Tudo sobre Lagevrio (molnupiravir): o primeiro antiviral oral contra a COVID-19 | Novo medicamento COVID-19

Artigo revisto pelo Dr. Jan de Witt

On the 4th of November 2021, the Medicines and Healthcare products Regulatory Agency (MHRA) of the UK approved Lagevrio (molnupiravir) after reviewing its safety and effectiveness. Molnupiravir is the first oral antiviral for COVID-19 to be approved and the UK is the first country to approve it.

MHRA considers molnupiravir effective at reducing the risk of hospitalisation and death and authorised it for use in people who have mild to moderate COVID-19 and at least one risk factor for developing severe illness.

What makes molnupiravir different than other treatments is that it’s an oral tablet that could, depending on the type of approval it receives in each country, be taken outside of the hospital. The projected cost of around $700 per person for a 5-day course is cheaper than other treatments (such as remdesivir, an antiviral injection that costs $3,120 per treatment course), but not yet affordable as an over the counter medicine.

O Molnupiravir está disponível para pacientes fora do Reino Unido com base num uso compassivo ou numa base de paciente nomeado. Saiba mais saltando para a secção "Accessing Lagevrio (molnupiravir) outside of the UK".

What is Lagevrio (molnupiravir)?

O Molnupiravir é um medicamento antiviral administrado oralmente que inibe a replicação de certos vírus RNA, e é utilizado para tratar a COVID-19.

Molnupiravir is not a new treatment developed specifically for the coronavirus SARS-CoV-2. Research began in 2003 and it was initially developed to treat influenza at Emory University’s non-profit company DRIVE (Drug Innovation Ventures at Emory) in Atlanta, USA. In 2015, DRIVE’s chief executive George Painter offered it to a collaborator, virologist Mark Denison at Vanderbilt University in Nashville, to test against coronaviruses and found it worked against coronaviruses like MERS and mouse hepatitis virus.

When the pandemic started in early 2020, DRIVE licensed molnupiravir to Ridgeback Biotherapeutics, a biotechnology company that had previously developed a monoclonal antibody for Ebola, in hopes to fight against the coronavirus SARS-CoV-2 that causes the COVID-19 disease. Ridgeback soon partenered with the pharmaceutical giant Merck to accelerate its development.

The Emory researchers named their drug molnupiravir, after Mjölnir—the hammer of Thor.

Como funciona o Lagevrio (molnupiravir)?

Mechanism of action

When SARS-CoV-2 enters a cell, the virus needs to duplicate its RNA genome to form new viruses. Molnupiravir gets incorporated into RNA strands and mutates in random ways, so the virus then duplicates with mutations and over time, it causes more mutations that eventually kill the virus.

"Isso é o que chamamos mutagénese letal". O vírus muta-se essencialmente até à morte", diz Richard Plemper, um virologista da Universidade do Estado da Geórgia em Atlanta.

Because the mutations accumulate randomly, it’s difficult for viruses to evolve resistance to molnupiravir, which means the drug is effective against COVID-19 variants.

A full course treatment consists of four pills taken twice a day for a total of five days, starting no later than five days after the onset of symptoms.

Clinical trial

The latest trial, a Phase III trial conducted by Merck, was carried out globally in over 170 trial centers. The selected patients were required to have at least one risk factor associated with poor disease outcome (such as diabetes or heart disease) and received molnupiravir or placebo after they observed mild to moderate symptoms.

According to an interim analysis assessing results from 775 subjects, molnupiravir lowered hospitalisation or mortality risk by nearly 50% and was effective against all variants, including the Delta variant. From the group that was given molnupiravir, no deaths were observed, as opposed to 8 deaths in the placebo group.

A previous trial showed no benefit in treating patients already in the hospital with COVID-19.

A Merck não é a única empresa a investigar o molnupiravir. Em Outubro, dois fabricantes de medicamentos indianos, Aurobindo Pharma Ltd e MSN Laboratories, testaram independentemente o molnupiravir genérico em pessoas com sintomas moderados de COVID-19 numa mistura de indivíduos não hospitalizados e hospitalizados, e quiseram terminar os ensaios em fase tardia devido a não verem melhorias significativas, mas continuar os ensaios para pessoas com sintomas ligeiros que não tenham sido hospitalizadas. Os porta-vozes da Merck dizem que as empresas indianas definem "doença moderada" de forma diferente da dos EUA e incluíram na sua investigação pessoas que tiveram "doença grave" pelas definições dos EUA.

Some experts however doubt the usefulness of the drug.

ODr. Peter English, consultor reformado em doenças transmissíveis e antigo presidente do Comité de Medicina de Saúde Pública da Associação Médica Britânica, afirmou: "O problema para antivirais como o molnupiravir da Merck é que teriam de ser utilizados antes de as pessoas serem (geralmente) consideradas suficientemente doentes para precisarem de qualquer outra coisa que não seja um tratamento sintomático de autocuidado. A menos que um medicamento antiviral possa ser tornado tão barato e tão seguro que possa ser utilizado 'sob especificação' por pessoas que possam ter COVID-19, [é] pouco provável que seja de grande utilidade".

Safety concerns

Some experts have raised safety concerns due to molnupiravir’s mechanism of action. Molnupiravir causes viral RNA to mutate and there are concerns that it could cause other cells to mutate as well, causing cancer or causing abnormalities in developing fetuses. One study in animal cell cultures found mutations in cells treated with molnupiravir.

Os ensaios clínicos da Merck não incluíram mulheres grávidas ou a amamentar entre os participantes e as mulheres com potencial de procriação tiveram de utilizar métodos contraceptivos durante a duração do estudo ou ser abstinentes (também foi solicitado aos homens que utilizassem métodos contraceptivos ou que fossem abstinentes). Nas condições para participar, a Merck escreve "O tratamento com EIDD-2801 está contra-indicado em mulheres grávidas ou a amamentar e nos parceiros masculinos de mulheres grávidas".

Dr. Peter Hotez, an infectious disease specialist at the Baylor College of Medicine, notes there isn't any reason to think that molnupiravir would interfere with human genetics: "It's more of a theoretical concern, but it's something to keep in mind."

A MHRA escreve, nos seus documentos recentes que atestam a aprovação do molnupiravir no Reino Unido, que o molnupiravir não é recomendado para uso em grávidas, e recomenda que as pessoas com potencial de procriação "utilizem contraceptivos eficazes durante a duração do tratamento e durante quatro dias após a última dose de Lagevrio (molnupiravir)".

What is the approval status of Lagevrio (molnupiravir)?

Molnupiravir was approved in the UK in November 2021, a few weeks after the UK had purchased 480,000 courses of the drug from Merck. The UK will conduct a national study to gather more data about its effectiveness and will treat both vaccinated and unvaccinated patients.

Merck has filed for emergency approval for molnupiravir in the US and Canada, while the European Medicines Agency (EMA) has started reviewing the drug. The US has already purchased 1.7 million courses of the drug for approximately $1.2bn, while other wealthy countries, such as South Korea and Australia, have made purchase agreements or are currently in talks with Merck.

At the time of writing this article, 25 November 2021, the FDA was reviewing molnupiravir. At a White House COVID-19 briefing, 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.

Accessing Lagevrio (molnupiravir) outside of the UK

Molnupiravir is currently approved and available for UK residents — and there are regulations that allow for medicines to be imported in countries where they are not currently approved.

Os pacientes com doenças debilitantes ou potencialmente fatais têm o direito de aceder, adquirir e importar medicamentos com a ajuda dos seus médicos tratantes.

Os pacientes e os seus médicos podem fazê-lo com base no uso compassivo ou nos regulamentos de importação de pacientes nomeados, uma excepção legal à regra geral de que um medicamento normalmente só pode ser acedido após autorização/aprovação do mercado (qualquer que seja a redacção que utilizemos) no país onde o paciente vive. Esta excepção permite aos doentes aceder de forma legal, ética e segura e obter medicamentos que ainda não tenham sido aprovados no seu país.

Leia mais sobre a "base do paciente nomeado" aqui (EMA).

We are currently making efforts into sourcing molnupiravir so we can help you access Lagevrio (molnupiravir).

Upcoming medicines for COVID-19

Merck is trying to bridge that gap when it comes to molnupiravir. It recently granted royalty-free licenses to the Medicines Patent Pool, a U.N.-backed nonprofit, which will allow manufacturers to produce generic versions of the drug for more than a hundred low- and middle-income countries.

Merck is also researching whether molnupiravir could prevent infection after exposure to COVID-19. If it does, the drug could possibly be taken prophylactically when a person comes into contact with someone infected.

Paxlovid is another antiviral pill (produced by Pfizer) that shows effectiveness against COVID-19 and also sits with the FDA to be reviewed and potentially approved for use.

In November 2021, the EMA recommended authorising Ronapreve (casirivimab/imdevimab) and Regkirona (regdanvimab) for mild to moderate COVID-19 illness.

Other drugs under review by the EMA are:

• Paxlovid (PF-07321332; ritonavir)
• Kineret (anakinra)s
• Olumiant (baricitinib)
• RoActemra (tocilizumab)
• Xevudy (sotrovimab)
• Evusheld (tixagevimab / cilgavimab)