Is Pfizer Conceding Race in Hospitalized Covid Because of Todos Medical's Triple MOA Antiviral?

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The following post was written and/or published as a collaboration between Benzinga’s in-house sponsored content team and a financial partner of Benzinga.

  • New research suggests a third mechanism of action behind Tollovir
  • Third mechanism explains Tollovir’s robust data in severe disease where other antivirals have struggled
  • Tollovir quickly becoming the most promising antiviral in development

In March, Pfizer Inc. PFE indicated its oral antiviral drug PF-07321332 would be prescribed “at the first sign of infection.” It planned to use the intravenous formula lufotrelvir (PF-07304814) for hospitalized patients to create an “end-to-end treatment paradigm.” The big wrinkle in Pfizer’s paradigm-changing plan is that its only clinical trial is a 5-patient study in a hospital setting using radioisotopes to figure out how to safely dose future patients. 

The inability of PFE to quickly complete this 5-patient study is the equivalent of a no show at the start of a race. Competitor Todos Medical Ltd. TOMDF seems to be the only runner left in the hospitalized setting capable of reaching a lucrative endpoint.  A Peterson-KFF brief estimated that the average cost of COVID-19 treatment in a hospital was $20,000. The current number of patients hospitalized today is 47,020, which represents an immediate market of $940 million.  Finding a long-term solution that either prevents hospitalizations or reduces the time in the hospital has the potential to be worth billions.  

A critical new piece of medical research was published last week, and it set the stage for 1 specific class of COVID-19 antivirals to dominate the field. Main protease (MPRO) — also called 3CL protease — inhibitors are now expected to be the best ablators of COVID-19 disease. Only a handful of 3CL protease inhibitors are in development, including those owned by Pfizer and Shionogi 4 ADR SGIOY, but the leader in the field is Todos Medical.

Fortunately for savvy investors, TOMDF represents a unique opportunity since it only has a $25 million dollar market capitalization. Although its Phase 2 candidate Tollovir is expected to read out within the next 30 days, an extreme valuation gap exists as market participants have yet to grasp the likelihood of a positive readout more favorable than Merck & Co. Inc.’s MRK molnupiravir. As the date of the interim readout firms up, the valuation gap should start to correct itself from the extreme levels that exist today. The market clearly demonstrated that a COVID-19 antiviral approval is worth over $10 billion dollars based on the stock price jumps of Gilead Sciences Inc. GILD and Merck when their antivirals read out pivotal clinical data. 

Struggles for Other COVID-19 Antivirals

Most COVID-19 antivirals have been shown to have weak efficacy in hospitalized patients, with the most promising antivirals only showing significant benefit in patients who have some symptoms but aren’t at risk of having to go to the hospital. It is widely known that remdesivir has a modest effect in a specific set of hospitalized patients, and with many other antivirals blocking the same target (RdRp- RNA-dependent RNA polymerase) as remdesivir, it is no surprise that the likes of Atea Pharmaceuticals Inc. AVIR and Roche Holdings AG’s RHHBY AT-527 showed disappointing results even in the outpatient setting. Other antivirals targeting RdRp like Appili Therapeutics Inc.’s APLIF favipiravir and Adamis Pharmaceuticals Corp.’s ADMP TEMPOL might run into the same efficacy issues.

TEMPOL, despite targeting RdRp that has shown to be a weak target for SARS-CoV-2 (COVID-19), has a better chance than some of the other RdRp-targeting antivirals since it also has anti-inflammatory properties, setting it apart as a dual-mechanism of action (MOA) antiviral. That designation is important since COVID-19 patients can exhibit increased inflammation, so blocking the virus from replicating while also decreasing inflammation might have an increased effect on treating patients. However, according to the publication discussed below, Tollovir, TOMDF’s antiviral, is the only antiviral with a triple MOA and is poised to be the best-performing COVID-19 antiviral in the playing field.

Other antiviral-only drugs such as Pfizer’s protease inhibitor are also only being advanced in early stages of infection, which limits their utility and highlights their weakness in treating severe cases.

The New Research

The publication outlined 1 more MOA of Tollovir’s effect on COVID-19. The main protease, 3CL protease, generated by the virus was found to not only facilitate viral replication but also to damage blood vessel cells, particularly in the brain. Researchers found evidence of lost capillaries in the brain vasculature and linked it to the direct damage caused by the 3CL protease on those brain cells. The only antivirals that could mitigate this damage are the 3CL protease inhibitors.

What happens with 3CL protease in the endothelial (blood vessel) cells is a cleavage of an intracellular protein called NEMO. NEMO is like the traffic cop in the cell that keeps inflammatory gene signaling in check, so when it gets cleaved by 3CL protease, inflammation can run rampant. NEMO is also a key regulator of cell survival, so when it is cut by 3CL protease, the endothelial cells die while inflammation increases (necroptosis). Shown on the graphic below, this event causes destruction of brain capillaries, impeding nutrient and oxygen flow to the brain. This effect could also occur elsewhere in the body. 

The SARS-CoV-2 main protease Mpro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells

The most interesting thing implied by this research is that 3CL protease inhibitors used to treat COVID-19 patients might reduce long-haul COVID-19 by preventing inflammation.

Tollovir Is the Only Antiviral with Triple MOA

This new information sets Tollovir apart as the only antiviral with 3 MOAs. First, it blocks viral replication through the 3CL protease, which ensures no functional proteins are made from the polypeptides. Second, it reduces inflammation as measured in C-reactive protein levels through a separate mechanism. This effect is similar to how immune modulators meant for severely and critically ill COVID-19 patients work, like CytoDyn Inc.’s CYDY leronlimab, which has shown great promise in both acute and long COVID-19. Third, it is now known that the blocking of 3CL protease will have protective effects on the endothelial cells that COVID-19 infects, which should preserve oxygenation of tissue and organ function, as well as reduce cell death. No other antiviral in development has generated data that rivals the robust early data that Tollovir has, and given the unique triple MOA of Tollovir, it is unlikely that any of the others will generate such data.

Robust Efficacy of Tollovir

The triple mechanism of Tollovir in treating severe COVID-19 along with its early data suggesting robust efficacy in serious cases sets it up to be the leading and best-performing antiviral in development. An interim readout on Tollovir in hospitalized patients is expected shortly before MRK’s AddComm meeting on Nov. 30. With major catalysts so close and PFE out of the hospitalized race, investors need to watch this disruptive player called TOMDF. Its success could also trickle over and impact the development of molnupiravir, so MRK investors are encouraged to be vigilant. An oral COVID-19 antiviral could be worth billions, and investors who do their due diligence to understand the antiviral competitive landscape might find tremendous opportunity in a name that seems highly derisked.  

The preceding post was written and/or published as a collaboration between Benzinga’s in-house sponsored content team and a financial partner of Benzinga. Although the piece is not and should not be construed as editorial content, the sponsored content team works to ensure that any and all information contained within is true and accurate to the best of their knowledge and research. This content is for informational purposes only and not intended to be investing advice.

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