Most of the major vaccine makers like Moderna (Nasdaq: MRNA), Novavax (Nasdaq: NVAX), BioNTech (Nasdaq: BNTX), Johnson & Johnson (NYSE: JNJ), Sanofi (NYSE: SNY) Atra Zenica (NYSE: AZN), Cure Vax (Nasdaq: CVAC), and Inovio Pharmaceuticals(NYSE: INO), peaked in the beginning of August and have been trending down. The frenzied rise in valuation of the vaccine makers was fueled by the notion that approval of Pfizer’s (NYSE: PFE) vaccine was forthcoming even though Albert Boural, the CEO of PFE, warned investors in a CNBC interview in late July that COVID-19 vaccine immunity wanes and that a booster might be needed. Comirnaty, the brand name of the vaccine, received FDA approval on August 23. As the Delta variant raged on exponentially during the month of August it was becoming evident that vaccine protection wanes quickly and that boosters were going to be necessary. 

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Scrambling for a Solution: Booster Turmoil

Early in the booster debate, the concept of vaccination inequity in low-income countries was met with an international rebuke on August 4th, as the WHO asked for a moratorium on COVID-19 vaccine boosters. As policy makers had to come to grips with a third Delta wave, rising breakthrough infections, and no easy-to-administer therapeutics (besides dexamethasone), they had to toss aside their international reputation for the only tool they had, which was the booster. Lack of attention to the therapeutics side of the equation finally had consequences. 

The White House quickly scrambled to pressure the FDA to allow booster shots to stem the tide of breakthrough infections and introduced the idea of mandatory vaccinations, and eventually, the FDA acquiesced on September 22 with its approval of a booster in certain populations. Strikingly, the fallout from this rushed approval was the resignation of two top veterans at the FDA who were leading the agency's COVD-19 vaccine applications. Dr. Philip Krause and Dr. Marion Gruber stepped down because they believed a full FDA review of the data in favor of the shot needed to be accomplished before the booster was rolled out. At the time of approval, the data supporting the booster was based on a study of 306 participants aged 18-55 years and just 12 participants 65 and older.For an approval that could affect hundreds of millions of people, it appears their announced departure was designed to bring attention to the tiny group of 12 participants that were over 65 years old, who formed the basis of the important policy that would most likely affect millions of Americans. They were part of a group of scientists that published in The Lancet, stating:

"Current evidence does not, therefore, appear to show a need for boosting in the general population, in which efficacy against severe disease remains high".

Buried in the language of the Lancet is the essence of their protest. In stark contrast to what agendas policymakers are pushing, The authors discuss how immunocompromised people, while not displaying adequate protection, might also respond poorly again to a booster. They seem to be aligned with the WHO in the sense that it would make more sense to give that same vaccine to an individual with an active immune system that would result in more overall benefit, rather than giving a vaccine booster to someone who might not benefit, or even worse, respond negatively. These scientists would also be aligned with the idea of testing people for their levels of neutralizing antibodies as a proxy for needing a booster or not.It’s almost common sense that a person would be tested to see if they needed a booster before they were given one given the scarcity of supply.  

The only FDA EUA test for neutralizing antibodies is the cPass. Todos Medicals (OTCMKTS: TOMDF) Provista Diagnostics is one of the few automated labs in the country offering this test. This is a quantifiable test that could be used in consultation with a medical professional to determine the need for a booster. Although The Lancet doesn’t expressly use the word “testing,” if one were to substitute the word “evidence” with “testing” in the following quote, this represents a strong basis to call for widespread testing before administering booster shots.  

“Although the benefits of primary COVID-19 vaccination clearly outweigh the risks, there could be risks if boosters are widely introduced too soon, or too frequently, especially with vaccines that can have immune-mediated side-effects (such as myocarditis, which is more common after the second dose of some mRNA vaccines, or Guillain-Barre syndrome, which has been associated with adenovirus-vectored COVID-19 vaccines. If unnecessary boosting causes significant adverse reactions, there could be implications for vaccine acceptance that go beyond COVID-19 vaccines. Thus, widespread boosting should be undertaken only if there is clear evidence that it is appropriate.”

These scientists also put out a warning statement about unnecessary boosters and their implications. Despite these warnings, boosters are outpacing the rate of new inoculations, according to the Chicago Tribune.CDC data taken on October 8th showed that an average of 337,000 booster shots were administered versus an average of 201,000 people getting their first vaccine dose. Selling the concept of new vaccinations while people are scrambling for boosters because they fear they aren’t protected is detrimental to their objective of getting to herd immunity.If Israel is to be our guide in handling the Delta variant then their talks of a 4th dose after the approval of a 3rd dose of the booster weren’t scoring any points for those with vaccine hesitancy. Instead of taking a science-based approach, which utilizes testing antibody levels or cellular immunity measurements to stave off waning immunity, the policies have created a free-for-all for boosters and created an environment of vaccine polarization discussed in the Wall Street Journal. This is having a big impact on the rate of new vaccinations and has really formed a beachhead for the rising call for therapeutics.  

The Vaccination Slump

• Waning Efficacy of Vaccines
• Vaccine Mandates fueling Vaccine Polarization
• Vaccine Inequity to Boosters
• Lack of Common Sense Testing for Booster Shot Administration
• Limited Protection from Severe Disease

Antibody treatment uptake is huge and there is just isn’t enough manufacturing to keep pace with demand. The Federal government through the Department of Health and Human Services (HHS) actually started rationing monoclonal antibody treatment to states in mid-September according to case burden and utilization which primarily affected states in the South. Antibody treatments are very expensive and will never be able to effectively compete with oral antivirals. Regeneron (Nasdaq: REGN) and Eli Lilly (NYSE: LLY) currently have the only antibody treatments under EUA but they are both infusions administered in a hospitalized setting.  

One of the most promising treatments for critical disease that can easily be administered via subcutaneous injection is manufactured by CytoDyn (OTCMKTS: CYDY) and is currently still under development despite being the only drug to clearly demonstrate a mortality benefit.CytoDyn’s drug, leronlimab, showed in a phase 3 trial an 82% reduction in 14-day mortality. Despite the fact that this was a large randomized controlled trial that was statistically significant in a subset of patients that no other COVID-19 drug has shown a mortality benefit, the FDA sought more data and an easier to reach endpoint instead of mortality. This hardline stance on clinical trial design protocol came as a shock to the company who assumed the FDA would have leeway in issuing an EUA for the only COVID-19 treatment to show a mortality benefit after it approved Gilead’s (Nasdaq: GILD) remdesivir based on much more questionable data. Consequently, the company started trials in Brazil and promised the lion's share of the drug to Brazil on what should amount to a likely approval. Unfortunately, this drug is only available under right to try in the United States and not even approved for compassionate use.    

Oral Antivirals

Some of the pure-play oral antivirals like Atea Pharmaceuticals (NASDAQ: AVIR) and Todos Medical (OTCMKTS: TOMDF) have been performing well. The diverging trends from the vaccine makers seem to indicate that the COVID-19 market is responding to the promise of oral antivirals but hasn’t fully factored it in yet. Atea’s drug is called AT-527 and it is an oral antiviral that is being evaluated for prophylaxis, reduction in infectiousness, and reduction in Long Haulers symptoms. Their trials are conducted in partnership with Roche Holdings (OTCMKTS: RHHBY). AT-527 targets RNA-dependent RNA polymerase (RdRp) which is critical for the replication of the viral RNA. The company has an extensive number of trials and they have readouts expected in 3 studies before the end of the year. While they have encouraging data that suggests their drug is not mutagenic in nature like Merck’s (NYSE: MRK) molnupiravir, the preliminary data from their Phase 2 trial on hospitalized patients suggests that they may need to test for high viral levels before administration and use would be limited to patients with underlying conditions. Most studies have completely eliminated vaccinated patients but their clinical trial allows vaccinated patients after 40 days to accommodate breakthrough infections.    

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Atea Investor Presentation

While management appears optimistic about the prospect of AT-527 in hospitalized patients, the data tells a different tale. In the chart above, AT-527 can’t seem to get enough of a reduction of viral load from the control.They are measuring clinical outcomes like reduction in hospitalization, but the reality is that, like remdesivir, this drug is just a viral inhibitor and doesn’t have any immunomodulatory properties that could help hospitalized patients with the inflammation that they have which causes respiratory distress. They also have an ongoing study of mild-to-moderate outpatients and shooting for a reduction in hospitalizations like molnupiravir and time until alleviation of symptoms.  

The strongest oral antiviral candidate is Tollovir which is made by Todos Medical. Their recent release of Phase 1 data was absent any bad safety signals, and the upcoming interim readout of their Phase 2 trial places them ahead of the race with Pfizer (NYSE: PFE). While they don’t have a large data set or any published serology analysis, they recently presented case studies that strongly suggest Tollovir has anti-inflammatory properties and is a potent antiviral targeting the 3CL protease. PFE also has an oral antiviral drug (PF-07321332) which targets the same 3CL protease as TOMDF’s Tollovir. One of the very first viral particles made after the cell has been infected is the protease, which is responsible for cutting the viral proteins, allowing them to fold on themselves and turn into viral particles that will eventually assemble and become a new virus. Blocking this protease safely stops viral replication and allows the body time to mount an immune defense.

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Todos Tollovir Data

This clinical data set is very limited but also quite powerful because it shows a drastic reduction in CRP which is a key inflammatory marker seen in hospitalized patients. In the ongoing placebo-controlled study which is due for a readout after another 5 patients are dosed, the interim results could show a mortality benefit and worst case show an improvement in hospitalization. If a mortality benefit is seen at the Drug Safety Monitoring Board (DSMB) it would almost certainly request an emergency stoppage of the trial. This would lead to an EUA or a fast-track approval. With a mortality benefit demonstrated in the Phase 1, it doesn’t seem like a far-fetched idea that it could show a mortality benefit at the interim Phase 2 readout expected before November 30th based on the most recent video update. There is a strong mechanism of action that supports this speculation.    

Oral Entry Inhibitor

In-depth research of oral antivirals uncovered one oral COVID-19 treatment with an extremely strong proof of concept clinical trial that is not an antiviral, but rather an entry inhibitor. This means its target is the spike protein. The company, Pharmalectin Inc. actually published a peer-reviewed journal article that showed an elimination of viral load within 5 days with no side effects. This is stunning news when you consider people are quarantined for 10 days after testing positive. If this viral load was overlaid on the AVIR chart above it would resemble close to a vertical line. It also reduced infectivity and increased natural immunity by promoting high levels of IgG. It's one of these little pharma companies that has a brilliant idea if only some people would listen.  

Their drug is a galectin antagonist that appears to stop viral entry into the cell. The body of research related to galectins in coronavirus is voluminous, dating back to 2011. The most recent journal articles that discuss the prognostic values of galectin-3 or galectin-9 were eye-opening. These blood serum tests could predict COVID-19 mortality with incredible accuracy yet they go unused. Galectin-9 alone had a 95% sensitivity prognosticating mortality. Their conclusion was that “Gal-9 may serve as a therapeutic approach in COVID-19 infection.”Another article cited Galectin-3 as a prognosticator of mortality and suggested it was a way to stratify patients with ARDS. Surprisingly the private company Pharmalectin Inc. is owned by a public company Bioxtyran Inc. Bioxtran Inc. is raising $5.3 million via an S-1 offering. Their use of proceeds shows that they are at a Phase 3 level and they only need $2.7 million to reach their endpoint. The company is very quiet and has no press releases. If they secure funding or break their silence this could be one to watch.      

Investment Summary

It seems even more self-evident than before that therapeutics are the missing link in the White House’s COVID-19 strategy. With the rising number of breakthrough infections the vaccine is clearly not stopping the spread as originally planned. Policies that give preference to vaccine card holders are equally as dangerous by giving people a false sense of security. For example, some restaurants in California require proof of a current vaccination to get into a restaurant while displacing a patron with a current negative COVID-19 test. The public is seeing the various cracks in the vaccination-only strategy and that is translating into lowered expectations for the vaccine makers. Vaccines with quickly waning effectiveness cannot protect against the community spread. The lack of adequate testing surveillance is partially responsible for this latest delta wave as many thought in early summer the pandemic was ending. The epic blunder of not utilizing the cPass as a screening test to determine booster eligibility has created a state of vaccine polarization that cannot be undone.  

Mutations are likely to continue and the next one that finds its way around the current vaccines would leave the world completely unprotected. This cycle has to stop, and only oral antivirals that are easy to dispense, easy to mass-produce, and safe to take can put an end to the pandemic and the variants that come with it. Tollovir made by TOMDF is the most promising oral antiviral because it cares not about vaccination status, cares not about underlying conditions, cares not about what stage of disease you are in, and just focuses on ridding the virus as quickly as possible, reducing infectiousness, and making the person feel better. While molnupiravir might work on a very narrow subset of patients its safety profile is questionable and it has nowhere near the safety profile of Tollovir.          

At some point stopping the spread has to be a priority. Many that get the disease can end up with Long Haulers. Vaccines are unable to stop this which is why disease prevention via oral antivirals is so essential. Instead of letting science lead to answers and solutions, the FDA has chosen to rely on big pharma even though little pharma seems to have the perfect package. How many more people have to die for a p-value? People are demanding an oral antiviral now and the rise in TOMDF seems to be reflecting those attitudes because TOMDF has an oral antiviral with extremely strong mortality data and an interim readout possible before Merck's meeting with the FDA about molnupiravir. However, what makes them standout is their ability to produce a nutraceutical equivalent that can be purchased today at www.mytollovid.com or Amazon.com.Virally spreading the message of this nutraceutical may be the key to actually beating the virus instead of living with it. Although some have written off the hope of finding a cure for this plague the only thing that we should be writing off is the hope of big pharma finding that solution. There are clear indications that smaller players have viable solutions that save lives and have better risk profiles than the big pharma whose focus is on recurring revenue streams instead of healing people.