All those new virus inhibitors won’t stop the pandemic

There has been a rapid succession of press releases about new drugs against Covid-19 over the past month. Pfizer reported in early November success with virus inhibitor ritonavir. This could reduce the risk of hospitalization and death by 89 percent – provided the course starts within three days of the first symptoms of the disease. AstraZeneca reported last week a similar result with a cocktail of two monoclonal antibodies: 88 percent less risk of hospitalization and death. GlaxoSmithKline applied for marketing authorization in Europe last week for sotrovimab, for the treatment of Covid patients who are in hospital with mild symptoms. And last week, the European Medicines Authority EMA accelerated advice on the new virus inhibitor molnupiravir from Merck/MSD, in anticipation of market approval, to enable countries to deploy this drug in emergency situations. Again via a press release reported the manufacturer in October that molnupiravir has a 50 percent effectiveness against hospitalization.

“If it is true what is claimed, the pressure on the hospitals could of course be significantly reduced,” says virologist Ab Osterhaus, who works at a university in Hanover. He immediately adds a disclaimer: “I sometimes give advice to pharmaceutical companies about this. I am not doing this for money or fame, but I would like to see progress in this area as soon as possible.”

Cut-throat competition

The crux, according to Osterhaus, is that the treatment starts as early as possible. “As soon as someone tests positive who you expect to have a high chance of ending up in hospital, you should start treating them right away,” says Osterhaus. “Then they see results that are close to 80 or 90 percent effectiveness. In the ideal circumstances of a clinical study – where early treatment is easier to organize – this will be a bit nicer than usual. But even if in practice it would only be half that, you could still keep a lot of people out of the hospital. And that would be a huge relief. ”

“Well”, responds infectiologist Mark de Boer of the LUMC in Leiden, “unfortunately we can’t do much with the nice figures in the press releases. The competition between those pharmaceuticals is fierce. For a pharmaceutical company, a press release probably aims to highlight a drug as best as possible, but that is of little use to us as a community. We can only assess the drug on objective scientific data.”

Substances have now been registered for which we have not yet seen any publications

Mark de Boer infectious disease specialist

De Boer is chairman of SWAB, the Antibiotic Policy Working Group Foundation, which draws up guidelines in the Netherlands for drug treatment of Covid in hospitals. He warns that promising drugs may be disappointing in practice. Experience with the virus inhibitor remdesivir has shown that, says De Boer: “In the first studies, remdesivir seemed to have a significant impact on the disease burden for a certain group of corona patients. But in follow-up studies, we saw that this effect is not demonstrated every time, which also casts doubt on the clinical effectiveness. That is also the reason why the use of this drug in Dutch hospitals has decreased in the past year. Despite the fact that until recently remdesivir was the only drug registered for the treatment of Covid-19, it is still going to disappear from treatment guidelines because it does so little. Of course, we all want something to replace it, but then those new antivirals have to be more effective.”

According to De Boer, it is a persistent misunderstanding that new medicines that have been approved by the EMA are immediately available for patients in the Netherlands from that moment on. “However reliable the EMA’s assessments are, that does not tell you how such a product fits into existing treatments. For which patients do the benefits outweigh the drawbacks and when is the best time to administer the drug? You have to think about that very carefully.”

And that is where there is a problem, says De Boer: “There are now substances registered, or almost registered, about which we have not yet seen any publications. We then do not have good data to determine the indication [wanneer, voor welke patiënt] to decide. We can already see that coming when we start talking about molnupiravir.”

Pills or injections

The new covid medicines from various manufacturers anticipate that the treatment of SARS-CoV-2 infections will already take place before hospitalization. This can also be seen in the formulation of the medicines; the drip gives way to pills or long-acting injections.

However, such preventive treatment to prevent worse will only make sense for people who have a good chance of ending up in hospital due to a corona infection. “It makes no sense to give this to healthy 25-year-olds,” says De Boer. “It only makes sense in risk groups, for example people over seventy or people who have undergone a kidney transplant. And even then you cannot predict in advance who will become so seriously ill that hospitalization is necessary. With all these drugs, that means that you may have to treat as many as twenty patients to prevent one admission.”

Illustration Laura Langerak

The question is also who will prescribe these drugs. If they are general practitioners, they will also have to draw up their own guideline for this. And there will have to be a special infrastructure for it.

Some pharmaceutical companies are already imagining that their new antiviral drugs can also be used preventively, just like vaccines, to prevent contamination. AstraZeneca developed antibodies that are broken down less quickly in the body. The cocktail can be given by injection into the gluteal muscle. In a press release, the company already announced the results of a comparative study: compared to a placebo, there was an 83 percent reduced risk of symptomatic Covid-19 after six months, with no serious illness or death. Osterhaus is skeptical: „Really prophylactic [preventief] It is almost impossible to use those antibodies,” he says, “because that would simply be too expensive given the large number of people in risk groups.”

To be clear: vaccination is by far the cheapest and also the most effective

Ab Osterhaus virologist

De Boer questions the use of virus inhibitors as protection against infection. “We don’t know whether you can safely administer these pills to people over a longer period of time,” he says, “what people often forget is that the safety of such a drug still needs to be well researched. Molnupiravir has only been studied as a cure for a very short period of five days. ”

Osterhaus and De Boer are of one mind on this: antiviral pills or injections are not an alternative to vaccinations. “It is an improper comparison,” says De Boer. “That idea stems from the polarization in society between vaccinating and not vaccinating, but that is actually a shame. From a medical perspective, there is no competition at all between vaccination against disease and other means of combating the disease. They complement each other. Prevention comes first with the vaccine, but it is never perfect, and then you try to compensate for the disease burden and death that you still have with antiviral drugs. And of course it’s good to be able to do something in both phases.”

“To be clear”, Osterhaus also says, “vaccination is by far the cheapest and also the most effective. Vaccination usually protects you for at least six months, if not longer, against serious illness. With antibodies or antivirals, there is a price for every infection, of course. We had the same discussion with influenza, during the Mexican flu. Powerful virus inhibitors such as oseltamivir were then marketed and the conclusion was also: it is a nice addition to the armamentarium, but it is absolutely no substitute for vaccination.”

Tongue twisters Guide to bizarre drug names

New medicines are often given bizarre names that are sometimes difficult to pronounce or remember. A confusing sprawl threatens if there are many, such as now with covid. Who knows what though the conventions are in pharmaceutical naming can be identified more quickly.

For

Within the virus inhibitors category, the substance name usually ends with the ending -vir. They are substances that block the virus’s replication by disrupting the virus’ genetic code or by disrupting crucial enzymes that the virus needs to make copies of itself. In addition to remdesivir, flavipiravir, molnupiravir and ritonavir are in the spotlight as drugs against covid.

Mab

The chemical name of monoclonal antibodies almost always ends with -mab. It refers to the English abbreviation for antibody “monoclonal antibody”. They are called monoclonal because it involves one specific antibody that is grown in large quantities in cells. Combinations of two such antibodies are often used as medicine to prevent the virus from escaping easily. A week ago, the European Medicines Authority EMA approved the cocktail of casirivimab and imdevimab as a medicine against Covid, as well as the drug regdanvimab. More are on the way: sotrovimab, and the cocktail tixagevimab/cilgavimab.

Son, mab, nib, kinra

Immune inhibitors dampen the influence of various inflammatory factors, signaling substances of the immune system that lead to an exaggerated response of the immune system to the virus infection. Here the naming is less clear, but often the ending of the name still refers to the identity of the molecule. Dexamethasone is such an old drug that it has a fairly traditional chemical name. Tocilizumab and sarilumab are identified by their names as monoclonal antibodies. Baricitinib in its name betrays its effect as an inhibitor (-nib stands for inhibitor) as does anakinra, where the ending -kinra stands for interleukin receptor antagonist.

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