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Antiviral drug failure against Covid-19: from promise to reality

In late 2021, a batch of promising new antiviral drugs were introduced against the coronavirus responsible for the COVID-19 pandemic: the drugs Lagevrio (molnupiravir), from Merck, and Paxlovid (nimatrelvir and ritonavir), from Pfizer.

At the time, both pharmaceutical companies issued press releases in which the clinical results were so positive that they were expected to mark another stage of the pandemic. A phase in which these treatments, along with vaccines, will further dramatically reduce the impact of COVID-19 on the population. Among many upbeat messages nearly a year ago, European Health Commissioner Stella Kyriakides said of Paxlovid that it has the potential to make a real difference for people at high risk of developing severe COVID.

According to Pfizer, Paxlovid was able to prevent 89% of hospitalizations and deaths among patients with the highest risk of severe COVID-19 if the drug was administered within the first five days of infection. On the other hand, Merck claimed that Lagevrio reduced the risk of hospitalization or death in patients with the disease by about 50%. In addition, these drugs had two great advantages: they could be taken orally, which allowed them to be prescribed and taken outside the hospital, and their large-scale synthesis was easy, so initially there would be no major restrictions on access to them.

The excellent results of preliminary analyzes of clinical trials of both antiviral drugs were disseminated through press releases before these trials were peer-reviewed and published in scientific journals. A business modus operandi that became popular in the wake of the pandemic and which was very useful in attracting investors and boosting the stock market. However, many health professionals and researchers were skeptical of this practice, which prevented many details about the efficacy and safety of promising antiviral molecules at the time.

On January 28, 2022, paxlovid was authorized for marketing in the European Union – following approval by the European Medicines Agency (EMA) – for the treatment of adults who do not require supplemental oxygen and who are at increased risk of COVID-19. 19 serious. The Spanish government has announced the purchase of 344,000 doses of the drug at an undisclosed price due to confidentiality provisions (in the US, the cost of a treatment cycle was $530). The drug was indicated for patients at risk and was used for mild symptoms.

As for Lagrevio, the EMA on November 19 allowed national European authorities to use the drug, pending its authorisation, in an emergency situation where, for example, there was an increase in infections and deaths. from COVID-19. On November 25th, nearly two months after Merck announced in a press release that its drug cut the risk of death and hospitalization in half, they released new clinical trial results. This showed a significantly lower benefit, the effectiveness increased from 50% to 30%, and the statistical significance (probability that the observed benefit was due to the drug rather than chance) was much lower, to the point of not being clear at all. That the drug was really effective. Spain has not signed any major joint acquisitions with Lagrevio.

The reasons why the two drugs did not make the expected difference in the pandemic differ radically between the two. Paxlovid has been shown to be highly effective in real-world trials in people over 65 years of age who were vaccinated and infected with the Omicron variant. However, this drug is hardly used in Spain. Many factors limit its use. First, paxlovide has many drug interactions. Given that the target population is the elderly, who are usually treated with one or more drugs, many patients are not candidates for the Pfizer drug because of potential safety concerns.

Another important reason that limits the prescription of an antiviral is the need to use it within the first five days after the onset of symptoms in order for it to be effective. In many cases, two circumstances complicate this situation. On the one hand, the procedures and procedures for the drug to reach the patient in many autonomous communities are slow and time-consuming, delaying its use or forcing the doctor to reconsider his prescription. On the other hand, since mass vaccination, the appearance of the Omicron variant and the massive infections it caused in the Spanish population, many elderly people no longer go to the doctor when they have mild symptoms to find out if it could be COVID-19 and get early treatment .

Lagevrio’s story is much more disappointing. As of November 23, Merck’s drug is in the process of being authorized by the EMA, but it is likely that it will never happen. motives? Since the optimistic press release about Lagevrio’s preliminary results, several clinical trials have failed to find any benefit in reducing the risk of death or serious illness in COVID-19 patients.

In the UK, where more than 2.2 million doses of the drug have been bought after conditional authorization (a less demanding mechanism than the usual procedure), there has been severe criticism of this. Several experts believe that this action is a waste of public money without scientific support, since the effectiveness of Lagevrio was, at best, questionable from the beginning. In the end, molnupiravir, nicknamed Thor’s hammer (Mjölnir), did not prove to be a hammer against SARS-CoV-2, despite its variant, as Merck research director Dean Lee said.

The disappointment of oral antiviral drugs against SARS-CoV-2 teaches us two valuable lessons. For one, it’s dangerous to trust pharmaceutical press releases that tout glowing preliminary results for their drugs, because the reality may not be so promising when they reach the real world. Second, it matters little that a drug is very effective in the real world if there are significant barriers to those who need it at the right time.

How many doses of Paxlovid and Lagevrio have been used in Spain? According to data provided to by the Spanish Medicines Agency, De Lagevrio (through compassionate use) only 540. About Paxlovide, it is estimated that around 13,000 treatments have been used so far (less than 5% of the government’s purchases).

Source: El Diario





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