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Msg  11030 of 12907  at  6/26/2021 12:00:53 PM  by

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SA story with a brief description of Leronlimab, author is long CYDY

Merck Desperate To Get Back In Coronavirus Race, With A Pill
Jun. 26, 2021 12:18 AM ETMerck & Co., Inc. (MRK)CYDY, GILD, JNJ...20 Comments17 Likes
Theodore Zucconi profile picture.
Theodore Zucconi
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Special Situations, Biotech, Senior Management Consultant.

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Ph.D. in chemistry, Masters certificates in International Finance and Program/Project Management. Over 38 years experience in high tech and biotech.
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Summary

Competitors beating Merck for COVID-19 treatment.
Proof of Molunupiravir efficacy is elusive.
Merck's track record in this area is poor.
Green and blue coronavirus cells under magnification intertwined with DNA cell structure
matejmo/E+ via Getty Images
Merck (MRK) is looking for redemption, and a way to get back into the race is to develop a pill that can treat COVID-19. As the 2nd largest vaccine maker in the world they were the favorite to win the vaccine race, but they squandered their positioning with a late start and were unable to get any traction in their development. They are in a similar situation where they were the odds on favorite to produce a COVID-19 pill, but the competition is heating up as they are pitted against treatments that are more efficacious. The companys expertise and recent success is from Keytruda and oncology, so they really need a win in the COVID-19 indication to stay relevant in the infectious diseases space.

Mercks Trials and Tribulations in COVID-19

In November 2020, Merck knew they were losing the vaccine race as Moderna (MRNA), Pfizer (PFE), and Johnson & Johnson (JNJ) posted interim results that generated high levels of efficacy. In response to this good data Merck did a pivot and purchased a very promising therapeutic candidate for severe and critical hospitalized COVID-19 patients called MK-7710 from OncoImmune for $425 million. In January 2021 it was clear they lost the race for a COVID-19 vaccine and they discontinued their development citing inferior immune responses.

Merck has a long history of vaccine and infectious diseases development, beginning in 1943 with the first effective treatment for tuberculosis. Through the next few decades, they developed vaccines for smallpox, mumps, measles, rubella, hepatitis B, and chickenpox. Infectious disease treatment and vaccines have long played a large part of Mercks innovation and success, and so their COVID-19 vaccine failure is a big blemish on their leadership position in the space.

In a quest to still be relevant in the vaccine arena, they partnered with JNJ to produce their COVID-19 vaccine. In April 2021 they completely scrapped their plans to develop OncoImmunes drug and chose to focus on molnupiravir. Their expertise in manufacturing was supposed to help scale OncoImmunes drug, but they never got to that point because the FDA wanted more data.

After a failed vaccine trial, they were hoping to create some magic with their antiviral pill, called molnupiravir, to fill the void of an easy-to-take antiviral therapeutic that prevents people from needing hospitalization. Despite the company floundering around in an attempt to stay relevant in the COVID-19 space, the development of an oral antiviral to help prevent hospitalization is a good strategy, hopefully one that Merck can finally deliver on.

COVID-19 Early Treatment Options

Right now, no treatment exists where a clinician can prescribe a treatment that definitely lessens the chance of hospitalization upon diagnosis. The closest treatment that showed promise in a phase 2 trial was a subcutaneous injection of a monoclonal antibody called leronlimab, which helps prevent a cytokine storm and inflammation that damages the lungs. The drug is manufactured by CytoDyn (OTCQB:CYDY) and demonstrated a statistically significant reduction in the NEWS2 endpoint, which is a prognosticator of hospitalization.

However, the FDA required a larger study so it appears that the company chose to focus on the severe to critical population instead. They already had a trial started for this population. They are also running a trial for long-haulers which may have a larger population than the severe to critical population now that the vaccines are widely administrated.

Gilead Sciences (GILD) well-known remdesivir is administered intravenously, which means it will only be useful in already-hospitalized patients; nobody wants to be hospitalized before they can receive treatment. There are no oral antivirals that are approved. Leronlimab is a subcutaneous shot. While not approved, it is worth mentioning that Jubilant Pharma, an Indian company, is working on an oral form of remdesivir with no new safety/ tolerability issues when compared to the injectable dose.

An oral form of remdesivir could make its way to market, but headlines like WHO drops remdesivir from its official list of COVID-19 treatments, dont help its chances. There are other treatments out there like the monoclonal antibodies from Eli Lilly (LLY) and Regeneron (REGN) that help fight COVID-19 by neutralizing the virus once a person is already infected, but they are difficult to administer and treatment must be completed soon after the infection starts. Variants could also dramatically limit the effectiveness of the neutralizing antibody cocktails. Bamlanivimab, Eli Lillys drug, had its EUA pulled on April 21, 2021 due to the rise of the new variants in the United States.

The Contenders

Merck may be a giant in the race to find a COVID-19 antiviral pill, but it has intense competition from big pharma rivals Pfizer (PFE), Roche Holdings (OTCQX:RHHBY), and small cap biotech Todos Medical (OTCQB:TOMDF).

Pfizer

Last month Albert Bourla, the CEO of Pfizer, said in a CNBC interview that their drug PF-07321332 may represent a cure.

That could be a game changer. The compound that we are talking about and you said very well the numbers, it is a protease inhibitor. The good thing is that this is also the first molecule that is coming from this type of class, this is an advantage because you can combine it with other classes.

Pfizer recently launched its Phase 1 clinical trial of PF-07321332, an oral 3CL protease inhibitor. This phase 1 study is a multi-dose study in hospitalized clinical trial participants with COVID-19. In vitro results showed potent antiviral activity against SARS-CoV-2 and other coronaviruses.



A testament to the effectiveness of new manufacturing techniques, is that this compound was first synthesized in late July 2020. The biological data was so encouraging that they had up to 210 people working on the project at one time. Unfortunately, not much has been released about the potential side effects yet. They were supposed to release the safety data at the Spring American Chemical Society meeting last month, but failed to elaborate.

Generally protease inhibitors are not associated with too much toxicity and are expected to be a well-tolerated treatment against COVID-19. They did, however, provide details of the mechanism of action (MOA). The drug is a protease inhibitor that targets the main protease, called 3CLpro, once inside the virally infected cell. Binding to the viral enzyme (called a protease), prevents the virus from replicating in the cell.

Proteases are essential building blocks of SARS-CoV-2 because they take large polyproteins translated from viral mRNA and cut them into different pieces which then assemble into an RNA replicase-transcriptase complex (RTC). This is used to build the whole virus RNA and also the protein subunit RNA through discontinuous transcription. If the proteins stay covalently bound together, they cant assemble to help transcribe the new virus RNA, as well as the RNA to make the protein subunits properly (like the spike protein). Protease inhibitors have been effective at treating other viral pathogens such as HIV and hepatitis C virus, both alone and in combination with other antivirals.



Tackling SARS-CoV-2: proposed targets and repurposed drugs

In the graphic above, one can see the various steps the coronavirus takes to replicate. The light blue RTC is what is formed after the 3CLpro cleaves the larger protein into smaller pieces, and that RTC replicates negative RNA that is both the full length and in pieces. Those eventually get turned into the viral mRNA to get put into the new virus, while the smaller pieces are translated to make various proteins for the new virus like the spike protein and membrane protein. When the 3CLpro is blocked, the mRNA, structural proteins, and non-structural proteins for the new virus cannot be made.



Pfizer also has an intravenous protease inhibitor called PF-07304814 which is currently in a Phase 1b trial of hospitalized COVID-19 patients. Their strategy of an oral pill and intravenous drug for hospitalized patients, represents an end to end solution for future COVID-19 patients, similarly to what Todos Medical is doing.

Todos Medical

Todos Medical also has a 3CLpro inhibitor, both as a drug and as a commercially available supplement. The company might not have the balance sheet and marketing resources of Pfizer, but they are in an envious position. Tollovir, the drug, is essentially pharmaceutical grade Tollovid, the product that is currently available for sale as a supplement. Whether or not people connect the dots and realize that Tollovid is generic and a version of Tollovir, remains to be seen.

In fact, the company recently was granted a Certificate of Free Sale by the U.S. FDA for a higher-dose, 5-day course of Tollovid, which mirrors the dosing regimen of Pfizers oral 3CLpro inhibitor. Sometimes one can simulate the pharmaceutical grade drug by taking more of the generic. The technology of Todos appears to be very similar to the drug Pfizer developed last year. Both are 3CL protease inhibitors and according to available data, both appear to work.

Tollovir works in essentially the same way as PF-07321332 by inhibiting the protease from cleaving the polypeptide which is the first long protein translated by the cell after infection. It appears the mechanism of action between both drugs is identical. The only differences appear to be the clinical trial design and the fact that Todos supplement is sitting on store shelves while Pfizer's drug is still in clinical development.

Roche

Roche and its partner Atea Pharmaceuticals (AVIR) are also limiting participation in their recently launched late-stage trial of their AT-527 drug to COVID-19 patients experiencing symptoms for less than five days. Atea said final trial results are expected before the end of this year. AT-527 can be thought of as a way better version of remdesivir, as it acts by blocking viral RNA polymerase (albeit on a different site).

Also referred to as RNA-dependent RNA polymerase (RdRp), viral RNA polymerase synthesizes a complementary RNA from a template of RNA and is therefore essential in copying the viral RNA. In preclinical studies, Atea showed that free base of AT-527 had about 7 times lower triphosphate active metabolite concentration in primary human epithelial cells (the type of cells that get infected by COVID-19), as compared to a normalized dose of remdesivir, and according to Atea, the drugs metabolite was 8-fold more inhibitory against SARS-CoV-2 than molnupiravir.

What this means is that, if AT-527 continues to be well tolerated, it will likely be a much more efficacious drug than remdesivir, and one that basically does the same thing biologically. Couple that with the fact that it is an oral drug and remdesivir could be eclipsed. Chugai Pharmaceutical Co. (OTCPK:CHGCY), a controlled subsidiary of Roche, also in-licensed AT-527 from Roche for the Japan market. The companies recently commenced dosing in a phase 3 in non-hospitalized mild-to-moderate COVID-19 patients.

The Genesis of Molnupiravir

Merck believes that molnupiravir could be the next Tamiflu, a drug that lessens the side effects of the flu when taken early. With a rising number of variants in the world the overall efficacy of the vaccine will eventually diminish, lowering the protection level of the vaccinated. The antivirals are essentially a necessary stop gap measure to treat people until booster shots are available.

Molnupiravir is a result of a collaboration between Merck and Ridgeback Biotherapeutics whereby Merck got the worldwide rights to develop EIDD-2801 in exchange for an undisclosed upfront payment and specified milestones, as well as a share of the net proceeds upon approval. In this collaboration, MRK is responsible for the clinical trial development.

Molnupiravir is a small molecule drug taken as an oral antiviral that has broad spectrum activity against RNA viruses such as SARS-CoV-2. The drug acts as a ribonucleoside analog for an enzyme called RNA-dependent RNA-polymerase, which SARS-CoV-2 uses to replicate. In essence, molnupiravir inserts itself into the RNA of the virus, which increases the viral mutation rate to the point that the virus can no longer replicate and dies -- a process called viral error catastrophe.

The idea behind using molnupiravir in COVID-19 traces its origins to 2003, when Emory University was studying a similar compound in an intravenous formulation that was active against a range of RNA viruses like Hepatitis C, seasonal flu, Severe Acute Respiratory Syndrome (SARS), and Middle East Respiratory Syndrome (MERS). Shortly after the discovery it was set aside because the early version wasnt absorbed well orally.

It wasnt dusted off until the Venezuelan equine encephalitis virus hit in 2013. They changed the chemical structure and turned it into a pro-drug (an inactive drug that is converted into an active drug upon absorption, typically designed to improve the pharmacokinetic profile of the drug so that it stays in the body longer). This oral form of the drug sat on the shelves until the latest pandemic.

Once tested last year, researchers realized it was effective against many viral strains, making it ideal for this pandemic. The drug is able to cross the blood-brain barrier, which makes it essential for viruses that tend to infect the central nervous system. Since it's a small molecule it gets absorbed in the bloodstream quickly, and can make its way to the lungs fast so that it can treat respiratory infections. The quick uptake makes it an ideal drug for early infections.

Fox contributor Mark Siegel heralded the drug as the Holy Grail of the pandemic. This interview opened up people's eyes to the possibility of an oral antiviral. Some of his claims were a little over the top but he did temper his comments by saying they showed promising signs of effectiveness in reducing the virus in patients. He liked the idea of a pill that was taken on the first day of infection because by doing so it limited the severity of the disease.

One critic of the drug is former Head of US Biomedical Advanced Research Development Authority, Rick Bright, who had concerns that the drug could be mutagenic (cancer causing), and similarly, the drugs in this class seem to cause reproductive toxicity in animals.

Trial Results

Merck first approached COVID-19 treatment with its antiviral by testing in hospitalized patients, but that trial was stopped as they figured out that hospitalized patients primarily have inflammation and the virus is not as relevant at that point. So, Merck proceeded with mild-to-moderate patients, where patients are enrolled within a week or their symptom onset. The weakness with this study was that the treatments were not taken immediately upon a positive PCR test.

So the conundrum is - how do you give the drug to people upon diagnosis when the tests are not conducted in the same manner? Proving efficacy in this early stage of disease is no easy feat because people sometimes get better without the drug. Demonstrating clinical benefit early in the disease is nearly impossible which is why they waited up to 7 days to get the harder to treat people that still had elevated viral loads, but with patients that were still having difficulty clearing the virus.

In the phase 2 trial, Merck and Ridgeback demonstrated 0% of patients who took molnupiravir had positive viral culture at day 5, while 24% of placebo still had a positive viral culture. There were no safety signals with the drug and only 4 serious adverse events reported in the 202 patient trial. They even did animal studies at higher doses and of longer duration that indicated molnupiravir was not mutagenic or genotoxic. The safety data demonstrated that there were no drug-related adverse events that led participants to discontinue treatment and there were no drug-related deaths.

Phase 3 Trial

Merck is planning a large outpatient trial of molnupiravir for patients with at least one risk factor for poor outcomes. This means that patients with advanced age, obesity, or diabetes could qualify for the trial. They are only allowing people in the trial that were symptomatic for less than 5 days. In their phase 2 trial they recruited patients that were symptomatic for less than 7 days. This tightening of the clinical trial criteria limits the amount of cherry picking of patients in the study. The dosing regimen is 800mg of molnupiravir twice a day for 5 days.

Investment Summary

Merck has had many failures over the past year in COVID-19. They really need a win outside the realm of oncology. Unfortunately their track record of picking winners in this COVID-19 space has been abysmal. Their collaboration with Ridgeback appeared to be out of desperation and typically these situations dont tend to work out. A huge positive for MRK was the great press they got from Fox contributor Marc Siegel, however, caution is warranted because after comparing the oral antivirals, it should be clear that Merck doesn't have the best technology.

This race comes down to time to market. Its unlikely that investors will accept that Todos won the race because they currently have an antiviral on the shelves in the form of a nutraceutical. For a big pharma like Merck this is just not a credible threat. Investors can sit back and wait to see if Todos gets any distribution deal or generates any meaningful sales. This means that Pfizer is the one to watch and they are on a winning streak and have produced the largest number of doses of the vaccine to date.

Pfizer might have better technology, but their trial design is weak compared to Merck. Pfizer has indicated they will have results before the end of the year, but Merck has indicated top line results will be coming in September or October with a planned interim analysis. They also foreshadowed that they plan to present data from hospitalized and non-hospitalized patients at an upcoming conference, which could be a catalyst depending on the data.

Merck plans on winning and expects to have at least 10 million doses of therapy produced later this year. If Merck executes flawlessly and the variants come back in the fall then there is a good chance Merck is going to split the coronavirus pie with Pfizer. On the other hand, Todos could play the spoiler in this race, but that's a tall order that requires them to complete a clinical trial and get a distribution agreement before MRK announces their topline data. May the best horse win for all our sakes.

This article was written by

Theodore Zucconi profile picture.
Theodore Zucconi
510 Followers
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Ph.D. in chemistry, Masters certificates in International Finance and Program/Project Management. Over 38 y... more
Special Situations, Biotech, Senior Management Consultant.

Contributor Since 2017

Ph.D. in chemistry, Masters certificates in International Finance and Program/Project Management. Over 38 years experience in high tech and biotech.
Disclosure: I am/we are long CYDY. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.

Additional disclosure: CYDY is a long term hold


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