Pfizer’s (NYSE: PFE) PAXLOVID has risen to prominence as the top COVID-19 antiviral in the world. The speed at which they rose to prominence is awe-inspiring given that it normally takes an average of 9 years to develop a drug. The secret behind Pfizer's quick development of the 3CL protease inhibitor is that there is no secret. This is very good news for the ONLY other company developing a 3CL protease inhibitor to compete with PFE. The quick development wasn’t due to big pharma’s clout, a well-designed trial, or massive trial sites. The drug simply works!
Trial Stoppage for Efficacy
After getting to an interim point in their phase 2 /3 study the DSMB stopped Pfizer's trial for efficacy. PAXLOVID, is a 3CL protease, and more and more research is uncovering an immersive mechanism of action (MOA) that positions it as a central target of the disease pathogenesis in COVID-19. There is a reason the stock rose $20 billion in valuation on the excellent clinical trial results. It boils down to the fact that the 3CL protease is the best target for COVID-19. The only other drug company actively developing a 3CL protease inhibitor is Todos Medical (OTCMKTS: TOMDF). TOMDF is days to weeks away from that same interim point Pfizer reached just weeks ago where they saw that huge value inflection spike. There is a library of clinical evidence backing up the science, as well as various biological mechanisms being uncovered that explain why this target is working so well in the clinic.
Antiviral MOA
On the surface, when comparing COVID-19 antivirals, there are many candidates that in different ways target the viral RNA replication process by interfering with RNA-dependent RNA polymerase (RdRp). By blocking this protein directly involved in replicating RNA, new RNA doesn’t form and the viral life cycle cannot continue. Drugs such as Gilead’s (NASDAQ: GILD) remdesivir as well as Merck’s (NYSE: MRK) molnupiravir, Atea Pharmaceuticals (NASDAQ: AVIR) AT-527, and even Adamis Pharmaceuticals (NASDAQ: ADMP) Tempol all in some manner interfere with RdRp.Pfizer’s drug, however, targets a unique protein called the 3CL protease, which is one of the first proteins translated during the viral replication process. The purpose of any protease is to chop the polypeptides into usable viral proteins. These usable proteins form up to make the viral replication machinery (nonstructural proteins such as the proteins that make-up RdRp) to manufacture more viral proteins. Without the protease, which is the equivalent of saw needed to build a house, the virus was not able to replicate its RNA or make the structural or proteins required for new virions. Pfizer went through the process to make a very detailed mechanism of action (MOA) video to showcase this druggable target. To the untrained eye, it shouldn’t matter which antiviral target is blocked. The viral replication process stops either way, right? What the untrained eye is missing is the fact that the 3CL protease also aids the virus in multiple ways by messing up the infected cell—the host’s own proteins.
The Clinical Evidence
Pfizer (PFE) just announced the stoppage and data release of their phase 2/3 PIC-HR clinical trial which was testing their oral antiviral, PAXLOVID, in the mild (non-hospitalized, at risk of progressing to severe illness) COVID-19 setting for “overwhelming efficacy.” Their pill is expected to be approved fairly soon as the clinical trial showed PAXLOVID reduced the risk of hospitalization by 89% and risk of death by 100% in their interim analysis. Just a few weeks prior, Merck had touted the news that its antiviral, molnupiravir, reduced death also by 100%, but hospitalization only by 50, in its phase 3 interim data readout.Merck and the RdRp targeting companies had a glimmer of hope that they could dominate the antiviral marketplace, but Pfizer’s data knocked it out of the park, leaving Merck in the dust yet again in the COVID-19 race, once in vaccines and now in antivirals. If the efficies were similar, it would be a different story, but Pfizer’s pill arguably couldn’t have performed any better. 3CL protease is just a better target than RdRp.There’s clinical evidence from other companies backing up this case. First and foremost, another 3CL protease inhibitor in development from Todos Medical (OTCMKTS: TOMDF), called Tollovir, was tested in hospitalized patients (a different patient population with a different and sometimes varying disease phenotype). Their observational study showed a faster recovery with Tollovir, as well as a 100% reduction in death, which is much harder to achieve when patients are already hospitalized.
Source: Todos Medical Press Release, October 4th, 20201
So both in the non-hospitalized setting (Pfizer) and hospitalized setting (Todos Medical), the 3CL protease inhibitors showed very robust efficacy as well as a good safety profile. On the other hand, all the RdRp inhibitors either lack clinical data or have underperformed the 3CL protease inhibitor competition.We already saw this underperformance in the nonhospitalized setting as well; while 3CL protease inhibitor Tollovir reduced mortality by 100% and reduced hospitalization days significantly, while remdesivir, in its phase 3 trial in hospitalized patients, only reduced the death rate by about 25% (relatively). Further, RdRp inhibitor developer Atea Pharmaceuticals had a rough year, too. It posted phase 2 data showing AT-527 failed to meet its primary endpoint in the non-hospitalized setting, after which its partner, Roche (OTCMKTS: RHHBY) pulled the plug on their collaboration. AT-527 was supposed to be basically an improved version of remdesivir with better pharmacokinetics and binding affinity. Roche might be looking for a better target, and if it is, it will probably look to collaborate with Enanta (NASDAQ: ENTA) or Todos Medical, which is one of the few testing in vaccinated and unvaccinated individuals, as these companies have 3CL protease inhibitors.One of the last promising RdRp inhibitors standing is Adamis’ Tempol, remains to be seen, as there are no measurable clinical outcomes posted yet. Tempol had promising preclinical data but then the company jumped straight into a phase 2/3 trial. Hopefully the drug works, but given the failures and underperformance of other RdRp inhibitors, Tempol’s chances don’t look great.The other reason RdRp inhibitors are undesirable is because of their safety. It is well known that remdesivir often has to be discontinued due to safety issues and that late last year, the WHO recommended against the use of it regardless of disease severity. Merck’s molnupiravir works by promoting mutations in the viral RNA replication process through RdRp, so much so that the virus cannot be formed properly. According to Nature, this is called mutagenesis. This runs the risk of promoting viral variants as well as in the long term, cancer or birth defects, which is why clinical trial participants were asked to refrain from having sex.Besides the safety issues of these various RdRp inhibitors, this clinical evidence begs the question: why do the 3CL protease inhibitors work so much better? The answer is that the 3CL protease does more to harm the human body than help the virus replicate. It actively destroys key human proteins that ultimately allow the virus to replicate more, be more infectious, avoid being eliminated, and negatively affect cell survival. RdRp inhibitors basically do one thing only while 3CL protease inhibitors prevent dysfunction and damage at the cellular level.
Killing NEMO
Recent research uncovered how the 3CL protease inhibitors (Tollovir and PAXLOVID) can further protect infected cells and improve immune responses to coronavirus infection. These researchers found that the viral 3CL protease (aka main protease, Mpro), caused direct damage to blood vessel cells (endothelial cells), especially in the brain. They found evidence of destroyed capillaries within the brain vasculature—little tubules filled with scar tissue—and connected them to direct damage the 3CL protease was causing within those endothelial cells. The 3CL protease, when produced inside infected cells, cleaves a host protein called NEMO, after which NEMO doesn’t work. NEMO is a critical protein for two processes. The first is cell survival. Without NEMO, cells undergo necroptosis, an inflammatory cell death. Second, without NEMO, the alarm signals for the immune system (cytokines) are not sent out, so the immune system does not respond optimally to the infected cells. The picture below shows the destruction of capillaries in mice’s cortex and the replacement of a thin string like structure which is just scar tissue. This could impair oxygen and nutrient supply to the brain, and probably other parts of the body too, if they contain the string vessels after infection.
But that’s not the only pathology the 3CL protease causes in the body. It also blocks the cells from trying to prevent infection.
Preserving the Cellular Recycling Factory
Inside all cells there is a recycling mechanism called autophagy whereby the cell engulfs dysfunctional parts and uses enzymes to break it down into amino acids that it reuses. This same mechanism can be used to engulf and drive out invaders like microbes, intracellular pathogens like viral proteins, or whole viruses for that matter. It's called xenophagy when this recycling process is used to drive out the invaders such as a virus. It is an intracellular process that is driven by a glycoprotein called galectin-8. What is so interesting is that galectins have an affinity to bind to a conserved region of the spike protein. This is how the cell can actually target the virus or its spike proteins for destruction when the virus is inside the cell or in the process of replicating in the cell. Investors curious to what a galectin inhibitor can do to the virus outside the cell should read this clinical trial journal report. Source: Intracellular galectins sense cytosolically exposed glycans as danger and mediate cellular responsesThe researchers found about 150 other host cell proteins that are cleaved and rendered useless by the 3CL protease. Galectin-8 just happens to be one of the key ones. The 3CL protease truly destroys cells from the inside.
“We discovered that the virus attaches to and deactivates an important sensor protein in the host cell called galectin-8, which protects the cell against infection. By deactivating galectin-8, SARS-CoV-2 disarms a cell's antiviral defense system and allows the virus to take over the host."
This cellular hijacking is essentially a coup d'état as it prevents the cell from mounting its normal antiviral mechanisms. Couple this with impairing the cell’s ability to survive and the infected cell might quickly succumb to the viral invader.The bottom line is that the 3CL protease is involved in numerous pernicious processes in the infected cell that would improve the virus’ ability to replicate and have a detrimental effect on the immune system’s ability to respond. By blocking the 3CL protease, not only is the viral replication stopped, but certain critical cellular functions like cell survival and xenophagy are preserved.
Antivirals for the Vaccinated?
Society needs antivirals, but clinical trials need to demonstrate that they work in vaccinated and unvaccinated people. After all, hitting the newswires recently has been the emergence of breakthrough infections. For instance, the most vaccinated (91%) country in the EU Ireland just saw a surge of hospitalizations—the highest it has seen in seven months—despite the mass vaccination strategy. The question is not “why?” but “who is next?” as people globally are in need of safe and efficacious antivirals.While the world waits for the first 3CL protease inhibitor to get FDA approval, 3CL supplements may be a way to protect loved ones during the coming surge into the holidays. Social media has connected the dots. Todos Medical’s main ingredients in their drug Tollovir seems to have made their way into a supplement that is called Tollovid that is FDA approved for free sale and is conveniently on Amazon (NASDAQ: AMZN). Tollovid is an all natural 3CL protease inhibitor. It's one of the highest priced immune supplements, but for good reason if it boosts the immune defense. The company also has a formulation called Tollovid Daily which is essentially a prophylactic version. As this next wave grips the country, word of this all natural way to boost the immune system will have consumers thinking if they really want to take a chance on their vaccine not working.
Investment Summary
Throughout the pandemic the therapeutic approach of targeting just one part of the viral disease progression has led to a plethora of failures. The biggest example of this type of failure in terms of dollars was the IL-6 inhibitor tocilizumab manufactured by Genentech. The NIH spent $470 million to sponsor this study only to learn that they needed to go after multiple cytokines. This is why companies like CytoDyn (OTCMKTS: CYDY), with their drug, leronlimab, which modulates levels of many cytokines, was so successful in the clinical trial setting, or why companies such as Mesoblast (NASDAQ: MESO) or Athersys (NASDAQ: ATHX) are having success in the clinic with COVID-19 ARDS as injected adult stem cells can do many things at once. The secret to a successful drug in COVID-19 is targeting multiple mechanisms of action (MOAs) like Pfizer's drug PAXLOVID. It's an antiviral that also sounds the cellular alarm and preserves cellular defense and survival. In general, the concept is that the more MOAs that are targeted the better the clinical outcomes. It is going to be very interesting to see the readout of Tollovir manufactured by TOMDFl in the coming weeks because they target the 3CL protease in very much the same way except that their drug has an additional mechanism of action as it includes an anti-inflammatory ligand and can reduce the body’s overactive, harmful immune response. Tollovir seems to be the COVID-19 antiviral with the most mechanisms of action and the only clinical trial left taking on vaccinated and unvaccinated.
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Disclosure: Insider Financial and its owners do not have a position in the stocks posted and have posted this article for free without editorial input. This article was written by a guest contributor and solely reflects his opinions.
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