Highlights

In early November 2021, Pfizer has reported a successful clinical trial of its experimental drug Paxlovid (nirmatrelvir + ritonavir), which has been studied in the treatment of adult patients with COVID-19 infection caused by the new coronavirus SARS-CoV-2.

Administration of Paxlovid to patients with mild-to-moderate COVID-19, who were at risk of severe disease, resulted in an 89% reduction in the risk of hospitalization or death. This appeared to be true if Paxlovid was administered within 3 days of the onset of COVID-19 symptoms.

Administration of Paxlovid within 5 days of COVID-19 symptoms manifestation reduced this risk by 85%.

  • According to the final results of the clinical trial of Paxlovid, disclosed in mid-December 2021, Pfizer’s drug for COVID-19 reduced the risk of hospitalization or death by 89% and 88% when administered within 3 and 5 days of the onset of COVID-19 symptoms, respectively. Among older patients, the risk reduction was even better, at 94%.

Paxlovid is an oral antiviral drug designed to suppress coronavirus replication.

  • Paxlovid is likely to retain its highest antiviral efficacy against the Omicron variant of SARS-CoV-2 coronavirus, which is all anyone is talking about right now.
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Pfizer said that during the COVID-19 pandemic, Paxlovid will be offered at prices based on each country’s income level: advanced economies will pay more than poorer ones. For example, the U.S. government expects to pay $530 per course of Paxlovid.

Pfizer intends to produce more than 200,000 therapeutic courses of Paxlovid by the end of this year. In the next 2022, the U.S. pharmaceutical giant will be able to produce 200 million courses of Paxlovid.

The closest competitor to Paxlovid is the oral antiviral drug molnupiravir, developed by Merck & Co. and Ridgeback Biotherapeutics and already approved in the UK under the brand name Lagevrio.

Since the efficacy of Paxlovid compared to molnupiravir was significantly better, Pfizer’s stock quotes rose by 10%, while the stock prices of Merck & Co. fell by the same amount. The quotes of mRNA-vaccine producers Moderna and BioNTech each lost 20%.

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 According to Pfizer, the impressive clinical efficacy of Paxlovid gives hope for early regulatory approval. The American pharmaceutical giant is confident that the U.S. Food and Drug Administration (FDA) will not wait long for a decision, let alone convene an expert Advisory Committee, as in the case of molnupiravir.

Industry observers estimate that demand for Paxlovid, which is likely to be the drug of choice among recent COVID-19 disease sufferers, will be so high that Pfizer will make $18 billion on it next 2022.

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Molnupiravir: What U.S. Experts Said

FDA scientists took a detailed look at molnupiravir for treating COVID-19.

As of early December 2021, Pfizer had contracts with various countries to supply nearly 12 million therapeutic courses of Paxlovid.

In mid-December 2021, the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has recommended Paxlovid (nirmatrelvir + ritonavir) for treatment of adult patients with COVID-19 infection who do not require supplemental oxygen and who are at risk of developing severe disease. Paxlovid is not yet approved in European Union countries, but the recommendations are needed to support national regulators, who can possibly make their own decisions about the use of the drug without waiting for a final pan-European EMA verdict.

  • Paxlovid should be administered as soon as possible after the diagnosis of COVID-19 and within 5 days after the onset of symptoms. Paxlovid should not be combined with some other drugs, the list of which will be published later. Paxlovid is contraindicated in severe renal or liver dysfunction and is not recommended for pregnant, preparing to conceive, or breastfeeding women.

On December 22, 2021, the U.S. Food and Drug Administration (FDA) has approved Paxlovid under its Emergency Use Authorization (EUA) program.

  • Paxlovid is indicated to treat mild-to-moderate COVID-19 infection (confirmed by SARS-CoV-2 coronavirus testing) in adults and children (12 years and older, body weight 40 kg and above) at high risk for progression to severe disease requiring hospitalization or may be fatal.
Paxlovid (nirmatrelvir + ritonavir).

Paxlovid Approved in the U.S.

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Paxlovid: Clinical Efficacy and Safety of Coronavirus Treatment

The EPIC-HR (NCT04960202) phase 2/3 (randomized, double-blind, placebo-controlled, multicenter, international) clinical trial enrolled unvaccinated adult patients with laboratory-confirmed COVID-19.

Among the main criteria for participation: manifestation of COVID-19 symptoms no later than 5 days before randomization; course of COVID-19 with mild-to-moderate severity and not requiring hospitalization; at least one risk factor for severe COVID-19.

Risk factors included the following: age 60 or older, overweight, smoker status, chronic kidney disease, diabetes mellitus type 1 or 2, immunosuppressive disease, chronic lung disease, cancer (except skin cancer) in an active stage.

Subjects were given placebo or Paxlovid — orally every 12 hours for 5 days.

The primary endpoint was the proportion of patients who required hospitalization or who died at 28 days of follow-up from the start of treatment.

 

Interim Results

According to a planned interim analysis of data from patients (1,219 of the 3,000 to be included in the study) treated within the first 3 days of COVID-19 symptoms, 0.8% of patients (n=3/389; no deaths) were hospitalized in the Paxlovid group — versus 7.0% of patients (n=27/385; 7 deaths) in the placebo group.

Thus, administration of Paxlovid reduced the risk of hospitalization or death by 89% relative to placebo: risk ratio (RR) 0.11 (95% CI: 0.03–0.36; p<0.0001). The risk of death decreased by a relative 93%: RR 0.07 (95% CI: 0.00–1.16).

In patients who started treatment within the first 5 days of COVID-19 symptoms, 1.0% (n=6/607, no deaths) and 6.7% (n=41/612; 10 deaths) of the Paxlovid and placebo groups, respectively, experienced hospitalization.

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In other words, the use of Paxlovid reduced the risk of hospitalization or death by a relative 85%: RR 0.15 (95% CI: 0.06–0.34; p<0.0001). The risk of death was reduced by 95%: RR 0.05 (95% CI: 0.00–0.81).

The frequencies of treatment-induced adverse events were comparable in Paxlovid and placebo groups: 19% and 21% of subjects, respectively, experienced them — most adverse reactions were mild. Serious adverse events were recorded in 1.7% and 6.6% of participants, and 2.1% and 4.1% discontinued treatment because of adverse reactions.

 

Final Results

According to the final analysis, administration of Paxlovid within 3 days after manifestation of COVID-19 symptoms resulted in an 89% reduction in the risk of hospitalization or death from any cause relative to placebo (p<0.0001).

The risk of hospitalization was reduced by 89% (risk ratio [RR] 0.11 [95% CI: 0.04–0.28]) and the risk of death by 95% (RR 0.05 [95% CI: 0.00–0.90]).

  • In Paxlovid group, 0.7% of patients were hospitalized (n=5/697; no deaths) — versus 6.5% of patients in the placebo group (n=44/682; 9 deaths).

The use of Paxlovid within 5 days of COVID-19 symptoms manifestation reduced the risk of hospitalization or death from any cause by 88% relative to placebo (p<0.0001).

The risk of hospitalization was reduced by 88% (RR 0.12 [95% CI: 0.06–0.25]) and the risk of death by 96% (RR 0.04 [95% CI: 0.00–0.68]).

  • In Paxlovid group, 0.8% of patients were hospitalized (n=8/1039; no deaths) — vs. 6.3% of patients in the placebo group (n=66/1046; 12 deaths).

In a subgroup of elderly patients (65 years and older), a population particularly at high risk of hospitalization or death, Paxlovid reduced these risks by a relative 94% over a 28-day follow-up period (p<0.0001).

  • In Paxlovid group, 1.1% of patients were hospitalized (n=1/94; no deaths) — vs. 16.3% of patients in the placebo group (n=16/98; 6 deaths).

In the entire population of subjects followed up for 28 days, no deaths were reported among those receiving Paxloid — vs. 12 deaths (1.2%) in the placebo group.

Paxlovid provided a 10-fold (0.9 log10 viral copies/mL) drop in viral load from baseline to that assessed at day 5 of treatment compared to placebo, thus demonstrating its potent antiviral activity against the SARS-CoV-2 coronavirus.

The frequencies of treatment-related adverse events, which were mostly mild-to-moderate in severity, were almost identical, with 23% of patients in the Paxlovid group — vs. 24% in the placebo group. Administration of Paxlovid resulted in fewer serious adverse reactions (1.6% of subjects) and discontinuation of treatment (2.1%) — vs. the placebo group (6.6% and 4.2%, respectively).

 

Paxlovid: Mechanism of Action

Paxlovid is an oral antiviral drug that combines two compounds, nirmatrelvir and ritonavir.

Nirmatrelvir (PF-07321332) is a reversible covalent inhibitor of 3C-like protease (3CLpro), an enzyme needed by coronavirus for replication. Nirmatrelvir blocks the cysteine residue in 3CLpro, thereby inhibiting its activity at the proteolysis stage. Because 3CLpro is responsible for the cleavage of coronavirus polyproteins 1a and 1b, which contain 3CLpro itself, a papain-like protease (PLpro), and 14 other nonstructural proteins, they all cannot be released to perform their functions, resulting in inhibition of viral replication.

In vitro nirmatrelvir demonstrates antiviral activity against Alpha, Beta, Gamma, Delta, Lambda, and Mu variants of the coronavirus. Nirmatrelvir also works against the Omicron variant.

Ritonavir is a booster (enhancer) of nirmatrelvir. Ritonavir inhibits cytochrome P450 3A4 (CYP3A4), a hepatic enzyme that metabolizes xenobiotics, meaning it deactivates drugs. In other words, ritonavir increases the bioavailability of nirmatrelvir by helping to slow down the metabolism of this molecule so that it retains its activity in the body for a longer time and in higher concentrations.

A 5-day course of treatment with Paxlovid involves taking 20 tablets of nirmatrelvir and 10 capsules of ritonavir.

 

Paxlovid: What’s Next

Pfizer continues to study the applicability of Paxlovid in other human populations. For example, the EPIC-SR (NCT05011513) phase 2/3 clinical trial is evaluating the efficacy and safety of experimental COVID-19 treatment in unvaccinated individuals who are at standard risk, that is, at low risk of hospitalization or death. The trial includes a cohort of vaccinated patients with acute breakthrough symptomatic COVID-19 infection and risk factors for severe disease.

The EPIC-PEP (NCT05047601) phase 2/3 clinical trial is testing Paxlovid in a post-exposure prophylaxis task — to prevent COVID-19. Checking is among individuals with a negative SARS-CoV-2 rapid antigen test result who have had contact with a family member who is SARS-CoV-2 positive and symptomatic with COVID-19 within 4 days before randomization.

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Interim Results of EPIC-SR

According to the interim results of the EPIC-SR clinical trial, the primary efficacy endpoint has not been reached. Administration of Paxlovid did not result in a statistically significant difference with placebo in terms of sustained relief of symptoms of COVID-19 infection over four consecutive days.

Nevertheless, the use of Paxlovid was reflected by a 71% reduction in hospitalizations and no deaths from any cause (p=0.051).

  • In Paxlovid group, 0.7% of patients were hospitalized (n=3/428; no deaths) — versus 2.4% of patients in the placebo group (n=10/426; no deaths).

It remains to be seen how regulators will feel about this. It is possible that Paxlovid will be approved for use in all COVID-19 patients, not just high-risk ones.

 

Expert Comments

It should be understood that the stated efficacy rates of Paxlovid and molnupiravir at 88%–89% and 30%, respectively, by Pfizer and Merck & Co. cannot be directly compared without considering such factors as differences in the risk profiles of patients who took part in clinical trials and their demographic characteristics. If Paxlovid and molnupiravir were compared with each other, then everything would be clear. In addition, the clinical data collected do not mean that in a real population the effectiveness will match the declared efficacy.

It cannot be ruled out that in the future, Paxlovid and molnupiravir will be prescribed simultaneously. And it makes sense: just remember the highly effective therapeutic regimens for HIV and hepatitis C viral infections that involve taking several drugs at once. This is necessary in order to both increase the effectiveness of COVID-19 treatment and avoid the emergence of the drug-resistant variants of SARS-CoV-2.

A definite plus in the piggy bank of Paxlovid is its efficacy, which does not depend on the duration of COVID-19 (three or five days). As a rule, the effectiveness of antiviral drugs falls sharply with time after the manifestation of infection symptoms.

In addition, one would think that Paxlovid would not work in patients outside the high-risk group for progression of COVID-19 to severe disease. No, it works just fine: the 10-fold reduction in viral load (1 log10 viral copies/mL) in the EPIC-SR clinical trial could tell you that. It’s just that patients came across with a more or less strong and armed immune system that doesn’t assume a high rate of hospitalizations. A couple or three more hospital admissions and Paxlovid would have succeeded in terms of statistical significance.

If we talk about prescribing Paxlovid to all COVID-19 patients without exception, there is a risk of the rapid emergence of variants of coronavirus resistant to this drug. This is why its use should be limited to high-risk patients. For those who are vaccinated and have had a breakthrough infection, however, Paxlovid should not be prescribed unless there are serious risk factors for severe COVID-19.

Pfizer claims that Paxlovid is excellent against the Omicron variant. This is understandable since Omicron has only one mutation affecting the 3C-like protease (3CLpro) that the drug targets.

The issue of the price of Paxlovid remains relevant. Yes, Pfizer and Merck & Co. actually gifted Paxlovid and molnupiravir to poor countries, but countries with a more developed economic system will have to pay in full. But even here it is not so simple: just because some, for example, two countries are above average income ones, this does not mean that their national health systems take equally good care of their citizens, and therefore it is far from certain that they will do everything possible to ensure that everyone who suffers gets the right COVID-19 treatment in time. It all comes down to the budget.

Be that as it may, both Paxlovid and molnupiravir are a giant step forward in the face of the ongoing COVID-19 pandemic. There is considerable hope that oral treatment for coronavirus will spare the vast majority of patients from hospitalization, which will certainly drastically ease the pressure on more than overburdened health care systems around the world. Vaccines have played a huge role, but there are frequent cases of breakthrough infections where vaccination has not worked. Again, there are still too many unvaccinated people. The availability of affordable oral medications against COVID-19 would seamlessly add to the spectrum of control measures against this infection.

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Tanya von Reuss

BioPharma Media’s Scientific Editor.

Tanya has been dedicated to forensic science and molecular pathology for two decades. Her professional interests include thanatology, evidence-based medicine, and holistic medicine.

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