The has vaccines that can prevent most cases of Covid-19. It even has remedies that can help with the most severe symptoms of the disease. What it needs now is a Tamiflu for SARS-CoV-2.
It would be a pill calmly calibrated to target SARS-CoV-2, with tolerable side effects and a low price. And it will work just as well as antibody treatments that require an hour-long intravenous infusion, but it will come in handy that patients can take home.
“We are looking for something I can give to anyone in an urgent environment who can come in with exposure or a positive test,” said Nathaniel Erdmann, an infectious disease specialist at the University of Alabama at Birmingham Hospital. , which deals with Covid-19, said. An easy, oral, safe remedy. ‘
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As simple as it sounds, the process of developing new antiviral treatments is overwhelmingly complicated, even outside of a pandemic. Things can go disastrously wrong at numerous steps along the way, or drugs are too weak to stop the spread of the virus or sloppy to be safe. And SARS-CoV-2 is constantly evolving, which means scientists need to outfox natural selection to stay ahead of the game.
After all, the common cold is often caused by a coronavirus. And as scientists jokingly joke, after billions of dollars spent on research and development, there is still no cure for it.
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But in the case of Covid-19, it’s not a lack of trying. While the breathless search for a Covid-19 vaccine received the most attention, the National Institutes of Health made a comprehensive effort to find treatments for the disease itself.
Some drugs ended up being dead ends, such as the malaria drug hydroxychloroquine, and others were unexpected successes, such as the life-saving steroid dexamethasone. Among the highlights were the Gilead Sciences inhibitor, an intravenous antiviral drug that has been shown to modestly reduce hospitalization for patients with Covid-19. So did the antibody treatments of Eli Lilly and Regeneron, which helped keep high-risk patients out of the hospital.
What is still missing, however, is what NIH director Francis Collins called his ‘dream’: an extremely effective pill that can be given immediately after diagnosis.
“It’s just a long road,” Collins said in an interview. First, scientists must find molecular vulnerability in a virus, and then follow the process of examining hundreds of thousands of prospective drugs to find the few that cling to the target. Then medicinal chemists begin to grind a Goldilocks molecule that balances power, specificity and safety, and if all goes well in the Petri dish, animal tests must be done for a few more months before a single human takes a pill in a clinic can drink. trial.
“But I will tell you that it is an extremely high priority for Tony Fauci and Francis Collins and the Biden government to work with these companies to try and ensure that we speed it up,” Collins said. “Because this pandemic is going to be with us, even with big vaccines, and people are getting sick.”
There is hope, even in the short term. Now Merck is expected to present important data on an oral treatment such as remdesivir any day. Behind it is a treatment from Atea Pharmaceuticals, which was first developed for hepatitis C virus, which could have crucial results in the coming months. None were specifically designed for the virus that causes Covid-19, but experts said the treatments could still label many of the subjects of a hoped-for antiviral drug.
Perhaps the most promising is a new antiviral drug from Pfizer, a drug specifically designed for the SARS-CoV-2 virus that took its first clinical trial last month.
Scientists are sticking their fingers out that each shows at least a marginal benefit, as the history of virology suggests that the best way to beat Covid-19 is a cocktail of treatments with side effects. But beyond the immediate crisis, experts hope society is learning two important lessons: antiviral development is really difficult, and it’s even harder if you wait until a pandemic starts investing in it.
“We need to start thinking about biomedical research as an essential infrastructure,” said Angela Rasmussen, a virologist at Georgetown University’s Center for Global Health Science and Safety. ‘It reinforces that preparedness is not just about how willing we are to renew our way out of a crisis. It really means investing in drugs that may not be taken for granted when we pre-develop them. ”
How to make an antiviral drug
The real problem for drug hunters is that viruses do not fight fairly.
As soon as SARS-CoV-2 takes hold, he begins to use the body’s natural machinery to replicate itself. This gives the virus an edge. Scientists can spot quite a few vulnerabilities in a virus, but the majority of them will surely be shared by the host, making unsafe targets to attack with a drug.
“If you look at the number of antiviral drugs that exist compared to the number of antibiotics, there are so many fewer antiviral drugs,” said Brianne Barker, a biology professor at Drew University who specializes in the body’s response to viral infection. , said. ‘The reason for this is that viruses use our cells to reproduce, which is why you are looking for a remedy that hits a part of the viral reproduction without hurting our cells. And it’s not easy. ”
Step one in the antiviral development process is to remove that obstacle time and time again, in the laboratory, in animals and in healthy volunteers.
The next challenge is related to timing. The exact moment of viral infection begins with a countdown clock as the virus gradually awakens the immune system and creates a narrow period of time after which an antiviral agent is likely to be useless.
“For most viral diseases, the acute ones, the disease is really caused by the response of the host to it,” Rasmussen said. “If the virus gets a foothold and takes into account all these abnormal host processes, the horse is almost out of the barn, so to speak.”
For SARS-CoV-2, it can take from a few days to two weeks before those abnormal immune processes begin. This means that any clinical examination for an antiviral drug requires a fine design. Patients should have confirmed infections, but if they are already experiencing severe symptoms of Covid-19, they may be too far away to benefit from it.
Once a prospective antiviral developer has solved the timing problem, there is the problem of choosing a dose. Under normal circumstances, dosing is an exact science, studied in differentiated, escalating studies designed to isolate the perfect amount of medicine that can achieve a minimal risk benefit.
In the immediate time of the pandemic, drug developers understandably passed some of that methodical work and were educated in the spirit of distress. This makes every antiviral investigation a scientific act, said Craig Rayner, a Certara executive who worked on Tamiflu. Choosing the right dose can not only determine whether a trial will succeed, but also the manufacturing, rolling out and final cost of the drug in question.
“For every milligram above what is considered optimal, you waste it,” Rayner said. “And for every milligram below, you risk everything, because the virus has a chance to be smart and develop around it.”
This leads to the following obstacle to the development of antiviral drugs: even if you succeed, one drug is never enough. Unless a given antiviral agent can block 100% of viral replication, evolution will begin over time.
“In any other aspect of pharmaceutical products, you never have to be 100% effective,” Barker said. “But with antiviral drugs, if you allow replication at all, the virus is going to mutate around the drug.”
In the long run, the best chance of controlling SARS-CoV-2 is widespread vaccination, backed by a combination of antiviral treatments, experts said – a drug cocktail aimed at various facets of the virus to reduce the risk of to reduce mutation.
But first they need that Tamiflu.
The leading contenders
The first drug to test all the subjects of an ideal antiviral drug is molnupiravir, invented at the Emory Institute for Drug Development and developed by Merck and Ridgeback Biotherapeutics. The drug is a nucleoside analogue, designed to shed a wrench in the process of viral replication by misleading SARS-CoV-2 into damaging its own genetic material.
Merck enrolled about 3,000 patients, both hospitalized and recently diagnosed, for a nuclear test that will determine whether molnupiravir can help remove SARS-CoV-2 faster than placebo from the body and keep patients out of the hospital. Data are expected in the coming weeks, and experts are particularly focused on whether Merck’s drug can prevent patients with mild symptoms from developing severe Covid-19.
Behind Merck’s remedy is a treatment from Atea Pharmaceuticals that builds on antiviral success. Atea’s drug, AT-527, targets an enzyme key for viral replication, a similar approach to the healing treatments for Gilead Sciences for hepatitis C. Later this year, Atea expects to have Phase 2 data on the benefits of AT -527 for patients inside and outside the hospital. The company is also planning a larger Phase 3 study on outpatients.
Experts are hopeful that both drugs can make a difference. They have selected targets that are likely to reduce the risk of side effects, and they have designed studies to determine if they work in the key post-diagnosis window. However, some have expressed concern that because neither of the two treatments is specifically designed for SARS-CoV-2, there is a significant risk that it is not enough. When it comes to re-using antivirals, ‘they should theoretically work well,’ Rasmussen said, ‘but in reality they often do not.’
An antiviral drug from Pfizer, which is now in the earliest stages of human testing, could address the issue. Pfizer’s drug, aptly named PF-07321332, targets SARS-CoV-2’s spinal enzyme, the core of the virus’ replication process. That enzyme, called 3CL, is one of two that is specific to all coronaviruses. This means that if Pfizer can find the right dose and perform the right trials, it can be treated not only for SARS-CoV-2 but also for future pandemic viruses.
“What we can finally do here is cure the cold,” Collins said. “Then I don’t have to listen to the jokes anymore.”