Covid-19Drugs & Updates

Paxlovid: Pfizer’s new candidate drug to treat COVID-19

Nirmatrelvir [PF-07321332], also known as Paxlovid is an antiviral drug developed by Pfizer Laboratories and is specifically designed to tackle the SARS-CoV-2 virus. 

The available treatments, interventional (repurposed drugs and monoclonal antibodies) and preventative (vaccines), for tackling COVID-19 infections rely on the immune system. Some of these treatments have been scrapped by authorities as they were ineffective and caused severe side effects. Scientists also found that the efficacy of some of these treatments reduces over time.  

The newer variants of concern can resist treatments and vaccines that target the spike protein (found on the surface of the virus) which happens to be the most mutagenic region of the SARS-CoV-2 virus. Paxlovid, a new experimental antiviral drug works intracellularly (inside the viral cell) of the SARS-CoV-2 virus by inhibiting viral replication. Paxlovid was derived from a precursor called lufotrelvir, the phosphate prodrug of PF-00835231, an anticoronaviral agent. Paxlovid acts as a competitive inhibitor of Main Protease (MPro) and prevents further viral replication. 

Paxlovid (Nirmatrelvir), an orally active drug, is the first medicine specifically designed for SARS-CoV-2 and is not a repurposed molecule. Nirmatrelvir has shown consistent in vitro antiviral activity against the previously identified variants of concerns (i.e., alpha, beta, delta, gamma, lambda, and mu). The drug was also able to inhibit the 3CL protease associated with Omicron in an in vitro biochemical assay. This indicates Paxlovid’s potential to maintain robust antiviral activity against Omicron. Additional in vitro antiviral studies with this variant are underway.

In April 2021, Pfizer began phase I trials for Paxlovid. In September 2021, Pfizer began a phase II/III trial. In November 2021, Pfizer announced an 89% reduction in hospitalizations of high risk patients studied when the drug was given within three days after symptom onset. On 14 December, Pfizer announced that Paxlovid, when given within three days of symptom onset, reduced risk of hospitalization or death by 89% compared to placebo in 2,246 high risk patients studied. About 1% of patients (6 out of 607) who took Paxlovid within five days of the start of symptoms were hospitalised within 28 days of starting treatment compared with 6.7% of patients (41 out of 612) given placebo (a dummy treatment); none of the patients in the Paxlovid group died compared with 10 patients in the placebo group. 

There was a 10-fold reduction in the viral load in the patients that were given Paxlovid thus the drug can help reduce transmission among the infected people. There was also a 94% reduction in the symptom onset in people aged 65 and above. Overall the drug showed anti-Omicron activity and high efficacy and safety profiles. 

Paxlovid is proposed to be given as a blister pack for 5-days, twice a day: Two 150 mg tablets of Paxlovid, and One 100 mg of Ritonavir. Paxlovid will be given with a low dose of Ritonavir, another viral protease inhibitor used for HIV. In this case, Ritonavir will help increase the blood levels of Paxlovid without any antiviral effect itself by acting on a cytochrome (3A4) and preventing it from metabolising the Paxlovid drug. 

The FDA review of the Paxlovid data is expected to be complete before year end. EMA’s (European Medical Agency) human medicines committee (CHMP) has issued advice on the use of Paxlovid for the treatment of COVID-19. The medicine, which is not yet authorised in the EU, can be used to treat adults with COVID-19 who do not require supplemental oxygen and who are at increased risk of progressing to severe disease.

Merck’s Monupiravir (Lagevrio) is another investigative antiviral drug that shows potential to inhibit SARS-CoV-2 replication. However, the results of the full clinical trial were quite disappointing with the first trial showing a 50% relative reduction which at the half-way interim analysis point turned out to be ~30% relative reduction. There are also major concerns about how the drug has a tendency to cause lethal mutagenesis for the virus, and can therefore give rise to dangerous mutations.

The availability of Paxlovid should not in any way diminish the vital need to get all individuals vaccinated and boosted. Paxlovid is an intervention for infections and vaccination is the primary prevention therapy. 

“Emerging variants of concern, like Omicron, have exacerbated the need for accessible treatment options for those who contract the virus, and we are confident that, if authorized or approved, this potential treatment could be a critical tool to help quell the pandemic.” says Albert Bourla the Chairman and Chief Executive Officer of Pfizer.

Update: As of 22nd December, 2021, the FDA issued an emergency use authorization for Paxlovid to treat mild-to-moderate COVID-19 infections in adults, pediatric patients and high risk patients (for hospitalisation and death). 

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