Frankfurt The drug Paxlovid has so far been considered a breakthrough in Covid therapy. Pfizer’s antiviral drug is one of the most important weapons in the fight against the pandemic. It has shown good results in clinical trials and is one of the few Covid drugs that can be taken as a pill.
Regardless of this, many experts are pushing for the development of other active ingredients against Sars-Cov-2, the causative agent of Covid-19. Because there is growing concern that, sooner or later, variants could emerge that develop resistance to the Pfizer drug.
The reason for this is, on the one hand, the general experience that such resistances develop more frequently in mutating viruses and therefore combinations of several active substances often prove to be the most successful treatment strategy. This was shown, for example, in the treatment of HIV or hepatitis C, where therapies with two, three or even four different active substances have become established.
On the other hand, the observation that some patients suffered a relapse after initial treatment success with Paxlovid also attracted attention in recent weeks. This means that the viral load in these patients initially fell as expected, but after the end of the five-day treatment it rose again. Covid tests were then positive again despite the previous treatment.
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Theoretically, one of the reasons for this could be that the viruses in the affected patients mutated in such a way that Paxlovid loses its effect. Corresponding fears that the development of resistance is actually behind this phenomenon have not yet been confirmed.
Researchers expect resistant corona variants
Researchers at the American Rutgers University, for example, recently came to the conclusion in a combined analysis of a large number of virus mutations that the mechanism of action of the Pfizer drug is still intact, even with the omicron variants that have recently appeared.
At the same time, they warned that this need not remain the case. “So far, Omikron is still new enough for the treatments to continue to work. But as more people take Paxlovid, we expect resistance to emerge,” said medicinal chemistry professor Jun Wang, one of the co-authors of the analysis recently published in the journal Nature Cell Research.
The Covid drug is already a billion dollar business for Pfizer.
(Photo: via REUTERS)
In purely commercial terms, Paxlovid is already an extremely successful product thanks to extensive pre-orders from various governments. Pfizer expects sales of the drug to be at least $22 billion in 2022, which, based on the prices known to date, suggests a global order volume of more than 40 million therapy units.
The USA alone ordered 20 million packs of the drug, Germany one million. In addition, Pfizer has issued production licenses to various generics manufacturers.
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As far as the specific use of Paxlovid is concerned, the numbers are far lower so far. Doctors and patients are apparently still acting rather cautiously. According to the latest reports, only 660,000 patients in the USA were treated with the drug by mid-May. This corresponds to just three percent of the quantity ordered.
According to information from the Federal Ministry of Health, 263,000 of the 280,000 therapy units delivered so far were still in stock in Germany. According to this, a maximum of 17,000 people have been treated with Paxlovid in Germany since it was approved at the end of January. This corresponds to only around 0.1 percent of the 16 million cases of infection during this period and 1.7 percent of the one million units ordered from Pfizer.
Recurrences despite Paxlovid: Pifzer and FDA play down
The manufacturer Pfizer, as well as representatives of the American drug agency FDA, meanwhile point out that the described relapses in Covid diseases are a general phenomenon that is also observed in untreated Covid patients.
According to Pfizer research director William Pao, such relapses occurred in around two percent of the patients treated with Paxlovid in the clinical study. The proportion was similarly high in patients who received a dummy drug. However, the development will be monitored very closely, explained Pao in the most recent analyst call.
The Pfizer drug belongs to the group of protease inhibitors and blocks the main protease of the virus, called Mpro. Proteases are enzymes that can cut proteins and in this function are essential for the replication of the virus.
In a clinical study with a good 1,200 participants, the Pfizer drug reduced the risk of severe disease progression and hospital admissions by almost 90 percent if treatment was started within five days of the onset of symptoms. However, a study using Paxlovid to prevent Covid disease after exposure to the virus failed.
The FDA, which granted the drug emergency approval in December, has not yet questioned the positive test results in the Covid treatment. John Farley, FDA chief of infectious diseases, points to additional analysis showing that post-treatment relapses were not associated with an increased risk of serious illness. “Therefore, they do not change the conclusion of the clinical study that Paxlovid brings about a significant reduction in hospitalizations and deaths,” Farley said in a recent FDA update on Paxlovid.
What are the consequences after the relapses?
However, Pfizer and the US authorities do not quite agree on what consequences should be drawn from the relapses. Pfizer boss Albert Bourla has already brought up the idea of extending the duration of treatment beyond the previously planned five days. So far, however, he has encountered resistance from the drug supervisors.
There is no evidence to date that longer treatment duration or repeat treatment is beneficial, Farley said. The head of the American National Infection Research Institute, Anthony Fauci, announced that new studies would be carried out shortly.
On the one hand, a longer duration of treatment could increase the effect, but according to some experts, it could also increase the risk of accidental mutations occurring in the main protease that render Paxlovid ineffective.
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A sensible counter-strategy could be to combine Paxlovid with another active ingredient that targets a different molecular mechanism. From the point of view of some doctors, an obvious combination partner would be the Covid drug Lagevrio with the active ingredient molnupiravir, which was developed by the American competitor Merck & Co.
So far, however, such combinations have apparently not yet been tested clinically, neither with molnupiravir nor with other antiviral agents. In any case, such studies have not yet been listed in the clinicaltrials.gov database. According to a Bloomberg report, Pfizer has repeatedly refused to provide Paxlovid for such combination studies.
Pfizer could make a mistake with that. Because in the long term it should also make sense for the industry leader to test its Covid drug in combination with other active substances.
More: Covid business drives growth at Pfizer.