Round 4: Pfizer's Paxlovid Is Approved. Will It Knock Out Covid?

It's not totally absurd to compare our war against COVID with a boxing match. The virus clearly won Round 1; aside from masks and isolation, we were pretty much defenseless. Round 2 unanimously went to science; the vaccines worked very well, and perhaps we were on the cusp of ending the pandemic.

But it wasn't a knockout; the virus was saved by the bell.

Round 3 is harder to score. Although there is clear evidence that hospitalizations and deaths are mostly confined to the unvaccinated, no one expected the one-two punch of delta and omicron, once again sending the world into a panic, with lockdowns, mask mandates, and quarantines, none of which anyone was in the mood for. 

Round 4 started today, with the FDA granting Emergency Use Authorization (EUA) to Pfizer's Paxlovid (1,2), something that was a foregone conclusion. Paxlovid is an effective, direct-acting antiviral drug that can be taken orally in pill form. If life makes any sense at all, Round 4 will be won by science. But instead of a knockout, I would expect multiple knockdowns.

However, when added to the beatdown the virus took in Round 2 from the vaccines, we can reasonably expect that the match will end with both opponents standing and the judges awarding the match to science by points.

Translation: COVID isn't going away, but its threat to human health should be significantly reduced. 

All of this is possible because, unlike what happened with Merck's molnupiravir, the interim clinical results for Paxlovid held up in the final analysis, while molnupiravir's efficacy dropped significantly when all the data were analyzed. Pfizer's gain will likely be Merck's loss, which is a shame because the two drugs operate by a different mechanism and could be used to complement each other, just like cocktails of drugs of different classes turned HIV/AIDS into a manageable, chronic disease instead of a guaranteed death sentence. 

As I have written here and here, Paxlovid is a potent inhibitor of the viral M^pro (main protease) enzyme, which is responsible for chemically cutting newly-formed viral protein, which is initially a single long, non-functional chain, into multiple functional proteins that the virus requires for replication. This is not a novel approach; inhibitors of viral protease enzymes became approved drugs for both HIV/AIDS and hepatitis C.  

Clinical data were consistent with the antiviral profile of Paxlovid. In other words, both the inhibition of M^pro in an enzymatic assay and inhibition of viral replication in a cell-based assay were predictive (3) of the drug's efficacy in humans. The drug, when taken early in the infection, (4) reduced hospitalizations by 89% and deaths by 100% and had no adverse effects (5). As someone who did antiviral research in a former life, to me these data are nothing short of spectacular. 

Dr. Paul Offit, director of the Vaccine Education Center at the Children’s Hospital of Philadelphia, an FDA advisor, and a former ACSH Trustee had this to say:

Would you be more likely to take this drug than you would to get a vaccine? I think the answer to that question is yes...So therefore it is of value for those 40 million, 50 million people in this country who simply refuse to be vaccinated. I mean, this may keep them out of the hospital.

Dr. Paul Offit in an interview with CNBC

Dr. Offit also stressed that immunizing unvaccinated people remains the ultimate goal. Indeed, it is always preferable to prevent an infection than treat it. 

What About the Variants?

As expected, all the variants tested were susceptible to inhibition by Paxlovid; the drug operates by a mechanism that has nothing to do with the viral spike proteins. It shuts down the virus' internal "replication machinery," which operates independently of the spikes; these act to bind to host cells and permit their entry into the cells. Although it is conceivable, perhaps even likely, that eventually, the virus will mutate in a way to make Paxlovid less effective, this process will take much longer than the rapid-fire emergence of increasingly contagious variants we are now experiencing.

Supply Could be an Issue

Unlike molnupiravir (6), which is relatively easy to synthesize, PF-07321332 (now called nirmatrelvir), the active component of the pill is not; the molecule is far more complex and more effort and time are required to complete the synthesis. But, in anticipation of the EUA (and ultimately full approval) Pfizer invested $1 billion to increase its manufacturing capacity. 

Bottom Line

The addition of an effective antiviral drug to the arsenal of weapons against COVID should be a major advance in letting the steam out of a virus that has had a huge, two-year impact on the entire world. In the absence of any unpleasant surprises, we are witnessing the quintessential example of how pharmaceutical science (7) can defeat disease, as well as one of the most important medical advances of our time.

NOTES:

(1) Paxlovid is a two-drug combination of PF-07321332 aka nirmatrelvir, the active drug, and ritonavir, which inhibits its metabolism.

(2) At this time, the approval is limited to emergency use in both high-risk adults and high-risk pediatric patients 12 years of age and older weighing at least 40 kg. 

(3) All the enzyme and cell-based data in the world cannot predict efficacy in people. A successful oral drug must be well-absorbed, sufficiently stable to metabolism, and be effective with an acceptable degree of toxicity.

(4) Rapid, widely available testing is essential for using Paxlovid. Right now the U.S. is woefully lacking in this area.

(5) During the clinical trial, the drug-treated group reported slightly fewer side effects than the placebo group, probably indicating that the drug made them feel better.

(6) Molnupiravir just took the first of (presumably) many hits. France had ordered a bunch of the drug. They just canceled the order.

(7) No drug gets discovered and developed this fast. Ever. The pioneering work was done in 2003 when the Pfizer group was exploring possible coronavirus therapies. Paxlovid is closely related, although superior, to the first-generation experimental drugs.  

Conflict of Interest Statement: My IRA contains both Merck and Pfizer stock.