Virus World

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.

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 

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

A race against resistance

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

Target practice

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

Published in Nature (Jan. 22, 2022):

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

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/ 

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 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/

Drugmaker Merck & Co Inc on Thursday said its analysis of available data does not support the safety and efficacy of its anti-parasite drug, ivermectin, for the treatment of COVID-19.  Ivermectin, which is approved in the United States under the brand name Stromectol, is used mainly to treat roundworms, threadworms and other parasites. Officials in the Bolivian city of Trinidad had launched a campaign in May last year to give out free doses of ivermectin to combat the novel coronavirus, although the South American country's health ministry noted the lack of evidence for it as a treatment for COVID-19. (reut.rs/3oVnHsY). The company said its analysis of existing and emerging studies of ivermectin to treat COVID-19 found no scientific basis for a potential therapeutic effect against the respiratory disease caused by the novel coronavirus. (bit.ly/2Mz1NOW). Merck added that there was a concerning lack of safety data in the majority of studies testing ivermectin to treat COVID-19 and cautioned against the use of the drug beyond its use as an anti-parasitic.

Merck statement on Ivermectin use (Feb. 4, 2021):

https://www.merck.com/news/merck-statement-on-ivermectin-use-during-the-covid-19-pandemic/

The COVID-19 vaccine may spell the end of the pandemic, but while mass vaccination is not available it is vital to stop community transmission. The new antiviral drug MK-4482 / EIDD-2801 or Molnupiravir, has managed to suppress "completely" the transmission of the coronavirus in just 24 hours , according to studies by the Institute of Biomedical Sciences of Georgia State University.  "This is the first demonstration of an orally available drug that quickly blocks the transmission of SARS-CoV-2 , so it could be a game changer," the researchers explained in the work published in the journal Nature Microbiology .  The antiviral drug was developed at Emory University in Atlanta by the drug innovation company Drug Innovation Ventures at Emory (DRIVE), which was licensed by Ridgeback Biotherapeutics, which partnered with Merck & Co. Molnupiravir was originally designed to treat the flu and prevent the virus from making copies of itself, creating errors during viral RNA replication.

The experts detail that tests were carried out on ferrets and it was observed that they presented a reduction in the amount of viral particles. Then those ferrets were put with others that had not been treated. None of the ferrets in the second group became infected with COVID-19.  "We believe that ferrets are a relevant transmission model because they easily spread SARS-CoV-2, but for the most part they do not develop a serious disease, which is very similar to the spread of SARS-CoV-2 in young adults," he said. Dr. Robert Cox, a postdoctoral fellow in the Plemper group and co-lead author of the study.  “We observed early on that MK-4482 / EIDD-2801 has broad spectrum activity against respiratory RNA viruses and that oral treatment of infected animals with the drug reduces the amount of viral particles spread by several orders of magnitude, drastically reducing transmission. These properties made MK-4482 / EIDD / 2801 a powerful candidate for the pharmacological control of Covid-19 ”, the report adds.

If this ferret-based data is translated into humans, Covid-19 patients treated with the drug could become non-infectious within 24 hours of starting treatment. The drug can be taken orally, and treatment can be started early for a triple potential benefit: inhibiting patients' progress to severe disease, shortening the infectious phase to alleviate the emotional and socioeconomic cost of prolonged patient isolation, and containing quickly local outbreaks. Molnupiravir is currently in advanced phase II / III clinical trials. It is being tested in three different doses every 12 hours for five days in patients with SARS-CoV-2.

Findings published in Nat. Microbiology (Dec. 3, 2020):

https://doi.org/10.1038/s41564-020-00835-2

Although none of the coronavirus vaccines under development has proved its efficacy yet in clinical trials, at least 5.7 billion doses have been pre-ordered  around the world. First shipments of a COVID-19 vaccine created by Western laboratories have often been snapped up by the United States. Five vaccines — three Western and two Chinese — are in Phase 3 efficacy trials involving thousands of people. In a surprise announcement, Russian President Vladimir Putin claimed Tuesday that a vaccine dubbed Sputnik V — after the Soviet satellite — conferred “sustainable immunity” against the novel coronavirus. As research laboratories around the world race to develop a vaccine, manufacturers have received financing to help them prepare to have millions of doses ready to administer in 2021 or even before the end of the year.

Oxford University, working with the Swedish-British pharmaceutical group AstraZeneca, hopes to have results by September, while the US biotech company Moderna, partnering with the U.S. National Institutes of Health (NIH), is aiming for the end of the year, possibly November. U.S. President Donald Trump has launched “Operation Warp Speed” in a bid to develop, manufacture and distribute a COVID-19 vaccine to all Americans by January 2021. Hundreds of millions of dollars have been directed to vaccine developers, including nearly $500 million to Johnson & Johnson at the end of March. The United States has allocated funding to more companies than any other nation in the hope that one of them will come up with the vaccine to counter the highly contagious virus. So far, Washington has handed out at a total of at least $9.4 billion to seven vaccine developers and signed manufacturing contracts with five of them to provide 700 million doses. The companies involved are: Johnson & Johnson, Moderna, Oxford/AztraZeneca, Novavax, Pfizer/BioNTech, Sanofi/GSK, Merck Sharp and Dohme.  Two vaccine developers — Oxford/AztraZeneca and Sanofi/GSK — have signed or are in advanced negotiations with the European Commission to provide a combined 700 million vaccine doses. Britain, because of Brexit, is negotiating a separate pre-order of 250 million doses from four developers.  Japan is counting on 490 million doses from three suppliers, including 250 million from Novavax of the United States. Pharmaceutical giant Takeda bought the rights to a Novavax vaccine for Japan, which has funded the research. It would be produced locally.

Brazil chose a similar model, ordering 100 million doses from AstraZeneca and partnering with China’s Sinovac to produce 120 millions of CoronaVac, which is already undergoing testing with Brazilians. Clinical tests of two Chinese vaccine candidates — Sinovac and Sinopharm — are well underway but only a few international partnerships have been announced, the one with Brazil and a possible one with Indonesia. Russia said 20 nations have pre-ordered 1 billion doses of Sputnik V and that with foreign partners it would be able to produce 500 million doses a year in five countries. The Coalition for Epidemic Preparedness Innovations, launched in 2017 by Norway, India, the Bill and Melinda Gates Foundation and the Wellcome Trust, seeks to ensure that there is “equitable access” to future vaccines. It has pre-ordered 300 million doses from AstraZeneca for dozens of developing countries in a partnership with The Vaccine Alliance. Billions of doses would be produced for Asia and elsewhere by the giant Serum Institute of India (SII), the largest vaccine producer in the world. Novavax and AstraZeneca have separately signed agreements with SII to produce a billion doses each for India and low- and middle-income countries on the condition that they prove their efficacy in clinical trials.

Merck has largely stayed out of the COVID-19 battle, but exploded into it with three major deals and collaborations today. First, Merck is buying Austria-based Themis, a vaccines and immune-modulation therapies company focused on infectious diseases and cancer. Merck hasn’t disclosed financial details, except that it is a cash deal to buy all outstanding Themis shares.

Themis has a pipeline of vaccine candidates and immune-modulatory therapies that it has built using its measles virus vector platform. The vector was originally developed by researchers at the Institut Pasteur and licensed exclusively to Themis for specific viral indications. In March, the company joined a consortium with the Institut Pasteur and The Center for Vaccine Research at the University of Pittsburgh, which is supported by monies from the Coalition for Epidemic Preparedness Innovations (CEPI), to develop a vaccine candidate against COVID-19. “Building on the pioneering work of the Institute Pasteur, the Themis team has established specialized expertise that complements Merck’s own capabilities in the discovery, development, manufacturing and global distribution of vaccines,” said Roger M. Perlmutter, president, Merck Research Laboratories. “We are eager to combine our strengths both to develop an effective COVID-19 vaccine in the near term and to build a pandemic preparedness capability directed toward emerging agents that pose a future epidemic threat.”

Secondly, Merck is collaborating with IAVI, a nonprofit scientific research organization focused on global health challenges. They are partnering to develop a vaccine against COVID-19. The vaccine candidate uses the recombinant vesicular stomatitis virus (rVSV) technology that was used for Merck’s Ebola Zaire virus vaccine, ERVEBO. Merck has also entered an agreement with the Biomedical Advanced Research and Development Authority (BARDA), part of the office of the Assistant Secretary for Preparedness and Response within the U.S. Department of Health and Human Services (HSS)....

An experimental mRNA cancer vaccine developed by Moderna Inc and Merck & Co cut the risk of death or recurrence of the most deadly skin cancer by 44% compared with Merck's immunotherapy Keytruda alone, U.S. researchers reported at a medical meeting on Sunday.

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 

An experimental personalized mRNA vaccine in combination with the immunotherapy Keytruda reduced the risk of recurrence or death from melanoma in patients who had already had surgery, Moderna and Merck said Tuesday. The randomized trial included 157 patients with stage 3 or stage 4 melanoma who had already had surgery. Some patients received nine doses of the experimental cancer vaccine made by Moderna and the immunotherapy made by Merck every three weeks for about a year, and some received only the immunotherapy. Treatment with the experimental vaccine in combination with the immunotherapy reduced the risk of cancer recurrence or death by 44% compared with the immunotherapy alone, the companies said. The preliminary results of a Phase 2b trial were shared in a news release and have not been peer-reviewed or published. The companies said they will publish the full data in the future and share results at an upcoming conference. The companies said they will initiate a Phase 3 study in melanoma patients next year, and will study additional tumor types.

“Today’s results are highly encouraging for the field of cancer treatment. mRNA has been transformative for COVID-19, and now, for the first time ever, we have demonstrated the potential for mRNA to have an impact on outcomes in a randomized clinical trial in melanoma,” Stéphane Bancel, chief executive officer for Moderna, said in a news release. Moderna is the maker of one of the mRNA Covid-19 vaccines used in the United States. Moderna and Merck said serious treatment-related adverse events occurred in 14.4% of patients who received the vaccine and immunotherapy in the trial, and in 10% of patients who received only the immunotherapy. Keytruda has some known risks for serious side effects, the companies said. Moderna’s experimental cancer vaccine, mRNA-4157/V940, is designed to prime patients’ immune system to generate a response to their specific tumors. Merck’s Keytruda, which is already used in the treatment of melanoma, stimulates the immune system to attack tumors. According to the American Cancer Society, melanoma accounts for about 1% of all skin cancers, but it causes a majority of skin cancer deaths. It estimates that in 2022, about 100,000 new melanomas will be diagnosed, and more than 7,600 people will die from melanoma.

Press release (Dec. 13, 2022):

https://investors.modernatx.com/news/news-details/2022/Moderna-and-Merck-Announce-mRNA-4157V940-an-Investigational-Personalized-mRNA-Cancer-Vaccine-in-Combination-with-KEYTRUDAR-pembrolizumab-Met-Primary-Efficacy-Endpoint-in-Phase-2b-KEYNOTE-942-Trial/default.aspx 

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 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....

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 

Merck announced it is stopping development of both of the current formulations of the Covid-19 vaccines the company was working on. Merck said Monday it will stop developing both of the current formulations of the Covid-19 vaccines the company was working on, citing inadequate immune responses to the shots. Work will continue on at least one of the vaccines, which is being developed in partnership with the International AIDS Vaccine Initiative (IAVI), to see if using a different route of administration would improve how effective it is. The announcement marks a shocking setback for one of the most storied vaccine makers, and will raise tensions around readouts expected soon from other companies, including Johnson & Johnson and the upstart NovaVax. Merck said it remains committed to research on Covid-19 and will focus on two treatments it is developing. One is an antiviral medicine against SARS-CoV-2, the virus that causes the disease. The other is a medicine aimed at helping hospitalized patients by reducing the immune system’s over-response to the virus; it has already shown promise in clinical studies. “We’re disappointed by this result,” Nick Kartsonis, a senior vice president for infectious disease and vaccines at Merck Research Laboratories, said in an interview with STAT. “But it also allows us to continue to focus on our therapeutic candidates and move those forward. And, you know, we are open to continue the work to see if we can address the pandemic in any way we can add value.”

The results from a Phase 1 trial, described briefly in Merck’s press release, were resoundingly disappointing. The hope was that Merck’s vaccines, which were unique because they used viruses that could replicate once they were in the body, would be long-lasting, one-dose vaccines. The virus used for the vaccine being developed with IAVI is the one used in Merck’s successful vaccine against Ebola. The other vaccine used measles virus, a type of vaccine Merck has manufactured for decades. Both vaccines, however, produced lower levels of antibodies against SARS-CoV, including binding antibodies and neutralizing antibodies, than is seen in the blood of individuals who have recovered from Covid-19. Kartsonis said it was difficult to compare results from different studies because researchers have used different assays to measure antibody levels. But it appears neither vaccine performed as well as the Pfizer/BioNTech and Moderna vaccines, which resulted in antibody levels several times above those seen in people who have recovered from Covid-19, and the AstraZeneca/Oxford vaccine, which led to antibody levels roughly equivalent to those seen in people who have recovered from Covid-19. There are biologically plausible explanations for why the vaccine Merck was developing in partnership with IAVI underperformed in the Phase 1 trial, IAVI President Mark Feinberg told STAT. The vaccine was administered by intramuscular injection; an oral or intranasal administration route might work better, he said. “While these data are disappointing, this is not the end of the program for us,” Feinberg said.

Merck Press Release (Jan. 25, 2021):

https://www.merck.com/news/merck-discontinues-development-of-sars-cov-2-covid-19-vaccine-candidates-continues-development-of-two-investigational-therapeutic-candidates/ 

Merck has struck a deal to buy OncoImmune for its COVID-19 treatment CD24Fc. The $425 million cash acquisition will give Merck control of a fusion protein linked to improvements in clinical status in a phase 3 trial of severe and critical COVID-19 patients.  OncoImmune began 2020 by presenting data on the effect of CD24Fc in allogeneic hematopoietic stem cell transplant patients. The use of CD24Fc in the population was underpinned by evidence that CD24 fusion proteins negatively regulate damage-associated molecular patterns, thereby countering a mechanism that may amplify graft-versus-host disease. As evidence of the effect of SARS-CoV-2 accrued, OncoImmune spied an opportunity to use CD24Fc to treat the sickest COVID-19 patients. OncoImmune began a clinical trial in April to test the theory that CD24Fc fortifies an innate immune checkpoint against excessive inflammation. With OncoImmune sharing interim phase 3 results to support the theory in September, Merck has agreed to pay $425 million upfront to buy the biotech. The deal is centered on CD24Fc. OncoImmune is spinning out other assets to form a new biotech owned by its existing shareholders. Merck is set to invest $50 million in the new biotech. The deal, which features undisclosed regulatory milestones and sales-based payments, adds another element to Merck’s attack on COVID-19. Merck tasked a research group to the virus in late January but was slower than some of its peers to disclose efforts to combat COVID-19. The Big Pharma made its splash in the last week of May, when it disclosed three deals for vaccines and antivirals.

Merck now has two COVID-19 vaccines in the clinic, albeit at an earlier stage than rival candidates, and an antiviral in phase 2/3 development. Those programs cover assets that may prevent infection and treat patients with mild-to-moderate COVID-19. OncoImmune moves Merck into another area of the COVID-19 response.   OncoImmune is testing CD24Fc in severe or critical COVID-19 patients. Participants in the phase 3 required supplemental oxygen support, noninvasive ventilation, high flow oxygen devices, invasive ventilation or extracorporeal membrane oxygenation. An interim review took place once 146 patients in the placebo-controlled trial experienced clinical recovery. The review linked CD24Fc to a 60% higher probability of improvement in clinical status versus placebo and a more than 50% lower risk of death or respiratory failure. The median recovery time in the CD24Fc group was six days, compared to 10 days in the control cohort.  The results suggest CD24Fc may help a population failed by multiple other drugs. The World Health Organization recommends against the use of remdesivir in hospitalized patients, anti-SARS-CoV-2 antibodies have failed in the population and efforts to repurpose existing inflammatory disease drugs floundered. Dexamethasone is a rare example of a drug that improved outcomes in severe patients.  Some patients in the OncoImmune trial received drugs including dexamethasone and remdesivir. In patients who received corticosteroids, such as dexamethasone, median time to recovery was 15 days. Median recovery time in patients who received corticosteroids and CD24Fc was five days.

The White House is eager to project progress, but the public-private partnership it has created still faces scientific hurdles, internal tensions and questions from Congress. The Trump administration has selected five companies as the most likely candidates to produce a vaccine for the coronavirus, senior officials said, a critical step in the White House’s effort to deliver on its promise of being able to start widespread inoculation of Americans by the end of the year. By winnowing the field in a matter of weeks from a pool of around a dozen companies, the federal government is betting that it can identify the most promising vaccine projects at an early stage, speed along the process of determining which will work and ensure that the winner or winners can be quickly manufactured in huge quantities and distributed across the country. The announcement of the decision will be made at the White House in the next few weeks, government officials said. Dr. Anthony S. Fauci, the federal government’s top epidemiologist and director of the National Institute of Allergy and Infectious Diseases, hinted at the coming action on Tuesday when he told a medical seminar that “by the beginning of 2021 we hope to have a couple of hundred million doses.”

The five companies are Moderna, a Massachusetts-based biotechnology firm, which Dr. Fauci said he expected would enter into the final phase of clinical trials next month; the combination of Oxford University and AstraZeneca, on a similar schedule; and three large pharmaceutical companies: Johnson & Johnson, Merck and Pfizer. Each is taking a somewhat different approach...