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Posted On: 06/30/2024 3:31:37 PM
Post# of 148870
From our friends at Reddit
Vast Indication On The Horizon
Greetings to you Folks. You didn't think I was done for the week, did you? Let's get right into it.
Why is this post on MASH? Because CytoDyn is in the midst of a murine study that is testing leronlimab with and without resmetirom, the currently approved medication for MASH. Results of this study are due in the fall, End of September 2024.
To give you an understanding of the magnitude of the MASH market, I wrote the following:
"We know that of the 333 million individuals in the US population and/or 8 Billion world wide at least, (a very conservative estimate): 1/25 have NASH and 1/100 have Stage 4 Hepatic Fibrosis. Extrapolating:
For USA, at least 10,000,000 have NASH and at least 3 Million have Stage 4 Hepatic Fibrosis.
For World, at least 300,000,000 have NASH and at least 80,000,000 have Stage 4 Hepatic Fibrosis.
These are VERY conservative numbers."
...
*"*Very conservatively we know:
For USA, at least 10,000,000 have NASH and at least 3 Million have Stage 4 Hepatic Fibrosis.
...
Of these, let's say very conservatively, that only 1 million are found to be Fibrosis Stage 2 or greater and are subsequently treated with 350mg Leronlimab weekly for only 8 weeks, just about 1/2 our trial.
8 weeks * 1,000,000 patients * $1,000 per vial = $8 billion over 8 weeks for treating merely a very tiny proportion of the patient population out there and only treating them for 1/2 of 1 course."
If leronlimab were in fact combined with resmetirom due to a successful trial, then the treatment would be extended over the course of the year in which resmetirom was approved for treatment and would be 6.5 x longer than the 8 weeks mentioned above. That would translate into 6.5 x $8 billion = $52 billion annual revenue @$1k per 350mg vial x 1 million patients per annum.
The very good news of this murine study is that if CytoDyn has the resources to extend this murine study from a 12-week study to at least a 20-week study, we understand through the CRO SMC, that the STAM mouse model used definitively results in HepatoCellularCarcinoma by 20 weeks. This is discussed by the CRO. This means that if SMC is paid to run the Press Released murine study for another 8 weeks, that is up to 20 weeks, extending into Thanksgiving 2024, then CytoDyn would learn whether the addition of leronlimab reduces or even eliminates the possibility of developing HCC. This would be a very important piece of information to acquire, and I would encourage CytoDyn to pay for it if at all possible.
"The benefits of eradicating this from one's life, improves liver health, reduces potential diabetes complications leading to less potential for cardiovascular disease. In addition, it leads to reduced possibility for liver disease, for hepatitis, for cirrhosis and for hepatocellular carcinoma and therefore for metastasis."
...
"About 25% of population has either NAFLD or NASH, (Think Type II Diabetes, Fat, hepatocyte ballooning, inflammation with or without fibrosis). 25% of that are NASH cases, (1/8 population), NASH leads to Cirrhosis, (Stage 4 hepatic fibrosis with or without fat and inflammation). Cirrhosis leads to liver failure. Liver failure leads to HepatoCellular Carcinoma, (Fat, Ballooning, Inflammation, Scarring and mutation)."
Essentially, resmetirom works by partially agonizing the Thyroid Hormone Beta Receptors intra-hepatically. Resmetirom pretends it is T3 and when it attaches to these Thyroid Hormone -Beta Receptors, then the intra-hepatic triglycerides are reduced, and fat is eradicated thereby reducing liver steatosis. These THR-Beta receptors exist mainly within the liver, and they are for the most part, not systemic. Resmetirom does not work systemically, but rather only locally, within the liver. Therefore, one of its main side effects is hepatotoxicity and so, liver function tests must be monitored when this drug is prescribed so the physician may know that he/she is not harming the liver with the prescription.
Given that resmetirom is not the actual hormone T3, but only a "look-alike" and given that it does not even contain the element Iodine, it is not nearly as effectual or as powerful as T3 and so huge quantities are necessary (in comparison to actual human hormone) in order to accomplish even just the scant effects of reducing liver steatosis. Daily dosing of 80 or 100mg is necessary to reduce liver steatosis while a patient who is hypothyroid might needs to take 80 or 100mcg micrograms of levothyroxine T4, (1,000 times less), to supplement their weakened thyroid gland and augment or completely replenish their daily required dose of T4 that is intended for the whole body, not just the liver. Synthroid or levothyroxine really is synthetic T4, but T3 is found in Armor Thyroid which is not synthetic but is derived from bovine sources and does contain T3, but nobody takes this to increase the rate of fat or steatosis metabolism in their livers.
Now, I was looking through CytoDyn's NASH Human trial and specifically at the heat map in the poster, and at the bottom of the heat map, the Thyroid Panel. Thyrotropin (TSH or Thyroid Stimulating Hormone), Thyroxine Free (Free T4) and Triiodothyronine (T3) is shown. I immediately recognized that in the arm that was most effective, the leronlimab 350mg treated arm, both T3 and T4 were both markedly elevated. This tells me that somehow, when dosed appropriately, leronlimab has a way of increasing the measured serum levels of T3 and T4. This elevation in T3 and T4 in blood serum is quite similar to the mechanism of action of resmetirom which increases "synthetic T3" specifically in the liver, one day at a time, if and only if the daily dose is taken orally.
Now, it is important to understand, that in general, reduced inflammation leads to increased Thyroid Hormone. Thank you both ohm20 & biloxiblues!! Wonderful work. It is very important to understand that linked document so read it twice. Certainly, it is known that during inflammatory conditions, thyroid hormone is reduced. Especially, of course, when the thyroid itself is inflamed as in Hashimoto's Thyroiditis. So, the reverse also is true, that when systemic inflammation subsides, be it Chronic or Acute, Thyroid Hormone subsequently increases.
Typically, T3 and T4 are usually controlled and regulated by TSH levels, but remember, an elevated inflammatory state could reduce these levels, but, TSH would tend to rise until the required quantity of T3 and T4 are measured in the blood serum. Thyroid Stimulating Hormone is there to stimulate the thyroid to produce more T3 and T4. But another way to increase blood serum levels of T3 and T4 is if the body does not consume those hormones, while leaving the formation of those hormone the same. Since T3 and T4 are used to metabolize fat within the body and within the liver, when that is happening, there would be less T3 and less T4 in the blood, because, that T3 and T4 would be located in the fat tissue, metabolizing it, so a lesser quantity would be found in the blood serum. So, as the work of reducing fat steatosis progresses along, over time, there would be less and less fat to metabolize, including the fat in the liver. In addition, as a result of less fat, there also would be less inflammation. As we understand from above, less inflammation leads to increased T3 and increased T4. At the end of the MASH treatment, there would be far less fat available to metabolize, so therefore, the T3 and T4 hormone would then accumulate higher in the blood serum until that is normalized by the body homeostasis controller with a reduced TSH signal. That is possibly what is happening in the leronlimab 350mg treated arm with the elevated levels of T3 and T4.
As we know, leronlimab lowers chronic inflammation and acute inflammation. By lowering chronic and acute inflammation, leronlimab increases T3 and T4 by facilitating the increase of TSH Thyroid Stimulating Hormone which then leads to the production of sufficiently more T3 and T4 to accommodate the increased metabolism of fat steatosis of the liver. When the levels of fat to metabolize have sufficiently decreased, those previously elevated levels of T3 and T4, via facilitated channels and with reduced cytokine interference, are permitted to be normalized back down to homeostatic levels. Taking a look at Triglyceride levels on the heat map, they were decreased in both 350mg and 700mg Haplotyped Matched which is in line with the reduction of fatty steatosis, exactly what resmetirom aims to do through intrahepatic binding with THR-Beta thereby reducing triglycerides.
This is essentially how resmetirom works, acting in a way, very similar to T3 in order to reduce intra-hepatic fat. Leronlimab does the same, but more indirectly but while employing actual human hormone, of T3 and T4 instead of a foreign THR-Beta agonist. It is clear that through a whole slew of mechanisms, T3 and T4 can be increased, such as through the reduction of inflammation leading to increases in these hormones, as a result of obstacles such as inflammatory cytokines being pulled away from the formation of these hormones in the thyroid gland, or a result of those hormones not being required as much anymore due to all the fat resorption and now having less fat to resorb.
What is important to understand is that leronlimab ALONE led to this increase in Thyroid hormone which means it happens regardless of adding any additional supplemental hormone. The hormone regulation of T3 and T4 happens as a result of taking leronlimab and they increase as well as decrease in their levels as we hope. With the administration of leronlimab, this automatic regulation of thyroid hormone levels happens naturally, and it is therefore not necessary to augment this with any hormone supplementation in the form of levothyroxine, Synthroid, Armour Thyroid or resmetirom. In the mileu of MASH, if nothing is added, T3 and T4 remain reduced and depressed, so MASH persists. Resmetirom essentially is hormone supplementation. Leronlimab naturally increases thyroid hormone levels to where they need to be to reduce liver steatosis by initially lowering inflammation, then that increased T3 and T4 levels subsequently reduce the fat in the liver.
If dosages are left the same, the combination leronlimab 350mg and resmetirom 80 could end up with a doubling of the number of patients that would benefit by the combination product. Right now, resmetirom successfully treats only about 10% of patients that are indicated for the treatment. At a minimum, leronlimab should double that. Madrigal might choose to lower the resmetirom dose instead, thereby reducing the side effect profile of that drug.
If CytoDyn is able to purchase an additional 8 weeks of the murine study and if at the end of 20 weeks, it is determined and understood that the combination of resmetirom with leronlimab leads to a reduced incidence of the development of HCC, this becomes a partnership made in heaven. Remember the vastness, the sheer immensity of this indication. How exceedingly great it is. That is why I mention heaven. In the day of this announcement, that the combination of leronlimab with resmetirom leads to significantly reduced incidence of HCC, I don't have to tell you where the share price goes, despite this study only being a murine model. Shorts are destroyed in an instant on that news.
It is not only this, but like I discussed in Outline of This Platform Molecule, many things are slated to happen this fall including what I left out of that discussion, the NIH along with Long Covid. All of this is consistent with the intelligent making of leronlimab into a Platform Molecule. A Molecule destined not to have any competition at least not for many years, because to overcome this Molecule, another mechanism of action that operates deeper than CCR5 blockade needs to be found and elucidated. CCR5 blockade is how it all unfolds, and that time is coming. Late fall to early winter.
Vast Indication On The Horizon
Greetings to you Folks. You didn't think I was done for the week, did you? Let's get right into it.
Why is this post on MASH? Because CytoDyn is in the midst of a murine study that is testing leronlimab with and without resmetirom, the currently approved medication for MASH. Results of this study are due in the fall, End of September 2024.
To give you an understanding of the magnitude of the MASH market, I wrote the following:
"We know that of the 333 million individuals in the US population and/or 8 Billion world wide at least, (a very conservative estimate): 1/25 have NASH and 1/100 have Stage 4 Hepatic Fibrosis. Extrapolating:
For USA, at least 10,000,000 have NASH and at least 3 Million have Stage 4 Hepatic Fibrosis.
For World, at least 300,000,000 have NASH and at least 80,000,000 have Stage 4 Hepatic Fibrosis.
These are VERY conservative numbers."
...
*"*Very conservatively we know:
For USA, at least 10,000,000 have NASH and at least 3 Million have Stage 4 Hepatic Fibrosis.
...
Of these, let's say very conservatively, that only 1 million are found to be Fibrosis Stage 2 or greater and are subsequently treated with 350mg Leronlimab weekly for only 8 weeks, just about 1/2 our trial.
8 weeks * 1,000,000 patients * $1,000 per vial = $8 billion over 8 weeks for treating merely a very tiny proportion of the patient population out there and only treating them for 1/2 of 1 course."
If leronlimab were in fact combined with resmetirom due to a successful trial, then the treatment would be extended over the course of the year in which resmetirom was approved for treatment and would be 6.5 x longer than the 8 weeks mentioned above. That would translate into 6.5 x $8 billion = $52 billion annual revenue @$1k per 350mg vial x 1 million patients per annum.
The very good news of this murine study is that if CytoDyn has the resources to extend this murine study from a 12-week study to at least a 20-week study, we understand through the CRO SMC, that the STAM mouse model used definitively results in HepatoCellularCarcinoma by 20 weeks. This is discussed by the CRO. This means that if SMC is paid to run the Press Released murine study for another 8 weeks, that is up to 20 weeks, extending into Thanksgiving 2024, then CytoDyn would learn whether the addition of leronlimab reduces or even eliminates the possibility of developing HCC. This would be a very important piece of information to acquire, and I would encourage CytoDyn to pay for it if at all possible.
"The benefits of eradicating this from one's life, improves liver health, reduces potential diabetes complications leading to less potential for cardiovascular disease. In addition, it leads to reduced possibility for liver disease, for hepatitis, for cirrhosis and for hepatocellular carcinoma and therefore for metastasis."
...
"About 25% of population has either NAFLD or NASH, (Think Type II Diabetes, Fat, hepatocyte ballooning, inflammation with or without fibrosis). 25% of that are NASH cases, (1/8 population), NASH leads to Cirrhosis, (Stage 4 hepatic fibrosis with or without fat and inflammation). Cirrhosis leads to liver failure. Liver failure leads to HepatoCellular Carcinoma, (Fat, Ballooning, Inflammation, Scarring and mutation)."
Essentially, resmetirom works by partially agonizing the Thyroid Hormone Beta Receptors intra-hepatically. Resmetirom pretends it is T3 and when it attaches to these Thyroid Hormone -Beta Receptors, then the intra-hepatic triglycerides are reduced, and fat is eradicated thereby reducing liver steatosis. These THR-Beta receptors exist mainly within the liver, and they are for the most part, not systemic. Resmetirom does not work systemically, but rather only locally, within the liver. Therefore, one of its main side effects is hepatotoxicity and so, liver function tests must be monitored when this drug is prescribed so the physician may know that he/she is not harming the liver with the prescription.
Given that resmetirom is not the actual hormone T3, but only a "look-alike" and given that it does not even contain the element Iodine, it is not nearly as effectual or as powerful as T3 and so huge quantities are necessary (in comparison to actual human hormone) in order to accomplish even just the scant effects of reducing liver steatosis. Daily dosing of 80 or 100mg is necessary to reduce liver steatosis while a patient who is hypothyroid might needs to take 80 or 100mcg micrograms of levothyroxine T4, (1,000 times less), to supplement their weakened thyroid gland and augment or completely replenish their daily required dose of T4 that is intended for the whole body, not just the liver. Synthroid or levothyroxine really is synthetic T4, but T3 is found in Armor Thyroid which is not synthetic but is derived from bovine sources and does contain T3, but nobody takes this to increase the rate of fat or steatosis metabolism in their livers.
Now, I was looking through CytoDyn's NASH Human trial and specifically at the heat map in the poster, and at the bottom of the heat map, the Thyroid Panel. Thyrotropin (TSH or Thyroid Stimulating Hormone), Thyroxine Free (Free T4) and Triiodothyronine (T3) is shown. I immediately recognized that in the arm that was most effective, the leronlimab 350mg treated arm, both T3 and T4 were both markedly elevated. This tells me that somehow, when dosed appropriately, leronlimab has a way of increasing the measured serum levels of T3 and T4. This elevation in T3 and T4 in blood serum is quite similar to the mechanism of action of resmetirom which increases "synthetic T3" specifically in the liver, one day at a time, if and only if the daily dose is taken orally.
Now, it is important to understand, that in general, reduced inflammation leads to increased Thyroid Hormone. Thank you both ohm20 & biloxiblues!! Wonderful work. It is very important to understand that linked document so read it twice. Certainly, it is known that during inflammatory conditions, thyroid hormone is reduced. Especially, of course, when the thyroid itself is inflamed as in Hashimoto's Thyroiditis. So, the reverse also is true, that when systemic inflammation subsides, be it Chronic or Acute, Thyroid Hormone subsequently increases.
Typically, T3 and T4 are usually controlled and regulated by TSH levels, but remember, an elevated inflammatory state could reduce these levels, but, TSH would tend to rise until the required quantity of T3 and T4 are measured in the blood serum. Thyroid Stimulating Hormone is there to stimulate the thyroid to produce more T3 and T4. But another way to increase blood serum levels of T3 and T4 is if the body does not consume those hormones, while leaving the formation of those hormone the same. Since T3 and T4 are used to metabolize fat within the body and within the liver, when that is happening, there would be less T3 and less T4 in the blood, because, that T3 and T4 would be located in the fat tissue, metabolizing it, so a lesser quantity would be found in the blood serum. So, as the work of reducing fat steatosis progresses along, over time, there would be less and less fat to metabolize, including the fat in the liver. In addition, as a result of less fat, there also would be less inflammation. As we understand from above, less inflammation leads to increased T3 and increased T4. At the end of the MASH treatment, there would be far less fat available to metabolize, so therefore, the T3 and T4 hormone would then accumulate higher in the blood serum until that is normalized by the body homeostasis controller with a reduced TSH signal. That is possibly what is happening in the leronlimab 350mg treated arm with the elevated levels of T3 and T4.
As we know, leronlimab lowers chronic inflammation and acute inflammation. By lowering chronic and acute inflammation, leronlimab increases T3 and T4 by facilitating the increase of TSH Thyroid Stimulating Hormone which then leads to the production of sufficiently more T3 and T4 to accommodate the increased metabolism of fat steatosis of the liver. When the levels of fat to metabolize have sufficiently decreased, those previously elevated levels of T3 and T4, via facilitated channels and with reduced cytokine interference, are permitted to be normalized back down to homeostatic levels. Taking a look at Triglyceride levels on the heat map, they were decreased in both 350mg and 700mg Haplotyped Matched which is in line with the reduction of fatty steatosis, exactly what resmetirom aims to do through intrahepatic binding with THR-Beta thereby reducing triglycerides.
This is essentially how resmetirom works, acting in a way, very similar to T3 in order to reduce intra-hepatic fat. Leronlimab does the same, but more indirectly but while employing actual human hormone, of T3 and T4 instead of a foreign THR-Beta agonist. It is clear that through a whole slew of mechanisms, T3 and T4 can be increased, such as through the reduction of inflammation leading to increases in these hormones, as a result of obstacles such as inflammatory cytokines being pulled away from the formation of these hormones in the thyroid gland, or a result of those hormones not being required as much anymore due to all the fat resorption and now having less fat to resorb.
What is important to understand is that leronlimab ALONE led to this increase in Thyroid hormone which means it happens regardless of adding any additional supplemental hormone. The hormone regulation of T3 and T4 happens as a result of taking leronlimab and they increase as well as decrease in their levels as we hope. With the administration of leronlimab, this automatic regulation of thyroid hormone levels happens naturally, and it is therefore not necessary to augment this with any hormone supplementation in the form of levothyroxine, Synthroid, Armour Thyroid or resmetirom. In the mileu of MASH, if nothing is added, T3 and T4 remain reduced and depressed, so MASH persists. Resmetirom essentially is hormone supplementation. Leronlimab naturally increases thyroid hormone levels to where they need to be to reduce liver steatosis by initially lowering inflammation, then that increased T3 and T4 levels subsequently reduce the fat in the liver.
If dosages are left the same, the combination leronlimab 350mg and resmetirom 80 could end up with a doubling of the number of patients that would benefit by the combination product. Right now, resmetirom successfully treats only about 10% of patients that are indicated for the treatment. At a minimum, leronlimab should double that. Madrigal might choose to lower the resmetirom dose instead, thereby reducing the side effect profile of that drug.
If CytoDyn is able to purchase an additional 8 weeks of the murine study and if at the end of 20 weeks, it is determined and understood that the combination of resmetirom with leronlimab leads to a reduced incidence of the development of HCC, this becomes a partnership made in heaven. Remember the vastness, the sheer immensity of this indication. How exceedingly great it is. That is why I mention heaven. In the day of this announcement, that the combination of leronlimab with resmetirom leads to significantly reduced incidence of HCC, I don't have to tell you where the share price goes, despite this study only being a murine model. Shorts are destroyed in an instant on that news.
It is not only this, but like I discussed in Outline of This Platform Molecule, many things are slated to happen this fall including what I left out of that discussion, the NIH along with Long Covid. All of this is consistent with the intelligent making of leronlimab into a Platform Molecule. A Molecule destined not to have any competition at least not for many years, because to overcome this Molecule, another mechanism of action that operates deeper than CCR5 blockade needs to be found and elucidated. CCR5 blockade is how it all unfolds, and that time is coming. Late fall to early winter.
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