to supply approximately 1.7 million courses of molnupiravir to the United States government. Merck has been investing at risk to support development and scale-up production of molnupiravir and expects to have more than 10 million courses of therapy available by the end of 2021.

Merck also plans to submit applications for emergency use or approval to regulatory bodies outside of the U.S. and is currently in discussions with other countries interested in advance purchase agreements for molnupiravir. Merck is committed to providing timely access to molnupiravir globally and intends to implement a tiered pricing approach based on World Bank data that recognizes countries’ relative ability to finance their public health response to the pandemic. As part of its access strategy, Merck has also entered into non-exclusive voluntary licensing agreements for molnupiravir with established generic manufacturers to accelerate availability of molnupiravir in 104 low- and middle-income countries (LMICs) following approvals or emergency authorization by local regulatory agencies. In addition to developing molnupiravir, Merck is contributing to the pandemic response by collaborating with Johnson & Johnson to support the manufacture of its COVID-19 vaccine. This procurement of molnupiravir will be supported in whole or in part with federal funds from the Department of Health and Human Services; Office of the Assistant Secretary for Preparedness and Response; Biomedical Advanced Research and Development Authority, in collaboration with the DOD Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense (JPEO-CBRND) under contract number W911QY21C0031.

About Molnupiravir

Molnupiravir (EIDD-2801/MK-4482) is an investigational, orally bioavailable form of a potent ribonucleoside analog that inhibits the replication of multiple RNA viruses including SARS-CoV-2, the causative agent of COVID-19. Molnupiravir has been shown to be active in several models of SARS-CoV-2, including for prophylaxis, treatment and prevention of transmission, as well as SARS-CoV-1 and MERS. EIDD-2801 was invented at Drug Innovations at Emory (DRIVE), LLC, a not-for-profit biotechnology company wholly owned by Emory University, and with partial funding support from the U.S. government. Since licensed by Ridgeback, all funds used for the development of EIDD-2801 by Ridgeback have been provided by Wayne and Wendy Holman and Merck. The Phase 3 portion (Part 2) of the MOVe-OUT study, evaluating the potential of molnupiravir to reduce the risk of hospitalization or death, is ongoing. Merck currently anticipates that, pending favorable results from MOVe-OUT, the earliest possible submission for an Emergency Use Authorization for molnupiravir will be in the second half of 2021. Merck and Ridgeback Biotherapeutics plan to share further findings from the ongoing molnupiravir development program with regulatory agencies as they become available. For more information on the molnupiravir clinical trial please visit https://merckcovidresearch.com/. In addition, Merck plans to initiate a clinical program to evaluate molnupiravir for post- exposure prophylaxis in the second half of 2021....

The drug company Merck released promising early data over the weekend on the Covid-19 antiviral it is developing with a private firm called Ridgeback Biotherapeutics, giving the company a shot at an entry into the coronavirus marketafter the failure of its vaccine efforts.  The data, which the company presented Saturday at a scientific conference, come from a Phase 2a trial involving 202 adults with symptomatic Covid-19 infections. The company reported that among subjects with infectious virus at the start of their experimental treatment, none of the 47 who received the drug remained positive after five days. Six of the 25 who received the placebo remained positive. Those patients were tested for the purposes of this endpoint not using RT-PCR tests, the so-called gold standard, but rather by isolation of samples in a Vero cell line culture. That is an interesting start, analysts said, though much remains to be seen about the antiviral, which is called molnupiravir.  “Good start, not yet definitive,” wrote Mizuho analyst Mara Goldstein in a note out Sunday. “We see these data as incrementally positive for molnupiravir as an oral antiviral therapeutic – supportive of further clinical evaluation – though not yet definitive.”

Merck has not yet published data on the primary efficacy objective of the study, which is reduction in time to a negative RT-PCR test in Covid-19 patients. And while it said that “no safety signals have been identified,” it didn’t offer details on the safety findings. In a note Monday morning, SVB Leerink analyst Daina Graybosch wrote that investors are likely to be frustrated by the missing information. “Although these results… are the most substantive set of clinical data we have seen yet for molnupiravir program, we expect investors will be disappointed by the low level of disclosure, as safety details and results from primary endpoint (viral detection by RT-PCR) were held back for a future undisclosed meeting,” she wrote. Shares of Merck were up 0.8% in premarket trading on Monday. The stock is down 10.6% so far this year, and off 7.4% over the past 12 months. “We continue to make progress in our Phase 2/3 clinical programs evaluating molnupiravir in both outpatient and hospital settings and plan to provide updates when appropriate,” said Roy Barnes, Merck’s head of global clinical development and the chief medical officer of Merck Research Laboratories, in a Saturday statement.  Merck is developing molnupiravir in collaboration with a private biotech company called Ridgeback Biotherapeutics.

Despite its position as a leading vaccine developer and manufacturer, Merck dropped its Covid-19 vaccine programs after disappointing early results. The company’s revenue remains heavily reliant on its blockbuster cancer drug, Keytruda. But in a note Monday, Citi Research analyst Andrew Baum wrote that the company’s potential in Covid-19 is “materially underestimated,” and that the data on Saturday raised his expectations for data still to come on trials of the drug. “The accelerated clearance of infectious mRNA in COVID-19 patients treated with oral molnupiravir builds on promising animal data… and increases our confidence for the pending interim phase III analysis of molnupiravir (in out-patient treated COVID-19 patients in particular),” Baum wrote. “Molnupiravir also has potential as a post exposure prophylactic for COVID-19 as well as potential utility for other mRNA viruses such as RSV.” Merck’s 2021 financial forecasts don’t include any potential revenue from Covid-19 therapeutics, Cantor Fitzgerald analyst Louise Chen wrote in a Sunday note.

Merck Press release (March 6, 2021):

https://www.merck.com/news/ridgeback-biotherapeutics-and-merck-announce-preliminary-findings-from-a-phase-2a-trial-of-investigational-covid-19-therapeutic-molnupiravir/

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 

Unused coronavirus medication for humans will be made available to treat cats in Cyprus, where they have been dying in their thousands from feline Covid, officials have announced. The government gave the green light in line with a recommendation from the agriculture ministry. A variant of coronavirus – feline infectious peritonitis (FIP), not transmittable to humans – has been wreaking havoc on the prolific cat population of the Mediterranean island. “Stocks of preparations that were used to treat human coronavirus cases and are no longer used can be made available,” the cabinet said in a statement. The medication, in the form of anti-Covid pills, will be supplied through veterinary services. Animal activists have said Cyprus was turning into an “island of dead cats”, saying the disease was likely to have killed much of its million-strong population. But Cyprus’s veterinary association said reports of up to 300,000 cats dying was an exaggeration, and put the number at less than 10,000. Legend has it that a Roman empress, Helena, first brought cats to Cyprus to combat poisonous snakes about 1,700 years ago. But archaeological evidence of cats’ domestication on the island dates back to 9,500 years ago to the Neolithic village of Shillourokambos, where the remains of a cat and a human were found deliberately buried together.

Molnupiravir, an antiviral medication that has been widely used against SARS-CoV-2, acts by inducing mutations in the virus genome during replication. Most random mutations are likely to be deleterious to the virus, and many will be lethal. Molnupiravir-induced elevated mutation rates have been shown to decrease viral load in animal models. However, it is possible that some patients treated with molnupiravir might not fully clear SARS-CoV-2 infections, with the potential for onward transmission of molnupiravir-mutated viruses. We set out to systematically investigate global sequencing databases for a signature of molnupiravir mutagenesis. We find that a specific class of long phylogenetic branches appear almost exclusively in sequences from 2022, after the introduction of molnupiravir treatment, and in countries and age-groups with widespread usage of the drug. We calculate a mutational spectrum from the AGILE placebo-controlled clinical trial of molnupiravir and show that its signature, with elevated G-to-A and C-to-T rates, largely corresponds to the mutational spectrum seen in these long branches. Our data suggest a signature of molnupiravir mutagenesis can be seen in global sequencing databases, in some cases with onwards transmission.

Preprint available at medRxiv (January 27, 2023):

https://doi.org/10.1101/2023.01.26.23284998 

The FDA granted emergency authorization to Merck’s molnupiravir, an antiviral pill shown to reduce hospitalization and death in cases of Covid-19, the second such treatment to be authorized. The Food and Drug Administration on Thursday granted emergency authorization to Merck’s molnupiravir, an antiviral pill shown to reduce hospitalization and death in cases of Covid-19, but only in cases where other FDA-authorized Covid treatments are not accessible or clinically appropriate. The approval comes a day after the FDA authorized an antiviral pill from Pfizer for much broader use in patients as young as 12. “Today’s authorization provides an additional treatment option against the COVID-19 virus in the form of a pill that can be taken orally. Molnupiravir is limited to situations where other FDA-authorized treatments for COVID-19 are inaccessible or are not clinically appropriate and will be a useful treatment option for some patients with COVID-19 at high risk of hospitalization or death,” Patrizia Cavazzoni, director of the FDA’s Center for Drug Evaluation and Research, said in a statement. 

A Merck spokesperson said Merck is ready to ship hundreds of thousands of courses of treatment within days of authorization and 1 million courses over the next few weeks in the U.S. Ten million courses are ready to be packaged and distributed worldwide. In clearing molnupiravir, developed by Merck and Ridgeback Therapeutics, the FDA accepted a narrow recommendation from a panel of advisers who were torn over whether to back the therapy. In a clinical trial, a five-day course of the pill was shown to be only modestly effective. The data also showed it could cause birth defects if used in pregnancy. Acknowledging those risks, the FDA included a number of warnings and precautions with its authorization. The drug is not recommended for use in pregnancy, but doctors can prescribe it to pregnant women at their discretion. Females of childbearing age should be using contraception during treatment and for four days after the final dose. Males of childbearing age are also advised to use contraception during treatment and for three months following their last dose. While Pfizer’s Paxlovid was authorized for children as young as 12, molnupiravir is not being authorized for patients younger than 18. Some data from animals indicate the drug might affect bone and cartilage growth.

Antivirals are seen as potentially critical weapons in the fight against Covid-19, buttressing but by no means replacing tools like vaccines and monoclonal antibodies. Ideally, oral treatments would be easy to access for patients who contract the SARS-CoV-2 virus and prevent hospitalization or death. The need has increased with the new Omicron variant, because many of the monoclonal antibodies against Covid appear to be less potent against it, while the oral antivirals appear to maintain their efficacy. But data on molnupiravir showed its potential could be limited. Initial results from a study showed it reduced hospitalizations by 50% — but that figure was revised downward to 30% after full data were released. In the 1,433-patient study, fewer patients died when they received the treatment. There were nine deaths in the placebo group in the final analysis, and one in the molnupiravir group. Patients in the study had mild-to-moderate Covid-19 and had at least one risk factor associated with poor disease outcomes, including being over 65, being overweight, or having cardiovascular disease. Pfizer’s Paxlovid appears to have advantages in both efficacy and safety, but molnupiravir is likely to still have a role. At the beginning of 2022, there will be a much greater supply of molnupiravir. Pfizer has said it will produce greater than 180,000 courses by the end of the year, and then will make 140 million courses in 2022.

EUA letter by FDA (Dec. 23, 2021):

https://www.fda.gov/media/155053/download 

Final trial data for molnupiravir were less convincing than what Merck previously reported and could alter how the FDA views the drug, which will be evaluated at a meeting Tuesday.  New study results disclosed by Merck & Co. on Friday indicated its COVID-19 pill molnupiravir may not be as effective as the company previously stated, a finding that could change how the Food and Drug Administration and its advisers view the drug at an upcoming meeting. In October, Merck said the drug reduced hospitalizations and deaths by nearly 50% in a large trial among people who had mild or moderate COVID-19. That announcement was based on a preliminary results from 775 trial participants, and the data were so convincing that outside study monitors directed Merck to stop testing early.  The result positioned Merck to bring the first oral COVID-19 treatment to market, a potentially significant tool to control outbreaks and protect vulnerable people. The company quickly filed for an emergency clearance in the U.S., an application FDA advisers will scrutinize at a public hearing Tuesday. The Biden administration has already preordered more than 3 million treatment courses. The drug was cleared for use in the U.K. on Nov. 4, and a regulatory review is underway in Europe as well. But the final study results Merck announced Friday, from all 1,433 volunteers enrolled in the study, raise questions about the drug's benefit. Overall, treatment reduced the relative risk of hospitalization and death in the trial by 30% versus placebo. Roughly 10% of the 699 people who received a placebo were hospitalized or died, compared to about 7% of the 709 patients treated with molnupiravir, Merck said.

Nine people given a placebo died, according to Merck, versus only one who was treated with molnupiravir. The drug's side effect profile was consistent with what the company previously reported. Briefing documents posted by the FDA on Friday indicated the agency is ready to authorize molnupiravir based on the interim study results, but struggling to decide who should be eligible for treatment. Merck has sought clearance for people with mild or moderate COVID-19 who are at "high risk" of worse outcomes, a similar group to those who can receive infused or injectable antibody drugs from Regeneron, Eli Lilly and Vir Biotechnology. But staff scientists raised some concerns about molnupiravir, including around evidence from animal studies of impaired bone and cartilage growth as well as the potential for birth defects. And because molnupiravir works by introducing a series of errors into a virus' genetic code, FDA scientists questioned whether the drug might trigger unwanted long-term effects or create new coronavirus variants. Additionally, the available safety data is limited, meaning rare side effects that haven't been detected in testing could occur when the drug is cleared for use in the broader population, FDA reviewers said. The agency plans to ask its advisors who should be authorized to receive the drug. The FDA and Merck agree that children won't be eligible, and molnupiravir hasn't proven effective for patients who are already hospitalized. But the agency suggested treatment may not be authorized for pregnant women, too.

The drug also didn't help patients who were "seropositive," or had antibodies against the coronavirus because of a previous infection, though the FDA appears wary of excluding that group — or vaccinated people — as a whole. Each have some risk of hospitalization or death, particularly the subsets of people more likely to develop severe disease, the agency said. All of these conclusions were reached before Merck released its final efficacy results, which indicated lower effectiveness for the drug overall. Surprisingly, among the half of study participants who weren't included in the initial analysis, 4.7% given placebo were hospitalized or died, compared to 6.2% of those who received molnupiravir. Merck didn't offer any explanations for why the drug seems to have performed worse, though Jefferies analysts speculated there may have been more seropositive patients involved, driving efficacy downward. In an amendment to its briefing documents, the FDA indicated its assessment of molnupiravir may now differ from the original review. The agency will provide "additional key safety and efficacy results" at Tuesday's hearing. The limitations could disadvantage Merck's drug from a COVID-19 pill developed by Pfizer which is also being reviewed by the FDA. Though it can be difficult to compare medicines across trials, Pfizer's drug, known as Paxlovid, lowered the risk of hospitalization and death by about 90% in a large study. That number could also change once the final numbers are tallied, however. Paxlovid is administered with ritonavir, an HIV medicine that's meant to extend Paxlovid's effects but interacts with many other types of drugs and could therefore limit use. Pfizer shares climbed 6% on Friday, while Merck's sank by about 4%. Merck is developing molnupiravir in partnership with Ridgeback Biotherapeutics, which licensed the drug from Emory University. 

Merck Press Release (Nov. 26, 2021):

https://www.merck.com/news/merck-and-ridgeback-biotherapeutics-provide-update-on-results-from-move-out-study-of-molnupiravir-an-investigational-oral-antiviral-medicine-in-at-risk-adults-with-mild-to-moderate-covid-19/ 

Pfizer said Tuesday it signed a licensing agreement to allow broader global access to its experimental Covid-19 pill.  The agreement with the Medicines Patent Pool, a United Nations-backed public health organization, would allow generic manufacturers to make the pill widely available in 95 low- and middle-income countries covering 53% of the world's population, the company said. The pill, known as PF-07321332 or Paxlovid, is to be given in combination with an older antiviral drug called ritonavir.  Earlier this month Pfizer announced topline results from its trial saying that an interim analysis -- done before the trial was scheduled to end -- showed an 89% reduction in the risk of hospitalization or death from Covid-19 among people given the drug within the first three days of symptom onset.  "Pfizer will not receive royalties on sales in low-income countries and will further waive royalties on sales in all countries covered by the agreement while COVID-19 remains classified as a Public Health Emergency of International Concern by the World Health Organization," Pfizer said in the statement. The Medicines Patent Pool, founded by Unitaid 10 years ago, facilitates rapid access to medicines for people in low- and middle-income-countries.

The company announced a licensing deal that will allow the drug, molnupiravir, to be made and sold cheaply in 105 developing nations.  Merck has granted a royalty-free license for its promising Covid-19 pill to a United Nations-backed nonprofit in a deal that would allow the drug to be manufactured and sold cheaply in the poorest nations, where vaccines for the coronavirus are in devastatingly short supply. The agreement with the Medicines Patent Pool, an organization that works to make medical treatment and technologies globally accessible, will allow companies in 105 countries, mostly in Africa and Asia, to sublicense the formulation for the antiviral pill, called molnupiravir, and begin making it. Merck reported this month that the drug halved the rate of hospitalizations and deaths in high-risk Covid patients in a large clinical trial. Affluent nations, including the United States, have rushed to negotiate deals to buy the drug, tying up large portions of the supply even before it has been approved by regulators and raising concerns that poor countries would be shut out of access to the medicine, much as they have been for vaccines. Treatment-access advocates welcomed the new deal, which was announced Wednesday morning, calling it an unusual step for a major Western pharmaceutical company. “The Merck license is a very good and meaningful protection for people living in countries where more than half of the world’s population lives,” said James Love, who leads Knowledge Ecology International, a nonprofit research organization. “It will make a difference.” Charles Gore, director of the Medicines Patent Pool, said: “This is the first transparent public health license for a Covid medicine, and really importantly, it is for something that could be used outside of hospitals, and which is potentially going to be very cheap.” 

“This is hopefully going to make things a lot easier in terms of keeping people out of hospital and stopping people dying in low- and middle-income countries,” he said. Mr. Gore said that more than 50 companies, from all regions of the developing world, have already approached the organization about obtaining a sublicense. The agreement with Merck, Mr. Gore said, is also critically important as a precedent. “I hope this will start a landslide of people coming to the Medicines Patent Pool, wanting to do licensing, because there’s no question that access has been the problem,” he said. “From a scientific point of view, industry have done a really brilliant job — firstly, providing the vaccines, and now providing treatments. But the access side of it has let the whole thing down.” Pfizer also has a Covid antiviral pill in late-stage trials, and Mr. Gore said the company is also in talks with the patent pool.  Molnupiravir was developed by Merck and Ridgeback Biotherapeutics of Miami, based on a molecule first studied at Emory University in Atlanta. All three organizations are party to this deal, which will not require a fee from any sublicensing company. Merck has submitted its clinical trial data to the Food and Drug Administration seeking emergency-use authorization; a decision could come in early December. Regulatory agencies in other nations that produce a version of molnupiravir will need to evaluate it. Some drug manufacturers will likely seek World Health Organization prequalification for their versions, so that they can bypass the country-by-country regulatory steps. Stephen Saad, chief executive of Aspen Pharmacare in South Africa, said his company expects to apply for a license to make molnupiravir and distribute it across Africa. He said that he believed that Aspen could make the drug for about $20 per course. The U.S. government has an agreement to buy 1.7 million courses of the drug, pending its authorization by the F.D.A., a deal that fixes the price at $712 per course. Mr. Gore said that he has been told by some in the field that a generic version of molnupiravir could be profitably produced for as little as $8 per course.

Under the licensing deal, Merck would continue to produce and sell the drug in wealthy nations and many middle-income ones at significantly higher prices. Merck had already taken the step of licensing eight large Indian drug makers to produce generic versions of molnupiravir, pending authorization. But the company feared that production in just one region would not be enough to ensure rapid access to the drug across the developing world, said Jenelle Krishnamoorthy, Merck’s vice president for global policy.  So the company also engaged in talks with the patent pool, which has deep experience in working with a network of global drug makers that can meet high-quality standards, including those required for W.H.O. prequalification, she said. “We knew we had to work faster, we had to do things we hadn’t done before, we had be more efficient,” Ms. Krishnamoorthy said. The licenses that Merck issued to the Indian generic makers restricts sales to developing countries and excludes most middle-income ones, including China and Russia — the site of a current raging Covid outbreak — raising the possibility that citizens in these nations, which often have weak health systems, will not get access to the drug. The patent pool agreement for molnupiravir also excludes middle-income countries and most nations in Latin America, Mr. Love said. “What are you going to do for countries like Chile or Colombia, Thailand or Mexico?” he asked. “They’re not in the license.

Merck said it is seeking FDA emergency use authorization for its experimental antiviral Covid-19 treatment, molnupiravir.  If authorization is granted, the drug, made by Merck and Ridgeback Biotherapeutics, would be the first oral antiviral treatment to fight Covid-19. It comes in capsule form. Merck said it is asking for authorization for the capsules to treat infected adults who are at risk of progressing to severe Covid-19 disease or hospitalization. Its submission is based on a study that was stopped at the interim point because the drug was working so well in more than 700 patients randomly assigned to take either molnupiravir or a placebo. "At the interim analysis, molnupiravir reduced the risk of hospitalization or death by approximately 50%; 7.3% of patients who received molnupiravir were either hospitalized or died through Day 29 following randomization, compared with 14.1% of placebo-treated patients," the company said in a statement.  "Through Day 29, no deaths were reported in patients who received molnupiravir, as compared to eight deaths in patients who received placebo." None of the volunteers in the trial had been vaccinated.

"The extraordinary impact of this pandemic demands that we move with unprecedented urgency, and that is what our teams have done by submitting this applicati on for molnupiravir to the FDA within 10 days of receiving the data," Merck CEO and President Robert Davis said in the statement.  Data from the trial has not yet been peer-reviewed or published. "Merck has been producing molnupiravir at risk and expects to produce 10 million courses of treatment by the end of 2021, with more courses expected to be produced in 2022," the company said. It has already sold 1.7 million treatment courses to the US government. The company said it will offer tiered pricing to provide access around the world, and will work with generic drug manufacturers to speed availability to low- and middle-income countries. At a White House Covid-19 briefing last week, Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, called the trial results "very encouraging," but said the drug needs close scrutiny by the FDA. "It is very important that this now must go through the usual process of careful examination of the data by the Food and Drug Administration both for effectiveness, but also for safety, because whenever you introduce a new compound, safety is very important," Fauci said, noting that vaccines remain "our best tools against Covid-19" by preventing infection and illness, rather than treating it.

KENILWORTH, N.J., July 9, 2021 – Merck (NYSE: MRK), known as MSD outside the United States and Canada, affirmed its commitment to enabling global access to molnupiravir through its voluntary license agreements and ongoing clinical program. As previously announced, Merck has entered into voluntary license agreements for molnupiravir with established Indian generics manufacturers.Merck has entered into these agreements to accelerate availability of molnupiravir in India and in other low- and middle-income countries (LMICs) following approvals or emergency authorization by local regulatory agencies.  Molnupiravir is an investigational oral antiviral agent currently being studied in a Phase 3 trial for the treatment of non-hospitalized patients with confirmed COVID-19. Merck is developing molnupiravir in collaboration with Ridgeback Biotherapeutics.

One of these generics manufacturers, Hetero, has announced that it has accumulated positive data from an open label clinical study of molnupiravir and has submitted these data to the Drug Controller General of India (DCGI).  Merck is encouraged by these promising data and looks forward to continuing to work with Hetero and other generics manufacturers that Merck has agreements with as they conduct studies of generic versions of investigational molnupiravir.  Merck, in collaboration with Ridgeback Biotherapeutics, is conducting an ongoing randomized placebo-controlled phase 2/3 clinical trial of molnupiravir in non-hospitalized patients with confirmed COVID-19 at more than 100 sites worldwide. For more information on this clinical trial visit https://merckcovidresearch.com. Merck has a long track record of making our medicines and vaccines accessible and affordable globally, and we remain committed to doing the same for molnupiravir. These voluntary license agreements are part of this commitment.

About Molnupiravir

Molnupiravir (EIDD-2801/MK-4482) is an investigational, orally bioavailable form of a potent ribonucleoside analog that inhibits the replication of multiple RNA viruses including SARS-CoV-2, the causative agent of COVID-19. Molnupiravir has been shown to be active in several models of SARS-CoV-2, including for prophylaxis, treatment, and prevention of transmission, as well as SARS-CoV-1 and MERS. EIDD-2801 was invented at Drug Innovations at Emory (DRIVE), LLC, a not-for-profit biotechnology company wholly owned by Emory University and is being developed by Merck & Co., Inc. in collaboration with Ridgeback Biotherapeutics. Since licensed by Ridgeback, all funds used for the development of EIDD-2801/MK-4482 have been provided by Wayne and Wendy Holman and Merck.

About Merck

For 130 years, Merck, known as MSD outside of the United States and Canada, has been inventing for life, bringing forward medicines and vaccines for many of the world’s most challenging diseases in pursuit of our mission to save and improve lives. We demonstrate our commitment to patients and population health by increasing access to health care through far-reaching policies, programs and partnerships. Today, Merck continues to be at the forefront of research to prevent and treat diseases that threaten people and animals – including cancer, infectious diseases such as HIV and Ebola, and emerging animal diseases – as we aspire to be the premier research-intensive biopharmaceutical company in the world. For more information, visit www.merck.com and connect with us on Twitter, Facebook,  Instagram, YouTube and LinkedIn.

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.....

New research in mice finds that molnupiravir stops the replication of the new coronavirus in grafts of human lung tissue.

• A study in mice found that molnupiravir (EIDD-2801) halted the replication of SARS-CoV-2 — the virus that causes COVID-19 — in grafts of human lung tissue.
• The drug also prevented infection when administered 12 hours before exposure to the virus.
• Clinical trials of the drug are ongoing to evaluate its safety in humans and whether it can make patients with COVID-19 less infectious.
• Previous research suggests that the drug could work against a range of coronaviruses that originate in bats, providing protection in future outbreaks.

A drug called molnupiravir, which scientists originally developed to treat influenza, is showing promise as a treatment for COVID-19. A study by researchers at the University of North Carolina (UNC) at Chapel Hill, recently published in Nature, found that the drug dramatically reduced the number of virus particles in a mouse model of the disease. It also protected against infection when given 12 hours before exposure to the virus and every 12 hours thereafter. 

Phase 2 and phase 3 clinical trials of molnupiravir are already under way, with some results expected as soon as March 2021.

In addition to testing the drug’s safety and efficacy, one of the trials is also investigating its effect on “viral shedding,” which is the amount of virus released into the environment by people who have it. Analyzing this helps determine how likely a person is to transmit the virus. Remdesivir, which speeds the recovery of adults hospitalized with the illness and which may reduce mortality rates, is currently the only proven antiviral treatment for COVID-19. One potential advantage of molnupiravir is that patients can take it orally, whereas remdesivir has to be injected. This would make molnupiravir easier to give to lots of people as a preventive, or prophylactic, drug in high risk settings, such as nursing homes and long-term care facilities. Another, more long-term benefit of molnupiravir is that it may be effective against other emerging coronavirus infections that — like SARS-CoV-2 — probably originate in bats.

To test the efficacy of molnupiravir against SARS-CoV-2, the researchers created a completely new model of COVID-19 in mice that may prove useful for testing the efficacy of other antiviral drugs. Human coronaviruses are unable to infect mouse cells unless researchers either adapt the viruses or genetically modify mice to produce receptors that allow them to invade cells. These models also fail to reflect the diversity of cells found in human lungs, where the infection can cause life threatening damage.

To get around these limitations, the researchers implanted human lung tissue into specially bred immunodeficient mice that tolerate foreign tissue

“Virus replication in this model occurs in bona fide human lung tissue and does not require any type of adaptation of the virus or the host,” the researchers write in their paper. They demonstrated that the newly emerged human coronaviruses SARS-CoV, MERS-CoV, and SARS-CoV-2 were all able to replicate in the implanted human lung tissue. “Our model allows researchers to directly compare infection between human coronaviruses and the effectiveness of potential preventative and therapeutic approaches,” says co-first author Dr. Lisa Gralinski, assistant professor of epidemiology at UNC. When infected with SARS-CoV-2, the human lung tissue sustained damage similar to that seen in the lungs of COVID-19 patients. The infection also induced an inflammatory response reminiscent of the excess inflammation that characterizes the disease in people.....

Findings published in Nature (Feb. 9, 2021):

https://doi.org/10.1038/s41586-021-03312-w