- Vaccines have less efficacy with COVID-19 variants
- Key 3CL protease inhibitors shows promise for any COVID-19 variants, and potentially all coronaviruses
- Pfizer’s and Todos Medicals drugs stop coronavirus replication in development; its 3CL protease inhibitor is the next best solution
- Consumers might flock to the Todos Medical supplement Tollovid if drug development stalls
Pfizer (PFE) is approaching COVD-19 with a complete end-to-end solution intent on capturing the lion’s share of the market. It’s no secret that viruses mutate. For the past 90 years, mankind has been using a vaccine to battle the most famous virus of them all called influenza. Vaccines have been able to eliminate polio, tetanus, rubella, but not the flu. Even with decades of vaccinations, the flu season still results in over 200,000 hospitalizations each year and is still considered a major public health threat.
COVID-19 could turn out to be a similar animal. Pfizer has a very successful COVID-19 vaccine that is expected to deliver 220 million doses by the end of May and on CNBC the CEO of Pfizer made a bold call to have their oral broad-spectrum viral inhibitor by the end of the year. The only thing standing in PFE’s way is a small $22 million market cap biotech called Todos Medical (TOMDF) who happens to be ahead of them in clinical trial development race and is going after exactly the same target called 3CL protease.
Pfizer’s new oral antiviral is expected to be very much like Roche’s (RHHBY) Tamiflu, which is an antiviral for influenza and was a blockbuster product about a decade ago. Tamilflu sold over three billion USD of product during the 2009 H1N1 swine flu outbreak. As many expected, the COVID-19 viruses are now mutating and some strains are working their way around vaccines while also becoming more contagious. The world cannot get by on vaccines alone and will need an easy-to-take antiviral. Todos Medical (TOMDF) is currently a phase 2 study while Pfizer is finishing up their phase 1.
TOMDF could beat PFE to the punchline, and if they do, its a multibillion dollar lottery ticket for TOMDF shareholders with only 3 names in the drawing if you you think Merck (MRK) has a chance with molnupiravir.
Investors are bound to reap the rewards from the company that quickly finds the best solution. PFE or TOMDF’s 3CL protease inhibitor is a viable solution to be COVID-19’s Tamiflu, or the Tamiflu for coronaviruses in general. The real question is whether or not they can get it approved in time before the variants decrease the effectiveness of the vaccines.
Decades of Vaccine Failures
Some of the worst epidemics over the past two decades were coronaviruses, including the 2002-2004 outbreak of SARS-CoV (severe acute respiratory syndrome), 2012 MERS-CoV (middle east respiratory syndrome), and then in 2019-2020, SARS-CoV-2, commonly referred to as COVID-19. Unfortunately, these viruses have been historically difficult to develop vaccines for, due to viral escape mechanisms and the safety concerns that surround all new vaccines. While this COVID-19 pandemic was handled much differently than outbreaks in the past, the historical vaccine development for viruses was completed only after the epidemics subsided, or vaccines failed to be developed successfully at all. Even with COVID-19, viral variants are likely to arise, gradually escaping immunity of the Pfizer (PFE), Moderna (MRNA), and J&J (JNJ) vaccines.
There are a number of viruses that still, after years of R&D, have no vaccine available on the market. HIV treatments have been a mainstay for which Gilead Sciences (GILD), Merck (MRK), J&J, Bristol Myers Squibb (BMY), AbbVie (ABBV), and GlaxoSmithKline (GSK) have brought in massive amounts of recurring revenues (>$30 billion worldwide) for years, using antivirals. Another example of a viral disease with no available vaccines is RSV (Respiratory Syncytial Virus), which is basically the common cold for most people, but it can easily kill infants and older adults.
The bottom line is that vaccines are a difficult way to combat some viruses such as coronaviruses, and big pharma needs something else in its toolbox to treat coronaviruses because of this.
Vaccine Trouble, Just Like Influenza
Loss of Potency
There are two primary reasons vaccines aren’t the magic bullet against COVID-19 and other coronaviruses. The first is obvious—vaccines against highly mutant viruses such as SARS-CoV-2 will have to be administered with booster shots as the viruses try to escape the population’s immunity, and because of that, the vaccine game is always behind the next mutant virus.
According to a recent article in Business Insider,
“Both Pfizer and Moderna said in January that they planned to develop and test booster shots to tackle the B.1.351 variant. That means vaccinated people may need to get a follow-up shot. Until then, people who’ve been vaccinated or previously got COVID-19 could still be at risk of infection from the B.1.351 and P.1 variants.”
Source: Woodward, A. (2021, March 12). One chart shows how well COVID-19 vaccines work against the 3 most worrisome coronavirus variants.
The vaccine will be less potent against all new strains that begin to circulate. In addition to the variants listed in the chart, there are a handful of other variants moving around the globe, and it’s only been about 18 months since COVID-19 started. What will the next 10 years bring? We will probably be stuck with COVID-19 variants forever.
Potential Harmful Side Effects
The second reason why vaccines really aren’t a magic bullet against coronaviruses, even potentially including COVID-19, is that these vaccines really have to be thoroughly tested before they can be administered; many people might not know it, but vaccines can have harmful effects and if they do, they need to be shelved and not sold.
Obviously, this safety testing comes before regulatory approval, but this is not uncommon for vaccines to have questionable safety profiles, as has been seen with the J&J COVID-19 vaccine and cases of blood clots and now more recently potentially myocarditis cases (heart inflammation) linked to the BioNTech/Pfizer vaccine. Vaccines need to have a pristine safety profile since they are given to people who don’t have a problem in the first place. The old adage of medicine is “primum non nocere,” or “first, do no harm.” It is unacceptable to unnecessarily put healthy people at risk of complications.
An excellent example of coronaviruses giving people dysregulated immune responses is a study done back in 2000 where researchers tried to give an inactivated virus vaccine to monkeys and then challenged them with the virus after they had been vaccinated. While some were protected from diseases, one which should have had immunity quickly developed severe lung damage (second from the left), due to antibody-dependent enhancement (ADE) of disease, whereby the virus uses antibodies created from the immune system to hijack immune cells. Normally these antibodies clear the virus, but in some cases like this, the antibody response is not right and the virus uses the antibodies to infect immune cells, which really hamstrings the further clearance of the virus.
Source: Wang, Q et al. (2016). Immunodominant SARS Coronavirus Epitopes in Humans Elicited both Enhancing and Neutralizing Effects on Infection in Non-human Primates. ACS Infectious Diseases, 2(5), 361-376.
In another experiment, antibodies from convalescent plasma were taken from patients who recovered from SARS-CoV-1, the prior coronavirus outbreak, and were administered to the monkeys, which were subsequently overcome by the cytokine storm, resulting in severe lung damage. Clearly, developers of vaccines need to be very cautious, and turnkey solutions aimed at stopping viral replication of any coronavirus that can be rapidly deployed in the event of another outbreak, whether it be a new epidemic or a new strain of COVID-19, are sorely needed. Not all vaccines are necessarily safe or effective, especially for coronaviruses, and Pfizer has recognized this and is forging a path ahead. After all, epidemics and pandemics are likely to become more common, and humanity can’t wait around for a vaccine to be developed every time a new virus shocks the world.
Epidemics and Pandemics to Become Prevalent
According to Gavi, The Vaccine Alliance, pandemics have been more frequent in recent years and are likely to become increasingly frequent for a number of reasons, a few of which are listed below:
- The first reason is global travel. Travel has never been easier and cheaper, and as the world population has also grown and more and more countries become developed, the number of people flying by plane has more than quadrupled over the last three decades.
- Urbanization also plays a major role in the creation of pandemics. Coupled with plenty of flights, over the past hundred years, the world has gone from a ratio of 2:1 rural to urban living to 2:1 urban to rural living. With people crowded together in cities and many growing areas struggling with sanitation and healthcare, these viruses will have ample breeding ground.
- Climate change, believe it or not, is also a factor. It affects various aspects of human living,, from access to food and water to more frequent hurricanes. Thus, it is no surprise that climate change can also increase the spread of viruses in various ways, including altering the natural range of disease-carrying insects like mosquitoes, which can carry malaria. The World Health Organization (WHO) estimates that between 2030 and 2050, climate change may result in the death of 250,000 people per year due to the spread of infectious diseases such as malaria and dengue fever. By the way, Dengue fever, though it has been around for years, only got an approved vaccine in 2019, and with major restrictions. Also, an increased risk of flooding due to severe weather also likely means that outbreaks of waterborne diseases like cholera and other diarrheic diseases will become more common.
- Healthcare worker shortages in less developed countries due to perpetual migration of nurses from low- and middle-income countries to high-income countries may continue to leave poorer countries around the globe with too few nurses and doctors to adequately care for their populations, further fueling outbreaks.
With pandemics on the rise and vaccines falling short, other types of drugs to deal with outbreaks are necessary.
Next Best Solution: Preventing Viral Replication
The next best solution is antiviral drugs with great efficacy and safety that can stop viral replication in its tracks. Though viruses mutate to avoid antibodies, certain parts of a virus don’t really seem to change much. In 2003, Pfizer identified a drug to block a specific protease, called 3CL protease (3C-like protease, C30 endopeptidase), that is a critical protein involved in coronavirus replication and developed a drug to block it for treatment of COVID-19. It is considered the “main protease” (Mpro) for coronaviruses and is a great target for COVID-19 as it is quite different from human proteases [1,2,3] compared to other coronavirus proteases.
For instance, PL protease from SARS-CoV-2 can also recognize a sequence on ubiquitin, which means an inhibitor for this protease might also block human deubiquitinase, which could easily deregulate a wide range of cellular processes, resulting in poor safety. So, the 3CL protease is the ideal target for specificity of a drug. In recent studies, Pfizer showed that with a high enough dose, they can completely prevent replication in vitro, and that the antiviral was synergistic with remdesivir for treating COVID-19. And studies have shown that the 3CL proteases are quite similar across coronavirus strains, so drugs blocking the protease active site may have efficacy across a wide range of coronaviruses. At worst, these inhibitors might be slightly modified for new coronaviruses.
Source: Breakthroughs at the Intersection of Health and Science. Protease Inhibitors to Fight COVID-19: Stopping the Virus’s Life Cycle
At the very least, it’s likely that this antiviral, called PF-07304814, being developed by Pfizer might block all the viral variants. At the most, it will have activity against a broad range of coronaviruses and protect humans from future coronavirus pandemics. Pfizer has initiated a Phase 1b study of PF-07304814, given intravenously (IV) for hospitalized COVID-19 patients. Pfizer’s New Oral Drug (PF-00835231)
Interestingly, the company is also working on an oral version of the drug, called PF-00835231, which is undergoing its own phase 1 clinical trial, multi-dose study in hospitalized clinical trial participants with COVID-19. Mikael Dolsten, MD, PhD., Chief Scientific Officer and President, Worldwide Research, Development and Medical of Pfizer, stated in their press release:
“We have designed PF-07321332 as a potential oral therapy that could be prescribed at the first sign of infection, without requiring that patients are hospitalized or in critical care. At the same time, Pfizer’s intravenous antiviral candidate is a potential novel treatment option for hospitalized patients. Together, the two have the potential to create an end to end treatment paradigm that complements vaccination in cases where disease still occurs.”
As mentioned before, this drug could potentially block other coronaviruses. PF-00835231 was also evaluated against 3CLpro from a variety of coronaviruses: alpha, beta, and gamma, but not delta, three of the four main subgroups. According to Pfizer’s pre-print:
“PF-00835231 demonstrated potent inhibitory activity against all tested coronavirus 3CLpro including members of alpha-coronaviruses (NL63-CoV, PEDV, FIPV), beta-coronaviruses (HKU4-CoV, HKU5-CoV, HKU9-CoV, MHV-CoV, OC43-CoV, HKU1-CoV), and gamma-coronavirus (IBV-CoV), with Ki values, ranging from 30 pM to 4 nM. The demonstrated activity is consistent with a potential therapeutic use against emerging coronaviruses. This inhibitory activity is restricted to coronavirus 3CLpros as PF-00835231 was inactive against a panel of human proteases and HIV protease. PF-00835231 showed detectable activity against human cathepsin B but 1000-fold weaker (6.9 nM vs 6 μM) activity compared to 3CLpro. Thereby, these data collectively support PF-00835231 is a selective in vitro protease inhibitor with broad coronavirus activity.”
In Vitro Tests Show Superiority to Remdesivir
Pfizer also tested the antivirals using a cytopathic effect (CPE) assay which takes the treated virus with the antiviral agent and then inserts it into live cells. If any of the cells become a breeding ground for the virus, the test fails and the antiviral is considered no good. Lastly, Pfizer also found that in its studies, PF-00835231 was more potent than remdesivir. With remdesivir generating $1.5 billion in sales in the last year or so, but it being limited to an intravenous infusion for hospitalized patients, it is in the realm of possibility that an oral antiviral for COVID-19 may outsell remdesivir, even with vaccines rolled out. People know that when they lose their sense of smell or have other odd symptoms, they might have COVID-19, and many will be eager for an antiviral.
Bridging the Gap to Approval – Oral Antivirals Currently Available
For those interested in protecting themselves from an infection now, there are supplements on the market that do the same exact thing as Pfizer’s antiviral. While many might not be aware of these options, it is helpful to spread the word to potentially keep at-risk people safe.
Curcumin and other natural product extracts have limited data suggesting antiviral activity against SARS-CoV-2 through binding affinity to 3CL protease, TMPRSS2, and ACE2. Highlighted were some flavonoids reported to bind to 3CL protease, some of which are somewhat well-known supplements, such as curcumin (turmeric extract) and quercetin. So, it is possible that people taking quercetin or curcumin could benefit. However, curcumin is known to have poor bioavailability so it is uncertain how well this strategy could work.
Fortunately, there is a product consumers can buy now. It’s called Tollovid, and it’s produced by a small $16 million market cap biotech company named Todos Medical (OTCMKTS: TODMF).
Tollovid is available for sale as a dietary supplement. It consists of herb extracts and a 3CL protease inhibitor, which has been shown to block 3CL protease. The company also has data from people who have taken Tollovid worldwide that suggests the supplement does indeed work. In addition to the excellent testimonials, the company also has about $2 million cash on hand to launch the product to meet the demand once the variant strains start spreading rapidly in the United States.
Tollovir, the clinically tested drug version of Todos Medical’s Tollovid supplement, is going through phase 2, and the company could easily turn the adaptive trial into phase 2/3 after analyzing which countries want it the most. Then, the product could be ready for FDA approval way before Pfizer’s 3CL protease inhibitor, and even potentially before competitors like Merck, which has an antiviral in development with a different mechanism of action.
The Clock Is Ticking: Competition Looming
TOMDF could get to market first, which would be a huge relief for people at risk of severe symptoms upon contracting COVID-19 variants. If it weren’t for Merck and Todos, the market potential for Pfizer’s 3CL protease inhibitors would be clearer, but since the small company with fewer resources might hit the market faster, perhaps it would be best for Pfizer to join forces with Todos as it nears approval as Pfizer understands the molecular target and has the resources to push the drug forward. If TOMDF advances their trial quickly its possible that they could be rewarded with a buyout offer from PFE in this scenario.
There are other antivirals in development, both oral and intravenous, but few products are already available on the market for COVID-19. If Pfizer wants to hit the market first as it did with its mRNA vaccine and gain a foothold on the antiviral market so it can be second after Gilead instead of lagging behind in third or fourth, it will have to beat Merck (MRK) to the punch.
Merck is developing an oral drug, molnupiravir, in an exclusive worldwide license from Ridgeback Biotherapeutics. The drug works as an antiviral for COVID-19, like an oral form of remdesivir, but it works in a totally different way, by promoting replication errors, thereby increasing the number of defective copies and lowering the ability of the virus to continue to replicate in subsequently infected cells. Merck conducted a phase 2a study of the drug, and according to the company, the results were promising.
This drug was previously studied by Pharmasset, a hugely successful biotech company that was acquired for $11 billion by Gilead (GILD) way back in 2011. Gilead/Pharmasset subsequently abandoned it after some time, as it wasn’t clear how safe the drug was. Rick Bright, former head of BARDA, had major concerns that the drug had mutagenic (cancer-promoting) activity, and that all the drugs in this class (of promoting replication errors) seem to cause reproductive toxicity in animals, which isn’t surprising given their mutagenic activity. Nonetheless, a short time of dosing may make the administration to patients likely to undergo worse symptoms in the near term acceptable, and Pfizer needs to beat Merck to market if it wants to bury the competition once and for all.
Trial Design Issues
The biggest risk factor impacting Pfizer’s aggressive year-end target is choosing the optimal clinical trial protocol. Todos Medical has a plan to test orally administered Tollovir in patients who are hospitalized while also gathering data on patients who take the Tollovid supplement before getting severe symptoms.
This plan represents a much better data gathering technique than Pfizer’s previous strategy of testing an antiviral in hospitalized patients. When a patient reaches the hospital, their disease state is predominantly hyper inflammation, aka “cytokine storm,” or at least is moving in that direction with viral titers on the way down.
So, at some point, inflammation is the primary problem and the virus is secondary in nature. If Pfizer doesn’t address this canary in the coal mine before they start the next trial it could delay their approval by forcing them to redo the clinical trial.
Source: Akhmerov, A., & Marbán, E. (2020). COVID-19 and the Heart. Circulation Research, 126(10), 1443-1455.
Data Lacking in Mild Patients
Other protease inhibitors have had trouble showing efficacy in clinical trials, but some have focused on hospitalized patients. According to NIH treatment guidelines for COVID-19, 3CL protease inhibitor lopinavir/ritonavir combo did not show efficacy in COVID-19 hospitalized patients, and there is not enough data in nonhospitalized patients, the ones that can be saved from symptoms before the virus replication goes out of control and before the immune system overreacts:
“The pharmacodynamics of lopinavir/ritonavir raise concerns about whether it is possible to achieve drug concentrations that can inhibit the SARS-CoV-2 proteases. In addition, lopinavir/ritonavir did not show efficacy in two large randomized controlled trials in hospitalized patients with COVID-19.
There is currently a lack of data on the use of lopinavir/ritonavir in nonhospitalized patients with COVID-19. However, the pharmacodynamic concerns and the lack of evidence for a clinical benefit among hospitalized patients with COVID-19 undermine confidence that lopinavir/ritonavir has a clinical benefit at any stage of SARS-CoV-2 infection.”
The NIH also cites nausea, vomiting, diarrhea, QTc prolongation, and hepatotoxicity as significant side effects. This doesn’t mean that 3CL protease inhibition is a bad strategy. What it means is that lopinavir/ritonavir are poorly tolerated drugs that have metabolism issues, and that they weren’t given to the right patients. There were a bunch of trial design issues cited by the NIH, including:
- Too low plasma concentrations of drug-using typical HIV dosing, far below levels needed to block SARS-CoV-2 replication,
- No clinical benefit in hospitalized patients in a large randomized trial in the UK,
- No mortality rate benefit in another international large, randomized trial for COVID-19 patients,
- No virological benefit in a moderately sized trial of hospitalized patients compared to standard of care
- Most of these studies are using HIV protease inhibitors hoping to block 3CL protease.
What this means is that companies need to dose the right population (not hospitalized, recently diagnosed), the right dose concentration, and with drugs actually designed or known to block 3CL protease. Thus, Todos’ approach actually seems the most promising because they are testing against a broader spectrum of patients, though only hospitalized patients through a bonafide clinical trial.
According to Todos’ press release, a phase 1 trial in hospitalized patients had encouraging data that helped them select a dose for their phase 2, so perhaps the prior failures in clinical trials for other protease inhibitor had to do with the drug selection and dose, and not as much so the state of the patient. After all, remdesivir helped patients who were hospitalized, but not ones who had progressed to needing ventilation.
Merck seems to have recognized the issue of dosing patients who have progressed past the stage of viral replication and into full cytokine storm pathology, as they and their partners, Ridgeback Therapeutics LP recently halted their trial of molnupiravir for hospitalized patients and are doing another trial with less severe patients, before inflammation is an issue and while the virus replication and infection is the primary issue. A Phase 2, 5-day course of treatment showed promise in non-hospitalized patients, with the drug arm measured completely virus-free at 5 days and placebo at 24% still infected. Todos recently was granted a Certificate of Free Sale by the United States FDA for a higher dose, 5-day regimen for its 3CL protease inhibitor supplement blend, Tollovid, which people can easily buy online.
So, with these promising 5-day results from Merck, a likely safer drug from Todos in testing for hospitalized patients and also available as a supplement online for those who have simply contracted the virus and want to eliminate the risk of developing severe symptoms, and Pfizer working on a similar strategy as Todos, patients should be looking at much better options than IV remdesivir in the future. These protease inhibitors for COVID-19 could be like Tamiflu for influenza, which is manufactured by Roche (RHHBY), and did billions in sales as H1N1 broke out.
Investors interested in Pfizer’s potential best-in-class COVID-19 and potential future coronavirus pandemic antiviral should closely monitor the competition and the safety of those products including remdesivir and Merck’s molnupiravir. As a hedge all PFE investors should buy TOMDF in case the company beats Pfizer to regulatory approval.
MRK has the right strategy with their antiviral but it could cause cancer so the drug itself is sub-par. TOMDF will likely find the best path forward as they will have data across a spectrum of disease and will continue to gather data from people across the world who take Tollovid, regardless of whether their Tollovir works on hospitalized patients. It’s not clear whether the clinical trial issues with other protease inhibitors have to do with other drugs’ tolerability, dosing regimen, affinities for 3CL protease, or patient selection, but given TOMDF already has data gathered from many people from their supplement and PFE already studied their drug in SARS-CoV-1, Todos and Pfizer’s drugs are the ones to bet on.
There’s a really large market potential for oral antivirals for COVID-19 as the virus is not going away. These antivirals given orally will probably steal most of the market share from GILD as nobody wants to wait to get hospitalized in the first place. The best way to be prepared is to have Tollovid handy and when one suspects that they have COVID-19, they can take the 5-day regimen and be done with the virus.
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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.