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Posted On: 11/13/2021 6:38:24 AM
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Great read on Cytodyn
https://seekingalpha.com/article/4469170-merc...-dominance
Merck's Plan B Percolates After Pfizer Announces Dominance
Nov. 13, 2021 3:14 AM ETMerck & Co., Inc. (MRK)ADMP, AMPE, BMY,CYDY,JNJ,PFE,RDHL,TOMDF1 Comment2 Likes
Summary
Rivalry with Pfizer starting to take shape.
First market mover advantage is a stop-gap measure.
Ideal partnership combination with Todos Medical.
Pencil - direction indicator - choice of plan a or plan b. Business strategy, failure analysis and not give up
Andrii Zastrozhnov/iStock via Getty Images
Merck (NYSE:MRK) is used to being a leader and getting its way. Many may have forgotten, but before COVID-19, MRK was considered the global vaccine titan. At the start of the pandemic, it would have been unfathomable to think that they would ultimately be knocked out of the race in such a dramatic fashion. Their initial hesitation to pursue the vaccine, which was based on the thinking that COVID-19 wouldn't turn into a pandemic, got them into trouble. Their fallback plan was to utilize their manufacturing expertise to find the right partner to play catch up. Neither of these plans panned out. The history books will show that Merck got to be a subcontract manufacturer for Johnson & Johnson's (JNJ) vaccine, but not much else. The titan may have fallen from grace, but investors that rule out a comeback could be missing out on an enormous opportunity.
Merck Vs. Pfizer Rivalry Begins
This image of just being a subcontract manufacturer has got to be gnawing at management and pushing them to do something big. After all, MRK developed one of the largest oncology drugs on the planet called Keytruda. The origins of Keytruda evolved out of a slugfest with Merck's immuno-oncology rival Bristol Myers Squibb (BMY) in 2014. The fact that Pfizer's announcement came a day after MRK's molnupiravir received approval in the United Kingdom shouldn't feel random to many investors. It was almost reminiscent of the news flow during the BMY slugfest for dominance in oncology. MRK pulled no punches during that war, and it's safe to say the MRK won't be accepting Pfizer's (PFE) dominance lying down either. It's game time, and a new rivalry has evolved.
First Market Mover Advantage
With the UK regulator, MHRA, granting approval of molnupiravir, MRK has its foot in the door and a first market mover advantage worldwide. With PFE dominating the COVID-19 headlines, MRK clearly needed a win in the COVID-19 space and finally got one with UK approval. The news was initially met with much fanfare, but it was fleeting because it only lasted for one day before PFE announced a trial stoppage for the efficacy of their drug PAXLOVID. Positive news for MRK broke over the weekend. In the Philippines, Merck was granted compassionate use approval for molnupiravir by the Philippines FDA. Then on November 8th, 2021 reports surfaced from an EU official that "talks with Merck were more advanced because it has already begun submitting data to the European Union's drug regulator." This is more anecdotal evidence that MRK isn't giving up and using anything that they have to their advantage but this is triage, not a plan.
Plan to Get Back in the Race
It's pretty clear that Merck hasn't given up and is going to get back in the race. They certainly aren't going to sit this one out and they have no time to develop anything internally, so the question is how and by what means. There is an opportunity so ripe for the picking it's hard to not see Merck go after PFE's rival Todos Medical (OTCQB:TOMDF). Both PFE and TOMDF have the same druggable target. They both are 3CL inhibitors Tollovir and PAXLOVID. The differences between the molecules are that PFE's drug is man-made whereas Tollovir is all-natural and derived from a special strain of gromwell root that has been screened with a proprietary assay to ensure the appropriate concentrations of the ingredient. The company also has a similarly named nutraceutical product that has its certificate of free sale from the FDA. Curiously they call it a 3CL protease inhibitor and an immune supplement. It seems like they needed to get cute with verbiage by not connecting the dots that Tollovir, their drug in clinical trials, is a concentrated version of the active ingredient in Tollovid. Consumers wouldn't have to wait for FDA approval of Pfizer's drug because a dietary supplement that targets the same 3CL protease is sitting on the shelf waiting to be purchased. It's clear that this could be very disruptive to PFE and its rollout because it's available for purchase now. This is clearly something MRK would like to control.
My Tollovid
Clock Running Out for Merck
This article does contain a lot of speculation, but the one unassailable fact is that time is running out. MRK needs to act sooner versus later. This means that they might have to engage multiple targets at once. They might also have to conduct quick due diligence in a vacuum and go with what is on the surface. It should be obvious that the ideal partner for MRK would be a company with an oral drug candidate that has better efficacy and better safety than Pfizer's drug. The drug would have to be far enough along in the approval process so that they could catch Pfizer. Only one drug candidate is left that can make this unbelievable leap forward - Tollovir. The price tag on TOMDF could go up exponentially in the coming weeks if they stop the trial early and push for a readout of their 30+ patients. It's widely expected that if they had similar trial results to their exploratory trial, then there is a huge possibility of a mortality benefit in the hospitalized setting which is something Pfizer hasn't even proven yet.
Other Contenders
In late stage disease if big pharma wants a win in a smaller COVID-19 market, then CytoDyn Inc. (OTCQB:CYDY) is a leading candidate. Their subcutaneously administered monoclonal antibody is called leronlimab and it definitely calms the cytokine storm. In their CD12 clinical trial which dosed patients in critical condition, they announced an 82% reduction in 14 day mortality in a large randomized controlled trial. They missed the top line by not having the correct endpoint and have since then started trials in Brazil to get the supplemental data the FDA needs expected in Q1 2022. From big pharma's perspective, there is very little risk of failure since they achieved a very robust degree of statistical significance in multiple endpoints including time of hospitalization. There is also evidence in their CD10 trial (mild-to-moderate patients) that leronlimab can be used earlier in disease. So from the perspective of big pharma they would only pay on the severe indication but would have an option to expand to earlier disease. This drug works by stopping the trafficking of the inflammatory macrophages and other immune cells to the site of inflammation thereby quieting the cytokine storm.
There was a recent shift in leadership at Ampio Pharmaceuticals (AMPE) to board members with big pharma connections. This lends credibility to a potential JV with big pharma. Ampion is another drug with promise in COVID-19. It too works by quieting the cytokine storm. It's essentially a repurposed osteoarthritis of the knee (OAK) drug that works on multiple cytokines besides just IL-6. It can be taken intravenously, inhaled, or through an injection and they haven't run into any dose limiting toxicities. In a phase 1 study of critically ill patients, Ampion showed a 78% reduction in mortality over the standard of care (SOC). It's currently enrolling 200 COVID-19 ARDS patients in a phase 2 study (CD-19) of inhaled Ampion with a readout expected of interim results by Q2 2022. The company also has a phase 1 study of inhaled Ampion for at home use in 30 Long Covid patients.
RedHill Biopharma (RDHL) had a readout in early October in moderately severe COVID-19 patients that showed a 62% reduction in mortality. They also did well on other endpoints like reaching room air in 14 days which translates in saving days of hospitalization. Their medium discharge from the hospital was 10 days versus 14 days in placebo. Their oral drug is called Opaganib which is a small molecule that is thought to work in both the viral and inflammatory stage of the disease. The mechanism behind their drug lies in its properties as an SK2 inhibitor. The cytokine storm in essence is inflammation that goes unchecked. SK2 inhibitors have shown in various disease indications that they can suppress inflammation. The drug also has some antiviral properties that are supposed to reduce the formation of filopodia which are the tendral-like arms that allow the virus to spread to neighboring cells. Their drug may also interfere with the formation of the viral proteins by inhibiting the proper folding of the proteins.
Adamis Pharmaceutical Corporation (ADMP) is developing an antiviral drug called Tempol which is an oral capsule pill with anti-inflammatory properties. The concept behind Tempol is that it has an effect on multiple pathways that reduces the amount of inflammatory cytokines and leads to a quieting of the cytokine storm. It also has a pronounced effect on reactive oxygen species (ROS) which helps perpetuate the inflammatory environment. The antiviral part of the drug was discovered by a team of NIH researchers that demonstrated it inhibited RNA replicase in animal studies. RNA replicase is the small viral factory (image below) that is assembled immediately after infection to make more viral copies. The method that the drug uses to interfere with the process of replication is to target non structural protein 12 (nsp12) which is part of the virus factory's transcription machine. Nsp12 (depicted below in red) needs iron sulfide clusters to support the protein and Tempol degrades the iron sulfide cluster which in turn destroys the key part of the factory.
PLOS Pathogens
Investment Summary
By no means is MRK out of options. All PFE did was to quote an old WWII movie Tora! Tora! Toral!, "awaken a sleeping giant and fill him with a terrible resolve." MRK is salvaging what it can out of molnupiravir by trying to take advantage of its first to market position. MRK has quite a few options-whether they choose CYDY to strategically position themselves in the subcutaneous market for a COVID drug for hospitalization and get the bonus of a combination drug to dominate the metastatic cancer market-or whether they look at AMPE's platform technology that has similarly good efficacy but gets them another drug that could compete in the osteoarthritis market and potentially synergize with one of their other OAK pipeline candidates. RDHL and ADMP are definite wild cards that show solid efficacy, but really don't have that much substance as a platform tech outside of COVID-19.
However, the ideal fit for MRK is TOMDF's Tollovir due to its likely superiority to PFE's PAXLOVID anticipated in a readout before the end of the year. In TOMDF's exploratory study, they had a strong mortality benefit. It should translate in their upcoming results and they might actually overshadow PFE because this inhibitor not only inhibits the virus but also acts as an immune modulator. They also found another mechanism that prevents the deactivation of the immune system. What is so stunning is that in clinical trials of Tollovir no deaths have been reported yet, but investors should be cautious because there have only been a very small number of patients dosed. The upcoming interim results for TOMDF should really get investors and possibly MRK frenzied ahead of the readout because they are one of a handful of drugs that have demonstrated efficacy and the only one with a perfect mortality benefit left. Whether MRK decides to pursue a partnership or an acquisition, it's clear that there are too many options on the table to not do something, especially when the most qualified candidate has a market cap well under $50 million and is on the verge of a Phase 3. Regardless of who MRK picks, these candidates are the cream of the COVID-19 therapeutics crop and should usher in another rise in the price of MRK on the announcement, which might be sooner versus later. In my mind they have already taken too long to add to their selection.
https://seekingalpha.com/article/4469170-merc...-dominance
Merck's Plan B Percolates After Pfizer Announces Dominance
Nov. 13, 2021 3:14 AM ETMerck & Co., Inc. (MRK)ADMP, AMPE, BMY,CYDY,JNJ,PFE,RDHL,TOMDF1 Comment2 Likes
Summary
Rivalry with Pfizer starting to take shape.
First market mover advantage is a stop-gap measure.
Ideal partnership combination with Todos Medical.
Pencil - direction indicator - choice of plan a or plan b. Business strategy, failure analysis and not give up
Andrii Zastrozhnov/iStock via Getty Images
Merck (NYSE:MRK) is used to being a leader and getting its way. Many may have forgotten, but before COVID-19, MRK was considered the global vaccine titan. At the start of the pandemic, it would have been unfathomable to think that they would ultimately be knocked out of the race in such a dramatic fashion. Their initial hesitation to pursue the vaccine, which was based on the thinking that COVID-19 wouldn't turn into a pandemic, got them into trouble. Their fallback plan was to utilize their manufacturing expertise to find the right partner to play catch up. Neither of these plans panned out. The history books will show that Merck got to be a subcontract manufacturer for Johnson & Johnson's (JNJ) vaccine, but not much else. The titan may have fallen from grace, but investors that rule out a comeback could be missing out on an enormous opportunity.
Merck Vs. Pfizer Rivalry Begins
This image of just being a subcontract manufacturer has got to be gnawing at management and pushing them to do something big. After all, MRK developed one of the largest oncology drugs on the planet called Keytruda. The origins of Keytruda evolved out of a slugfest with Merck's immuno-oncology rival Bristol Myers Squibb (BMY) in 2014. The fact that Pfizer's announcement came a day after MRK's molnupiravir received approval in the United Kingdom shouldn't feel random to many investors. It was almost reminiscent of the news flow during the BMY slugfest for dominance in oncology. MRK pulled no punches during that war, and it's safe to say the MRK won't be accepting Pfizer's (PFE) dominance lying down either. It's game time, and a new rivalry has evolved.
First Market Mover Advantage
With the UK regulator, MHRA, granting approval of molnupiravir, MRK has its foot in the door and a first market mover advantage worldwide. With PFE dominating the COVID-19 headlines, MRK clearly needed a win in the COVID-19 space and finally got one with UK approval. The news was initially met with much fanfare, but it was fleeting because it only lasted for one day before PFE announced a trial stoppage for the efficacy of their drug PAXLOVID. Positive news for MRK broke over the weekend. In the Philippines, Merck was granted compassionate use approval for molnupiravir by the Philippines FDA. Then on November 8th, 2021 reports surfaced from an EU official that "talks with Merck were more advanced because it has already begun submitting data to the European Union's drug regulator." This is more anecdotal evidence that MRK isn't giving up and using anything that they have to their advantage but this is triage, not a plan.
Plan to Get Back in the Race
It's pretty clear that Merck hasn't given up and is going to get back in the race. They certainly aren't going to sit this one out and they have no time to develop anything internally, so the question is how and by what means. There is an opportunity so ripe for the picking it's hard to not see Merck go after PFE's rival Todos Medical (OTCQB:TOMDF). Both PFE and TOMDF have the same druggable target. They both are 3CL inhibitors Tollovir and PAXLOVID. The differences between the molecules are that PFE's drug is man-made whereas Tollovir is all-natural and derived from a special strain of gromwell root that has been screened with a proprietary assay to ensure the appropriate concentrations of the ingredient. The company also has a similarly named nutraceutical product that has its certificate of free sale from the FDA. Curiously they call it a 3CL protease inhibitor and an immune supplement. It seems like they needed to get cute with verbiage by not connecting the dots that Tollovir, their drug in clinical trials, is a concentrated version of the active ingredient in Tollovid. Consumers wouldn't have to wait for FDA approval of Pfizer's drug because a dietary supplement that targets the same 3CL protease is sitting on the shelf waiting to be purchased. It's clear that this could be very disruptive to PFE and its rollout because it's available for purchase now. This is clearly something MRK would like to control.
My Tollovid
Clock Running Out for Merck
This article does contain a lot of speculation, but the one unassailable fact is that time is running out. MRK needs to act sooner versus later. This means that they might have to engage multiple targets at once. They might also have to conduct quick due diligence in a vacuum and go with what is on the surface. It should be obvious that the ideal partner for MRK would be a company with an oral drug candidate that has better efficacy and better safety than Pfizer's drug. The drug would have to be far enough along in the approval process so that they could catch Pfizer. Only one drug candidate is left that can make this unbelievable leap forward - Tollovir. The price tag on TOMDF could go up exponentially in the coming weeks if they stop the trial early and push for a readout of their 30+ patients. It's widely expected that if they had similar trial results to their exploratory trial, then there is a huge possibility of a mortality benefit in the hospitalized setting which is something Pfizer hasn't even proven yet.
Other Contenders
In late stage disease if big pharma wants a win in a smaller COVID-19 market, then CytoDyn Inc. (OTCQB:CYDY) is a leading candidate. Their subcutaneously administered monoclonal antibody is called leronlimab and it definitely calms the cytokine storm. In their CD12 clinical trial which dosed patients in critical condition, they announced an 82% reduction in 14 day mortality in a large randomized controlled trial. They missed the top line by not having the correct endpoint and have since then started trials in Brazil to get the supplemental data the FDA needs expected in Q1 2022. From big pharma's perspective, there is very little risk of failure since they achieved a very robust degree of statistical significance in multiple endpoints including time of hospitalization. There is also evidence in their CD10 trial (mild-to-moderate patients) that leronlimab can be used earlier in disease. So from the perspective of big pharma they would only pay on the severe indication but would have an option to expand to earlier disease. This drug works by stopping the trafficking of the inflammatory macrophages and other immune cells to the site of inflammation thereby quieting the cytokine storm.
There was a recent shift in leadership at Ampio Pharmaceuticals (AMPE) to board members with big pharma connections. This lends credibility to a potential JV with big pharma. Ampion is another drug with promise in COVID-19. It too works by quieting the cytokine storm. It's essentially a repurposed osteoarthritis of the knee (OAK) drug that works on multiple cytokines besides just IL-6. It can be taken intravenously, inhaled, or through an injection and they haven't run into any dose limiting toxicities. In a phase 1 study of critically ill patients, Ampion showed a 78% reduction in mortality over the standard of care (SOC). It's currently enrolling 200 COVID-19 ARDS patients in a phase 2 study (CD-19) of inhaled Ampion with a readout expected of interim results by Q2 2022. The company also has a phase 1 study of inhaled Ampion for at home use in 30 Long Covid patients.
RedHill Biopharma (RDHL) had a readout in early October in moderately severe COVID-19 patients that showed a 62% reduction in mortality. They also did well on other endpoints like reaching room air in 14 days which translates in saving days of hospitalization. Their medium discharge from the hospital was 10 days versus 14 days in placebo. Their oral drug is called Opaganib which is a small molecule that is thought to work in both the viral and inflammatory stage of the disease. The mechanism behind their drug lies in its properties as an SK2 inhibitor. The cytokine storm in essence is inflammation that goes unchecked. SK2 inhibitors have shown in various disease indications that they can suppress inflammation. The drug also has some antiviral properties that are supposed to reduce the formation of filopodia which are the tendral-like arms that allow the virus to spread to neighboring cells. Their drug may also interfere with the formation of the viral proteins by inhibiting the proper folding of the proteins.
Adamis Pharmaceutical Corporation (ADMP) is developing an antiviral drug called Tempol which is an oral capsule pill with anti-inflammatory properties. The concept behind Tempol is that it has an effect on multiple pathways that reduces the amount of inflammatory cytokines and leads to a quieting of the cytokine storm. It also has a pronounced effect on reactive oxygen species (ROS) which helps perpetuate the inflammatory environment. The antiviral part of the drug was discovered by a team of NIH researchers that demonstrated it inhibited RNA replicase in animal studies. RNA replicase is the small viral factory (image below) that is assembled immediately after infection to make more viral copies. The method that the drug uses to interfere with the process of replication is to target non structural protein 12 (nsp12) which is part of the virus factory's transcription machine. Nsp12 (depicted below in red) needs iron sulfide clusters to support the protein and Tempol degrades the iron sulfide cluster which in turn destroys the key part of the factory.
PLOS Pathogens
Investment Summary
By no means is MRK out of options. All PFE did was to quote an old WWII movie Tora! Tora! Toral!, "awaken a sleeping giant and fill him with a terrible resolve." MRK is salvaging what it can out of molnupiravir by trying to take advantage of its first to market position. MRK has quite a few options-whether they choose CYDY to strategically position themselves in the subcutaneous market for a COVID drug for hospitalization and get the bonus of a combination drug to dominate the metastatic cancer market-or whether they look at AMPE's platform technology that has similarly good efficacy but gets them another drug that could compete in the osteoarthritis market and potentially synergize with one of their other OAK pipeline candidates. RDHL and ADMP are definite wild cards that show solid efficacy, but really don't have that much substance as a platform tech outside of COVID-19.
However, the ideal fit for MRK is TOMDF's Tollovir due to its likely superiority to PFE's PAXLOVID anticipated in a readout before the end of the year. In TOMDF's exploratory study, they had a strong mortality benefit. It should translate in their upcoming results and they might actually overshadow PFE because this inhibitor not only inhibits the virus but also acts as an immune modulator. They also found another mechanism that prevents the deactivation of the immune system. What is so stunning is that in clinical trials of Tollovir no deaths have been reported yet, but investors should be cautious because there have only been a very small number of patients dosed. The upcoming interim results for TOMDF should really get investors and possibly MRK frenzied ahead of the readout because they are one of a handful of drugs that have demonstrated efficacy and the only one with a perfect mortality benefit left. Whether MRK decides to pursue a partnership or an acquisition, it's clear that there are too many options on the table to not do something, especially when the most qualified candidate has a market cap well under $50 million and is on the verge of a Phase 3. Regardless of who MRK picks, these candidates are the cream of the COVID-19 therapeutics crop and should usher in another rise in the price of MRK on the announcement, which might be sooner versus later. In my mind they have already taken too long to add to their selection.
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