New Covid Pills Offer Hope as Omicron Looms

"As the world worries that the Omicron coronavirus variant may cause a surge of cases and weaken vaccines, drug developers have some encouraging news: Two new Covid-19 pills are coming soon, and are expected to work against all versions of the virus.

The Food and Drug Administration is expected to soon authorize a pill made by Merck and Ridgeback Biotherapeutics, called molnupiravir, which reduces the risk of hospitalization and death from Covid-19 by 30 percent if taken within five days of the onset of symptoms.

Another antiviral pill, developed by Pfizer, may perform even better. An interim analysis showed that the drug was 85 percent effective when taken within five days of the start of symptoms. The F.D.A. could authorize it by year’s end.

Since the start of the pandemic, scientists have hoped for convenient options like these: pills that could be prescribed by any doctor and picked up at a local drugstore.

And these two pills may be just the beginning. With the threat of Omicron and other variants looming, scientists say we will need an arsenal of drugs to deploy against new foes — especially if those variants erode the protection of existing vaccines.

Researchers across the world are designing new drugs from scratch, precisely targeting weak points in the molecular structure of the coronavirus. And others are testing whether pills work better in combination than when taken on their own.

“Viruses are wily creatures, and you’ve got to stay ahead of them,” said Dr. Anthony Fauci, the government’s top infectious disease expert. “I think it would be naïve to think that if you get one or two good drugs, you don’t need any more — not when you have a virus that has already killed 760,000 Americans.”

First Pills

The scramble for Covid-19 pills started last year in the early days of the pandemic. At pharmaceutical companies and academic labs, researchers screened thousands of existing drugs to see if any worked against SARS-CoV-2, the virus that causes Covid-19.

This strategy was a long shot, but a success would have led to an antiviral pill more quickly than trying to make an entirely new drug. What followed was a brutal wave of failures. Antivirals that worked in Petri dishes failed when tested in animals, and those that worked in animals failed in clinical trials.

Even drugs that made it into clinical trials often proved disappointing. A flu drug called favipiravir delivered promising results in early trials, leading Canada-based Appili Therapeutics to begin a late-stage trial on more than 1,200 volunteers. But on Nov. 12, the company announced that the pill did not speed up recovery from the disease.

“Not everything in research is a big success,” Dr. Fauci said.

Merck’s new drug, molnupiravir, was studied in 2019 by a nonprofit company linked with Emory University as a treatment for Venezuelan equine encephalitis virus — a little-known pathogen feared as a potential bioweapon. When molnupiravir encounters a virus’s genes, it wreaks havoc, leading to a batch of new mutations. New viruses are often left unable to replicate.

In October, Merck announced the initial results of its molnupiravir trial: The drug reduced the risk of hospitalization and death by about 50 percent. Eager to curb the toll of Covid-19, the U.S. government has bought approximately 3.1 million courses of molnupiravir for about $2.2 billion.

But in the final analysis of the trial, the drug’s effectiveness dropped to 30 percent. At a Nov. 30 meeting of an F.D.A. advisory committee, experts discussed the potential for the drug to cause mutations not just in viruses, but in people’s own DNA. The committee voted to recommend authorizing molnupiravir, but only by a slim majority. And even the committee members who voted in favor of the drug expressed strong reservations, given the potential side effects.

 

Now, Pfizer’s drug is next to enter the spotlight. Its origins reach back nearly two decades, to when Pfizer researchers were searching for a drug that could fight the coronavirus that caused SARS. They decided to build a molecule that could block an essential viral protein, known as a protease. Proteases act like molecular scissors, cutting long molecules into pieces that help build new viruses.

 

The drug, originally called PF-00835231, lodged in the protease like a piece of gum crammed between scissor blades. PF-00835231 proved effective against SARS when given intravenously to rats.

The SARS epidemic ended before the Pfizer could launch a clinical trial. But after the Covid-19 pandemic hit last year, researchers at the company pulled the drug off the shelf to try against SARS-CoV-2.

They modified it to work against the protease of the new coronavirus and tinkered with the molecule so it would work as a pill. Paxlovid, as Pfizer has branded the drug, came out of clinical trials last month with terrific initial results: 85 percent effectiveness if taken within five days of the onset of symptoms. It remains to be seen if the number stays that high in the final analysis.

Shortly after announcing the interim results, Pfizer applied for F.D.A. authorization of Paxlovid and reached a deal with the U.S. government to provide up to 10 million courses of the drug for $5.3 billion.

As the F.D.A. reviews the company’s application, it will consider not just the effectiveness of Paxlovid, but also its potential side effects. Unlike molnupiravir, Paxlovid does not introduce mutations, so it probably won’t raise the same red flags.

“Given that it works through a different mechanism unrelated to our genetic material, it is less likely to cause changes in our DNA,” said Sara Cherry, a virologist at the Perelman School of Medicine at the University of Pennsylvania. But, she added, “protease inhibitors have different liabilities.”

Our own cells make proteases, which we use to whittle down our own proteins, enabling them to perform new jobs. While many protease-inhibitor drugs have proved safe, some of them can also lock onto our proteases instead of the proteases made by viruses. Still, the short course of pills needed to stop Covid-19 may reduce any such risk from a drug like Paxlovid.

Dr. Cherry said the advent of two antiviral drugs for Covid was “super exciting,” especially as Omicron spreads across the world. The pills will be particularly welcome, she said, if Omicron — or another new variant — turns out to reduce the effectiveness of vaccines. The worrisome mutations in Omicron are in the virus’s outer spike protein, which has nothing to do with the pills’ viral targets.

“That will definitely help us as a stopgap, if we really do need to change the vaccines,” Dr. Cherry said.

Winning Combinations

 

If history is any guide, the first antiviral pills to show promise won’t be the best. The first pill for H.I.V., a cancer drug called AZT, caused serious side effects and led to the evolution of AZT-resistant versions of the virus.

Years later, pills that target H.I.V.’s proteases proved to be less toxic and more effective than AZT. Scientists also found that combining the pills sometimes made them more effective. What’s more, it was harder for viruses to evolve resistance to the drug cocktails.

 

Dr. Cherry and her colleagues are mixing antiviral drugs to see how well they work against the coronavirus. In tests on infected human cells, they’ve found that combining molnupiravir and Paxlovid creates a more powerful impact than either drug has on its own.

This combined effect is known as additivity. But researchers are also searching for combinations that create “synergy”: an effect that’s bigger than just adding the effects of two drugs together.

“Additivity means one plus one equals two, and synergy means one plus one equals four,” said Dr. Mark Denison, a virologist at Vanderbilt University Medical Center. “And those are possible.”

Dr. Fauci, who oversaw the development of combination therapy for H.I.V. 30 years ago, said that the National Institutes of Health will be able to quickly test combinations of pills for Covid-19 in clinical trials.

And through the newly formed Antiviral Program for Pandemics, Dr. Fauci’s agency will have $3 billion to fund academic research centers developing new drugs. The first results from those studies, he said, could arrive in about a year.

Coronaviruses produce a host of proteins essential for their replication, and each could be a target of a new drug. When an infected cell makes a new piece of the virus’s RNA, for example, a viral protein called a helicase has to unwind it before it can be packaged into a new virus shell. Researchers are investigating drugs that block the coronavirus helicase, leaving the virus’s genes in a tangled mess.

Other researchers are aiming to attack not viral proteins, but the genetic material of the viruses themselves. When a coronavirus injects its RNA into a human cell, the molecule squirms into loops and kinks. These structures can then manipulate the human cell and are crucial for the virus’s survival.

In recent years, a handful of drug developers have gone after these tangles of RNA. “It’s a pretty small club,” said Amanda Hargrove, a chemist at Duke University.

Dr. Hargrove and her colleagues have modified various versions of a blood-pressure drug called amiloride so that they can latch onto viral RNA. In a study published on Nov. 26, the researchers found three amilorides that grab the RNA of SARS-CoV-2. In a laboratory experiment using infected monkey cells, they found that the amilorides could reduce the production of viruses thirtyfold.

If any of these experimental drugs prove effective, they could open the way for even more potent cocktails.

“You want to hit the virus from every single side,” Dr. Denison said. “You want to slash the tires and foul up the engine and screw up the brakes.”

At the Walter Reed Army Institute of Research, researchers are trying to build a pill that will work against all coronaviruses. They are looking for targets common to all coronavirus proteases. At the start of the pandemic last year, they screened 41 million compounds with the help of a computer trained to recognize potential drugs.

They ran experiments on the 800 best candidates and ended up with just a few top contenders, which they are now testing in mice.

Lt. Col. Brandon Pybus, one of the Walter Reed researchers, said that using artificial intelligence shaved many years off the project. But because the team is making a drug from scratch, they will not be able to move as fast as Merck or Pfizer toward an authorized pill. “It could be a matter of a few years, if resources permit,” he said.

Dr. Fauci and his colleagues intend to use the same strategy to search for antiviral pills that work on other viral families, such as flaviviruses, which cause diseases like dengue fever and West Nile fever, and togaviruses, which cause mosquito-borne diseases like chikungunya and eastern equine encephalitis.

“I have a great deal of confidence,” Dr. Fauci said, “in the creative ability of the investigators that are out there, some with crazy ideas, and some with ideas that look crazy that turn out to be really, really good.””

 

In order to force doctors to slave for pennies in Lithuania, they are broken psychologically using the methods employed by professional criminals in prisons.

 "The latest Laisvės TV journalistic research shows that the harassment, exploitation and psychological destruction of doctors is a systemic problem that is widespread and hidden in almost all Lithuanian hospitals." 

 

    Surveys show that at least a third of Lithuanian doctors experience psychological violence on a daily basis.

 

    The study reveals what methods are being used to destroy the doctor and force him to quit his job. Documents show that state-funded hospitals intimidate and legally persecute those medics who dare to talk about the violence they have experienced. 

 

Experts say the ongoing psychological violence, exploitation and burnout make medical services unsafe.

 

     Even future doctors face bullying, insults, humiliation and threats already during their studies. From the first days, they realize that there are different rules of communication between doctors. "A joke like that: a woman, it's a temple on two legs. Or: I find the most pleasant sound when a girl asks to repeat. And this is usually the case if the student asks to repeat, because she simply did not manage to write down something that the teacher dictated, ” - said Rasa, a medical student studying at the Lithuanian University of Health Sciences (LSMU).

 

Young people in their medical student's years are either frustrated or learn to adapt to a violent culture.

 

    "Silk wool is made from a student," says A. Gerliakienė. Representatives of LSMU did not answer the written questions.

 

    Residents are forced to work for free

 

    Later, when the residency begins, future doctors have to endure not only humiliation - they also have to put up with exploitation. In order to establish themselves in hospitals, residents are required to work for free during their holidays, to be on duty instead of their managers, and even to write research papers for them. "I remember working all night and wanting to go home the next day. I’m already putting things in when one doctor comes and says, where are you going? How are you going home here? You what, not a man? What will you do at home? I say: I would like to sleep. He just laughed,  and went away,” - says surgeon Vytautas, who did a residency in Kaunas clinics. The Laisvės TV research shows real documents of Kaunas clinics, which show that the official schedules according to which salaries are paid do not correspond to reality. There are cases where a young doctor has a day off scheduled, even though patient examination reports show that the doctor actually worked. And he didn't get a penny for it. “The time sheet that is on the paper, it does not correspond to reality even 5 percent. In my practice, I did not receive at least one extra euro for the hours worked during my employment,” - said the resident Vytautas. Tomas Lapinskas, one of the managers of Kaunas clinics, says that the hospital administration learned about this problem recently and has now started looking for solutions.

 

    The method of destruction is the manipulation of the work schedule

 

    Not only young but also experienced doctors face psychological violence in Lithuanian hospitals. The Laisvės TV study highlights key methods used to disrupt an unbehaving physician. One of the most common methods of mobbing is everyday schedule. Danutė Andriulienė, the head of the cardiology department of Šiauliai Hospital, suffered from the schedule of her line manager for two years. The hospital management illegally restricted her ability to perform her duties and she was forced to resign. "I can say: get up in the morning, brush your teeth, and feel sick, you can't brush your teeth. It was a humiliation, the crush was complete," - said the cardiologist. Finally, D. Andriulienė appealed to the Labor Disputes Commission and proved that she was forced to work in emotionally unhealthy working conditions. She received compensation of € 500. Remigijus Mažeika, the former head of Šiauliai Hospital, says that the hospital did not agree with the conclusions of the labor dispute commission, but they were not disputed out of respect for the doctor.

 

    Another method of psychological pressure is to change work schedules.

 

    Doctors often work in more than one hospital to earn a decent salary.

 

    So they desperately need a flexible work schedule. And that gives extra power to their managers, who can use schedules as a means of pressure. If the doctor does not suit his / her supervisor, his / her work schedule may be arranged in such a way that additional work, studies or raising children becomes impossible. “Because I was studying, I said from the beginning that I wanted to work nights and days in a row to simply have more of those holidays. They made me work for days from Monday to Friday, ” - says Jurga, an assistant nurse working in a Vilnius hospital.

 

    Crying surgeon request: allow surgery

 

    Deprivation of surgery or patients from another doctor is another common method of psychological violence. "One surgeon from an adjacent ward tried to kill himself precisely because he was deprived of all operations," -  says A. Gerliakienė, the head of the Medical Movement. Lina, who worked in the Vilnius Medical Institution, tells a similar story: “I saw a surgeon standing at the door of his Department head's office and begging him to have more surgery. The request ended in tears. The male surgeon cried. And says: I have a family, I have children, give me a job. And the head replies: Go away from my office.”

 

    The study tells a specific story when two surgeons from Klaipėda University Hospital were left without surgery because they were critical of the management of the pandemic at that treatment facility. In retaliation, one of the surgeons was overwhelmed with official warnings.

 

    The leader's command to the team is to ignore one colleague

 

    There are also cases when the managers of a medical institution turn one unbehaving doctor into a target for the whole team. "When you come to work, you say 'hello', but if there is a boss, all the colleagues even turn away," says psychologist Janina, who worked in Šiauliai. "You go alone and see that everyone is somehow avoiding you, they are afraid to communicate." Although Janina initially rejected the offer, she eventually decided to leave the job, unable to endure the psychological pressure and reduction in number of patients. "One employee went to the office secretly, the one with whom we agreed very well. Imagine: see if anyone sees, comes to my office, hugs, kisses, wishes to have a good road, a good life. And when she needs to leave the office, she says: open the door, see if anyone can see it,” - says Janina.

 

    Classical threat - audit threat

 

    Sometimes, in order to get rid of an unbehaving doctor, efforts are made to find even the slightest medical errors. Then even a trifle can make a doctor lose his job. Last year, Izabelė Juškienė, a family doctor at Antakalnis Polyclinic, was fired. During the pandemic, she headed outpatient fever clinics where COVID-19 tests were performed. One of the tests was not delivered to the laboratory on time. It was decided that this was a grave violation and Izabelė was fired. The secret audio recordings held by Laisvės TV reveal how Evaldas Navickas, the director of Antakalnis Polyclinic, was pressuring just before her dismissal. "There are two options," - E. Navickas said in the recording. - "Either you write a request and quit voluntarily (you don't have to smile here, there's a very serious offer here), or we'll actually do an audit that will put you to shame in this office." She applied to the Labor Disputes Commission and achieved a kind of victory there - Antakalnis Polyclinic concluded a peace agreement with the doctor. The serious violation allegedly committed by the doctor was revoked, and the grounds for dismissal were changed to dismissal by consensus. Antakalnis Polyclinic also paid compensation of about 20 thousand euros. Rūta Vanagienė, a representative of Antakalnis Polyclinic, stated that after concluding a peace agreement with the doctor, both parties had signed a confidentiality agreement, so they could not comment on the situation.

 

    Most doctors feel burnout

 

    Surveys of doctors show that more than 60 percent Lithuanian medics need however do not seek psychological help. They are afraid that this will be known at work and that they will be ashamed of it. 

 

"A person can get involved in tunnel thinking when he no longer sees another way out, because for him his specialty, his field, his choice is the only visible option. If you receive the right help from the environment or decide to seek that help yourself, you can get out of that tunnel thinking, see everything more widely and choose another path,” - said Kristina Norvainytė, President of the Young Doctors Association.

 

    Surveys show that 63 percent feels mild to moderate psychological burnout.

 

    According to experts, the widespread burnout among doctors makes medical services unsafe. "It seems 27 percent mortality rate in hospitals is due to the fact that employees experience mobbing,” - says A. Gerliakienė.

 

    After questions from journalists - lawyers threatening doctors

 

    Many of the medics interviewed by Laisvės TV were afraid to speak in public. They were afraid to be recognized by the persecutors, they were afraid of revenge. It is an uncommon practice for doctors to make a written commitment to remain silent about hospital problems. Sometimes even doctors who have won legal disputes cannot tell about the psychological violence they have experienced because they sign confidentiality commitments on labor dispute commissions. 

In one case, they have received letters from expensive lawyers representing hospitals. A concrete example: on the same day that the journalists of Laisvės TV wrote a letter to the Antakalnis polyclinic and asked about the doctor I. Juškienė, who was fired due to one COVID-19 test, the polyclinic immediately sent a threatening letter to the doctors. "We remind you of your commitment not to disclose or comment on confidential information," -  the threatening letter said. "If you find that you are in breach of this obligation, Antakalnis Polyclinic will defend our rights in accordance with the law: we will apply to the court asking you to pay a fine of 10 thousand euros."

 

    This may be one of the reasons why we know so little about psychological violence in hospitals. Doctors are systematically intimidated and punished for talking about their problems. And it's for taxpayers' money."