A simple pill to treat Covid-19

TThere are vaccines in his world that can prevent most cases of Covid-19. It even has drugs that can help the most serious symptoms of the disease. What I need now is Tamiflu for SARS-CoV-2.

It is a tablet that has been finely tuned to target SARS-CoV-2, with acceptable side effects and low cost. And it will work the same as those antibody treatments that require an hour of intravenous infusion, but it will come in a convenient packet that the patient can take home.

Nathaniel Erdmann, an infectious disease specialist at the University of Alabama Birmingham Hospital, who treats Covid-19, said: “Easy, oral, safe medicine.”

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It sounds simple, but the process of actually developing new antiviral therapies is overwhelmingly complex, even outside the pandemic. Whether the drug is too weak to stop the spread of the virus or is sloppy and safe, things can go disastrously in the myriad steps along the way. And SARS-CoV-2 is consistently evolving. In short, scientists need to defeat natural selection itself and stay ahead of the game.

After all, common colds are often caused by the coronavirus. And, as scientists cruelly joking, after billions of dollars in research and development, there is still no cure for it.

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But in the case of Covid-19, it’s not because of a lack of attempt. While the breathtaking search for the Covid-19 vaccine received the most attention, the National Institutes of Health made a thorough parallel effort to find a cure for the disease itself.

Some drugs were dead-end, such as the malaria drug hydroxychloroquine, while others were unexpectedly successful, such as the life-saving steroid dexamethasone. Among the glorious points was the Gilead Sciences Remdesivir. This is an intravenous antiviral drug that has been shown to moderately reduce hospital stays in Covid-19 patients. Similarly, antibody treatment with Eli Lilly and Regeneron helped keep high-risk patients away from the hospital.

But what NIH director Francis Collins called his “dream” is still missing. It is a very effective tablet that can be administered immediately after diagnosis.

“It’s just a long way,” Collins said in an interview. First scientists need to find vulnerabilities in the viral molecule, then the process of screening for potentially hundreds of thousands of drugs and finding a few drugs that latch on their targets begins. .. Next, medicinal chemists work to sharpen the Goldilocks molecule, which balances strength, specificity, and safety. If all goes well with the Petri dish, one person still needs to do a few months of animal testing before taking the pills clinically. trial.

“But this is a very high priority for Tony Forch, Francis Collins, and the Biden administration. We are working with these companies to make sure this is speeded up,” Collins said. Said. “This pandemic happens with us, even if we get a good vaccine, and people get sick.”

There is hope in the short term as well. Merck will publish Phase 3 data on oral treatment similar to remdesivir at any time. Behind it is a treatment with Atea Pharmaceuticals, which was first developed for the hepatitis C virus. This can have crucial consequences in the coming months. Neither was specially made for the virus that causes Covid-19, but experts said they could check many of the antiviral boxes that are still expected to be treated.

Perhaps most promising is Pfizer’s new antiviral drug, a drug specifically designed for the virus SARS-CoV-2, which entered its first clinical trial last month.

Scientists point to each showing at least a small benefit, as the history of virology suggests that the best way to defeat Covid-19 is a cocktail of therapeutics with complementary effects. Are crossing. But beyond the imminent crisis, experts want society to learn two important lessons: the development of antiviral drugs is really difficult, and you wait for the pandemic to start investing in it. Then it’s even more difficult.

Angelara Mussen, a virologist at Georgetown University’s Center for Global Health Sciences and Security, said: “It emphasizes that it’s not just how ready we are to get out of the crisis. It’s a drug that may have no obvious use when we’re developing it in advance. It really means investing in. “

How to make an antiviral drug

The fundamental problem for drug hunters is that the virus does not fight fairly.

As soon as SARS-CoV-2 is established, it begins to replicate itself using the body’s natural machinery. It gives the virus an edge. Scientists may discover a number of vulnerabilities in the virus, but most of them are certainly shared by the host, making drug attacks a dangerous target.

“The number of antivirals present is very small compared to the number of antibiotics,” said a professor of biology at Drew University, who specializes in the body’s response to viral infections. Brian Barker said. “The reason is that the virus replicates using our cells. You are looking for a drug that is part of the viral replication without damaging our cells. And it’s not easy.”

Step 1 of the antiviral development process is to overcome that hurdle many times in laboratories, animals, and healthy human volunteers.

The next challenge is about timing. The exact moment of virus infection begins a countdown clock as the virus gradually awakens the immune system, creating a narrow time frame. After that, antivirals may be useless.

“For most viral and acute illnesses, the illness is actually caused by the reaction of the host,” Rasmussen said. “If the virus has solidified its foothold and initiated all of these anomalous host processes, so to speak, the horse is already out of the barn.”

With SARS-CoV-2, it can take days to two weeks for these abnormal immune processes to begin. In short, clinical trials of antiviral drugs require delicate design. Patients need to be confirmed for infection, but if they have already experienced severe symptoms of Covid-19, it may be too far to benefit.

When a potential antiviral developer solves a timing problem, there is the challenge of choosing a dose. Under normal circumstances, medication is an accurate science and is being studied in step-by-step studies designed to isolate the complete amount of drug that can achieve benefits with minimal risk.

Shortly after the pandemic, drug developers naturally passed through some of their systematic work and made informed guesses in the spirit of emergencies. Craig Rayner, an executive at Tamiflu’s drug development consultancy Certara, said this would make each antiviral test a tightrope walk. Choosing the right dose can determine not only the success of the study, but also the manufacture, deployment, and final cost of the drug in question.

“Every milligram above what is considered optimal is wasted,” Reiner said. “And for every milligram below, the virus is clever and can evolve around it, putting everything at risk.”

It leads to the next hurdle in the development of antiviral drugs: even if you succeed, one drug is by no means sufficient. Unless a particular antiviral agent can block 100% of viral replication, evolution will begin over time.

“On the other side of the drug, it doesn’t have to be 100% effective,” Barker said. “But with antiviral drugs, if you allow replication, the virus mutates around the drug.”

According to experts, in the long run, the best way to control SARS-CoV-2 is extensive vaccination, backed by a combination of antiviral treatments. This is a drug cocktail that targets multiple aspects of the virus to minimize the risk of mutation.

But first, they need that Tamiflu.

Main candidate

The first drug ready to check all boxes of ideal antiviral drugs is Molnupiravir, developed by Merck and invented at the Emory Drug Development Institute. Known as a nucleoside analog, the drug is designed to throw a wrench during viral replication by tricking SARS-CoV-2 into destroying its own genetic material.

Merck is in an important trial to determine whether molnupiravir can remove SARS-CoV-2 from the body faster than placebo and prevent patients from being hospitalized in approximately 3,000 hospitalized and recently diagnosed patients. The patient has been enrolled. The data are expected in the coming weeks, and experts are particularly focused on whether Merck’s medications can prevent patients with mild symptoms from developing severe Covid-19.

Behind Merck’s drug is a treatment for Atea Pharmaceuticals based on the success of previous antiviral drugs. Atea’s drug, AT-527, targets enzymes that are key to coronavirus replication. This is a similar approach to Gilead Sciences’ hepatitis C treatment. From the hospital. The company is also planning a larger phase 3 trial for outpatients.

Experts expect both drugs to be able to make a difference. They designed a study that needed to select targets that were likely to minimize the risk of side effects and determine if they would work in their primary post-diagnosis window. However, some have expressed concern that neither treatment was specifically designed for SARS-CoV-2, leaving a significant risk of lack of each. When it comes to reused antivirals, “theoretically it should work,” Rasmussen said.

Pfizer’s antivirals, which are currently in the early stages of human testing, can address the problem. The catchy name PF-07321332, Pfizer’s drug, targets the backbone enzyme of SARS-CoV-2, which is the cornerstone of the viral replication process. The enzyme, called 3CL, is one of two specific to all coronaviruses. This means that if Pfizer finds the right dose and conducts the right tests, it could be a treatment for not only SARS-CoV-2 but also future pandemic viruses.

“What we might do here is to cure a cold,” Collins said. “Then I don’t have to listen to those jokes anymore.”