How the antiviral pill molnupiravir progressed in the hunt for COVID drugs

Pharmaceutical company Merck announced last week that an antiviral pill it is developing can halve hospitalizations and deaths among people with COVID-19. The results have not yet been peer reviewed. But if the drug candidate, molnupiravir, is cleared by regulators, it would be the first oral antiviral treatment for COVID-19. However, other currently authorized drugs must be administered intravenously or injected.

A pill could make treating patients earlier in their infection much easier and more effective. It could also prevent hospitals from overflowing, especially in places where vaccination rates are still low, such as many low- and lower-middle-income countries. Molnupiravir was so effective in a Phase 3 trial involving COVID-19 positive people at risk for serious illness that clinicians discontinued recruitment prematurely.

But it’s not yet clear whether this clinical trial success story will translate into a global shift in the fight against the pandemic. This week, two Indian drugmakers testing molnupiravir in people with moderate illness from COVID-19 sought to end their trials because they saw no “significant efficacy” for the investigational drug. Additionally, Merck’s findings, which apply to people with mild to moderate cases of COVID-19, were only disclosed in a press release – and have yet to be scientifically reviewed and submitted. to regulators for approval. And even though low-income countries can afford the drug, they might not have the diagnostic capacity to treat patients with molnupiravir early in their illness, when treatment could make a difference.

Hit early, hit hard

The other therapies offered for COVID-19, Gilead Science’s antiviral remdesivir and a cocktail of monoclonal antibodies from biotech company Regeneron, must be administered intravenously or by injection. This makes it difficult for people to access therapy until they are sick enough to land in the hospital. And remdesivir is only approved for those who are already hospitalized with COVID-19.

Still, it’s better to “hit early, hit hard” with antivirals, says Richard Plemper, a virologist at Georgia State University in Atlanta. The sicker the patient, the less effective the drugs are in treating the disease. A COVID-19 pill, which simply requires a prescription and a trip to the pharmacy once symptoms appear, would greatly facilitate early treatment.

COVID-19 is not the first disease caused by a coronavirus to have a serious impact on humans. But the 2002-2004 Severe Acute Respiratory Syndrome (SARS) epidemic quickly died down and the Middle East Respiratory Syndrome (MERS) epidemic in 2012 never became widespread, meaning that manufacturers of drugs had little incentive to develop antivirals against these diseases.

So when the first cases of COVID-19 appeared at the end of 2019, “there was no portfolio of antivirals pending,” says Saye Khoo, an infectious disease specialist at the University of Liverpool, UK. , who led a clinical trial of molnupiravir.

Initial efforts to find treatments focused on drugs already approved by regulators and resulted in only one winner: dexamethasone, a steroid aimed at easing an excessive inflammatory response in the sickest people. The FDA has not cleared the drug for this purpose, but it is widely used to treat the sickest people.

But even as researchers rushed to test approved drugs, drug companies and biotech companies scoured their libraries for any compound with known antiviral activity that could stop the SARS-CoV-2 coronavirus. These broad-acting antivirals weren’t designed specifically to target SARS-CoV-2, but it seemed mechanically feasible that they could. Unlike many drugs tested at the start of the pandemic, “there is a scientific rationale. You understand how they work, ”says Jay Luly, managing director of Enanta Pharmaceuticals, a Watertown, Mass., Company that is developing its own COVID-19 antiviral.

Gilead’s remdesivir is so far the only drug of its type to have received approval from the United States Food and Drug Administration. When used in a hospital setting, its effect is modest. In a Phase 3 trial, researchers found it reduced recovery time by a median of 5 days¹. Merck expects molnupiravir to be the next to receive clearance.

Hot pursuit

Molnupiravir began as a possible therapy for Venezuelan equine encephalitis virus at the nonprofit Drug Innovation Ventures at Emory (DRIVE) at Emory University in Atlanta. But in 2015, DRIVE CEO George Painter offered it to a collaborator, virologist Mark Denison of Vanderbilt University in Nashville, Tennessee, to perform a coronavirus test. “I was pretty blown away by it,” recalls Denison. He found it worked against several coronaviruses: MERS and mouse hepatitis viruses².

Painter also recruited his colleague Plemper to test the drug against influenza and respiratory syncytial virus. After the pandemic, however, plans changed. DRIVE has licensed the compound to Ridgeback Biotherapeutics in Miami, Florida. Plemper also pivoted to coronaviruses and tested the compound on ferrets. This silenced the virus’s ability to replicate, he says, but it also suppressed the transmission of the virus from infected ferrets to uninfected ferrets.³. The Merck data clue might also be true in humans: molnupiravir appeared to shorten the duration of SARS-CoV-2 infectivity in trial participants with the virus.

Molnupiravir, like remdesivir, is a nucleoside analogue, which means that it mimics some of the building blocks of RNA. But the compounds work in totally different ways. When SARS-CoV-2 enters a cell, the virus must duplicate its RNA genome to form new viruses. Remdesivir is a ‘chain terminator’. It prevents the enzyme that builds these RNA “chains” from adding further links. Molnupiravir, on the other hand, gets incorporated into the burgeoning strands of RNA and, once inside, wreaks havoc. The compound can change configuration, sometimes mimicking the cytidine nucleoside and sometimes mimicking uridine. These RNA strands become faulty blueprints for the next set of viral genomes. Wherever the compound is inserted and this conformational change occurs, a point mutation occurs, Plemper says. When enough mutations build up, the viral population collapses. “This is what we call lethal mutagenesis,” he adds. “The virus essentially mutates to death. And because mutations build up randomly, it is difficult for viruses to develop resistance to molnupiravir – another benefit for the compound.

But the compound’s mutagenic potential in human cells – the possibility that it could incorporate into DNA – raises safety concerns, some researchers say. Merck has yet to release detailed safety data, but “we are very confident that the drug will be safe if used as intended,” said Daria Hazuda, vice president of infectious disease discovery and Scientific Director of Merck, during a press conference. press briefing last Friday.

Waiting backstage

Other antivirals are in the works. Gilead Sciences is developing a pill version of remdesivir. And Denison suspects that if the antiviral were given to people early on on molnupiravir – when symptoms have barely appeared and viral loads are high – it would be just as effective. In a study presented to IDWeek, a virtual meeting of infectious disease specialists and epidemiologists held earlier this month, researchers reported the results of administering remdesivir infusions to people in early stages of COVID- 19 every day for three days. The number of study participants was small, but remdesivir appeared to reduce hospitalizations by 87% in people at high risk of developing COVID-19.

Biotech company Atea Pharmaceuticals in Boston, Massachusetts, also has an antiviral in the works. He was testing a nucleoside analogue against hepatitis C in a clinical study when SARS-CoV-2 emerged. The pandemic halted the trial, so Atea decided to focus on COVID-19. It has now partnered with Roche in Basel, Switzerland to develop its compound.

New York-based Pfizer was also ahead of the game. The company had been developing antivirals for SARS since the early 2000s, but abandoned them when the epidemic subsided. When the COVID-19 pandemic started, “they just blew the dust off,” Luly says. Researchers are now testing a pill form of a compound that has a mechanism of action similar to these original versions. It is the subject of phase 2/3 trials for the treatment of newly infected people.

Global Access

An effective oral antiviral would be an incredible asset in the fight against COVID-19, but it is not yet clear whether molnupiravir will be available to everyone. “Are we going to be in a situation where the price is reasonable in low and middle income countries?” ”Asks Rachel Cohen, North American executive director of the Drugs for Neglected Diseases initiative.

The United States has agreed to purchase 1.7 million courses of molnupiravir for $ 1.2 billion, which equates to approximately $ 700 per 5-day course. This is much less than the price of remdesivir or monoclonal antibodies, but still too expensive for much of the world. Merck, which is co-developing the compound with Ridgeback, has entered into licensing agreements with five Indian generic drug makers. These deals allow manufacturers to set their own prices in India and 100 other low and lower middle income countries.

But even though poorer countries can afford the drug, they might not have the diagnostic capacity to use it properly. While molnupiravir is to be given within the first five days of symptom onset, “it requires that we be able to diagnose people quickly,” Cohen explains. For many developing countries – and even some rich countries – “this is actually a huge challenge”.