AI
Monday, March 08, 2021 2:17:51 AM
Another articulate explanation of the CD12 results.
Fox News contributor Marc Siegel called molnupiravir the “holy grail” of the pandemic and predicted it could come to market in the next 4 to 5 months. Siegel claims that this is “the very first pill in our armamentarium against COVID-19.” This is completely inaccurate and sensationalistic. Prolectin-M, a galectin inhibitor, currently being developed by Bioxytran, demonstrated in a peer reviewed journal that 3/5 (60%) were RT-PCR negative at day 7 while molnupiravir showed 47/182 (25.8%) were RT-PCR negative at day 5. This apples to apples comparison showed that Merck’s drug was already smoked months ago, and molnupiravir is nothing but sensationalized news. The focus needs to turn toward CytoDyn and their tremendous mortality benefit and what the FDA plans to do about it.
Unfortunately for CytoDyn, a data anomaly is potentially delaying what would normally result in an almost automatic Emergency Use Application (EUA) with the FDA. What happened is that more people aged 65+ were included in the leronlimab group. Instead of being randomized 2:1 they were randomized 3:1. In this age group the likelihood of death is 3-4 times higher in critical patients. This created a situation where it dramatically impacted the mortality rate of the placebo population. In this critical population that is over age 65 it's not uncommon to see a mortality rate of 70 - 80% which would greatly skew the numbers.
Although not specifically stated, the mortality rate in the placebo arm had to be around 22.7%. In the past Pourhassan, the CEO of CytoDyn stated that there were 87 deaths in both arms of the trial in which 384 were ultimately enrolled. Since they didn’t reach statistical significance it infers the variance could be a percentage in either direction. A 21% - 24% mortality rate in the placebo arm of the severe to critical population is extremely low compared to the recently reported studies. In the tocilizumab study the placebo arm showed a 35.8%. In the dexamethasone trial they showed a 41.4% mortality rate and in a pure study on the mortality rate of critically ill patients on ventilators they showed at 35.7% mortality rate.
In a typical study the over 65 population represents about 45% of the population so this would tilt the scales by 10 patients which would likely result in 8 more deaths in the placebo arm and 8 less deaths in the leronlimab arm. In a clinical trial with 87 deaths a 16 death swing represents 18% swing in mortality. When the placebo mortality rate slides over 10% over the best published studies worldwide it's almost an impossible comparator unless the data is that good.
The data is actually so good that in spite of this dramatic shift in patient mortality rate they were able to pull out some amazing clinical trial results that demonstrate a tremendous mortality benefit. Keep in mind that even if a drug shows a modicum of efficacy like tocilizumab did there is an excellent chance of approval. Please keep reading, and you will see that there is no other conclusion that can be drawn except that the drug works and that a statistical anomaly should not condemn thousands of people to their deaths.
Clinical Trial Results
CytoDyn’s headline number was a 24% reduction in the mortality rate in the mechanically ventilated critical patient population, but there was no p value! The question is why was it not statistically relevant? The answer is simple, because they only had 62 patients total in both arms of the critical trial. That means at best they had 20 evaluable patients in placebo, and maybe only 5 over 65 making it almost impossible to reach statistical significance in this sub-population. For this group they simply have to do another trial to get more data, but here is the bright spot. In this critically ill patient population they shortened the time to recovery by 6 days and had statistical relevance (p=.005). Not only does this help clear up the ICU it dramatically impacts the cost of critical care which UCLA Doctor Otto Yang estimates is $25,000 per day. Approval of this drug is going to save the American taxpayer a ridiculous amount of money per critical patient.
What is so significant about the last statistic is that the company announced it almost has the green light to start another trial for 140 critically ill COVID-19 patients with the endpoint of length of hospital stay. If any readers believe in statistics, this p=.005 means that when they finish this next trial they will likely meet their primary endpoint of length of hospital stay and be a shoe in for approval. This approval could be worth tens of billions factoring in label extension and be the quickest pathway to approval. In a recent interview with Dr Been, the CEO of CytoDyn indicated his consultants think the clinical trial could be done in as little at 3-4 weeks because all the infrastructure and clinical trial sites were enrolling over 20 daily toward the end of the trial.
Taking into account the age adjustment Pourhassan also said:
“If that age adjustment was allowed to be done for that population (critical) which is not allowed, so we didn't present it, but if we did, we would have had 40% better mortality” - Nader Pourhassan - CEO CytoDyn
The biggest disappointment in the handling of this clinical trial rests with the Data Safety Monitoring Committee (DSMC). Their role is to ensure that a drug which has promise meets its primary endpoints. It has the power to recommend an adjustment to the primary endpoint at interim analysis. They are the ones that recommended the company to finish the trial and they estimated the company was likely to hit its primary endpoint of mortality. Just so we are clear not one drug has ever hit its primary endpoint in COVID-19 for mortality, not dexamethasone, not Remdesivir, or more recently tocilizumab. CytoDyn was slated to be the first and had they changed the endpoint like the DSMC recommended in so many other trials, leronlimab would have hit its endpoint of reducing the time out of the hospital by 6 days and been statistically significant. Approval would have likely been this week had they simply recommended they change the primary endpoint to what everyone else was doing, but the DSMC made a huge blunder that could ultimately cost tens of thousands of American lives.
The good news is that this blunder of the DSMC could be undone by the interim chief of the FDA. Janet Woodcock, the new chief, has the power to look at secondary endpoints. CytoDyn gave them a huge statistically significant endpoint in a massive subpopulation of their study. There were 384 in the modified-intent-to-treat (mITT) group. In Dr Been’s interview viewers learned that there were 309/384 (80.4%) that used “commonly used COVID-19 treatments.” The bottom line is that the subgroup, which represents 80% of the clinical trial, was statistically relevant and met the primary endpoint with a p=.0319. In other words they crushed the endpoint.
There was also a subset of dexamethasone alone to see how it did in comparison to combination therapy with leronlimab. While it's unclear how big this subpopulation is, the data is statistically significant with a p=.0552. The analysis of the secondary endpoints with the age adjusted analysis permitted by the FDA also revealed “numerical superiority over the placebo group, with some secondary endpoints approaching statistical significance.” The most widely used drug in COVID-19 is dexamethasone, and this study revealed combination therapy with leronlimab improves outcomes without any side effects. It too was statistically relevant.
More news is expected out of CytoDyn. They expect to announce the severe trial results and the results from the Open Label Extension. They also have an executive summary of the data being readied for an 8-K filing. The CEO also talked of major news with Health Canada and the MHRA which is the United Kingdom's regulatory agency. In fact, CytoDyn just announced they got an www.cytodyn.com/newsroom/press-releases/detail/503/cytodyn-to-file-acce…">https://www.cytodyn.com/newsroom/press-releases/detail/503/cytodyn-to-f…">accelerated rolling review and an Interim Order (IO). For those unfamiliar with Health Canada’s IO, its equivalent to an EUA. The company announced they were given the green light to file it. It would allow the importation of a drug like leronlimab contingent on CytoDyn conducting a clinical trial. For any investors reading this it means revenue from Health Canada could be days to weeks away for CytoDyn. Investors are also expecting a NASDAQ uplisting once the company lands an EUA from a country or revenue.
FDA Action Plan
The FDA currently has the top line results of the severe to critical clinical trial for leronlimab and gave CytoDyn guidance to pursue a quick 140 patient clinical trial for critical patients with an endpoint of time of hospitalization. The trial missed its primary endpoint by a hair due to a data anomaly where more critical patients over the age of 65, which have a mortality rate of approximately 75%, were placed in the active arm of the trial. This inadvertent move inordinately reduced the overall mortality of the placebo arm of the trial. Instead of facing a historical placebo mortality rate of 35% the company was more likely facing a 23% mortality rate. The deaths not reported in the placebo arm dramatically shifted the scales, and in spite of the overwhelming clinical twist of fate the clinical trial still met its endpoint! The FDA knows how to adjust for these anomalies, but with 10’s of thousands of American lives hanging in the balance will they do the right thing of approving an EUA?
At this point in the pandemic it will be interesting to see if the newly anointed FDA chief follows her own guidance which was released in www.fda.gov/media/137926/download">https://www.fda.gov/media/137926/download">February 2021 on page 11. For critically ill patients the FDA is suggesting an endpoint of 60 days not 28 days for critical patients. They are also recommending time to sustained recovery as a primary endpoint. CytoDyn also announced this weekend the discharged alive endpoint at Day 28. It showed leronlimab was 166% better than the placebo arm with a 28% probability of walking out of the hospital versus an 11% chance of walking out of the hospital. Since all this data is being tracked in the clinical trials setting it will be interesting to see what transpires over the coming days.
If this top line news circulates in clinician circles that lerononlimab works and is no longer available for their patients under the Open Label Extension (OLE) arm, there could be an incredible outcry for an immediate EUA. Some might not realize that an OLE is just a stopgap measure enacted by the FDA for clinicians to give a drug the FDA believes could be approved and causes no harm while getting more information supportive of the trial. For the clinicians that have seen the 40% reduction in mortality adjusted for age, it is reasonable to suspect that will be knocking down the FDA’s door demanding an EUA approval versus seeing the death that will transpire over the coming 90 days waiting for the trial to finish enrollment. If an EUA isn’t granted almost immediately Janet Woodcock can almost be assured of a congressional investigation as the clinicians write their congressmen.
This clinical trial data is a homerun for the planet. This is why Canada, Great Britain, Brazil, and the Philippines are racing to approve the drug. If the FDA moves too slowly, these other countries may sell out CytoDyn’s immediate supply of leronlimab leaving the United States without any protection. In the www.youtube.com/watch?v=Xduqr2uDkSw">https://www.youtube.com/watch?v=Xduqr2uDkSw">interview with Dr. Been, the CEO, Nader Pourhassan indicated that the www.cytodyn.com/newsroom/press-releases/detail/502/cytodyn-to-hold-webc…">https://www.cytodyn.com/newsroom/press-releases/detail/502/cytodyn-to-h…">conference call on Monday March 8th at 4PM EST would address one of their most pressing issues, which they believe is supply. Apparently, the company is not the slightest bit worried about FDA approval and the missed endpoint because the data is squarely in their corner and they have multiple international partners desperately looking for a solution and quite frankly don’t need the bureaucracy of the FDA to start generating revenue.
Closing Thoughts
There was a mistake in age stratification of about 10 patients in a 384 patient clinical trial that could decide the fate of the future treatment of COVID-19. The Data Safety Monitoring Committee was lax in assuring the clinical trial met its primary endpoint and ultimately its charter to protect patients. With https://covidtracking.com/data/charts/us-currently-hospitalized">40,000 COVID-19 hospitalizations in the United States and a drug that saves 1 out of every 4 treated it's hard to believe the FDA would be willing to condemn 10,000 people to death over the coming month because they didn't give a EUA of a perfectly safe drug that does no harm. The additional trial of 140 patients seems like a C- level executive’s response. Janet Woodcock is due to get a flood of emails Janet.Woodcock@fda.hhs.gov">mailto:Janet.Woodcock@fda.hhs.gov">Janet.Woodcock@fda.hhs.gov if she doesn’t quickly make a top level executive decision regarding leronlimab. A EUA just feels like the right thing to do in a time like this. Leronlimab has unequivocally proven that it takes dying off the table and brings it back into flu-like proportions and should be approved post haste.
Fox News contributor Marc Siegel called molnupiravir the “holy grail” of the pandemic and predicted it could come to market in the next 4 to 5 months. Siegel claims that this is “the very first pill in our armamentarium against COVID-19.” This is completely inaccurate and sensationalistic. Prolectin-M, a galectin inhibitor, currently being developed by Bioxytran, demonstrated in a peer reviewed journal that 3/5 (60%) were RT-PCR negative at day 7 while molnupiravir showed 47/182 (25.8%) were RT-PCR negative at day 5. This apples to apples comparison showed that Merck’s drug was already smoked months ago, and molnupiravir is nothing but sensationalized news. The focus needs to turn toward CytoDyn and their tremendous mortality benefit and what the FDA plans to do about it.
Unfortunately for CytoDyn, a data anomaly is potentially delaying what would normally result in an almost automatic Emergency Use Application (EUA) with the FDA. What happened is that more people aged 65+ were included in the leronlimab group. Instead of being randomized 2:1 they were randomized 3:1. In this age group the likelihood of death is 3-4 times higher in critical patients. This created a situation where it dramatically impacted the mortality rate of the placebo population. In this critical population that is over age 65 it's not uncommon to see a mortality rate of 70 - 80% which would greatly skew the numbers.
Although not specifically stated, the mortality rate in the placebo arm had to be around 22.7%. In the past Pourhassan, the CEO of CytoDyn stated that there were 87 deaths in both arms of the trial in which 384 were ultimately enrolled. Since they didn’t reach statistical significance it infers the variance could be a percentage in either direction. A 21% - 24% mortality rate in the placebo arm of the severe to critical population is extremely low compared to the recently reported studies. In the tocilizumab study the placebo arm showed a 35.8%. In the dexamethasone trial they showed a 41.4% mortality rate and in a pure study on the mortality rate of critically ill patients on ventilators they showed at 35.7% mortality rate.
In a typical study the over 65 population represents about 45% of the population so this would tilt the scales by 10 patients which would likely result in 8 more deaths in the placebo arm and 8 less deaths in the leronlimab arm. In a clinical trial with 87 deaths a 16 death swing represents 18% swing in mortality. When the placebo mortality rate slides over 10% over the best published studies worldwide it's almost an impossible comparator unless the data is that good.
The data is actually so good that in spite of this dramatic shift in patient mortality rate they were able to pull out some amazing clinical trial results that demonstrate a tremendous mortality benefit. Keep in mind that even if a drug shows a modicum of efficacy like tocilizumab did there is an excellent chance of approval. Please keep reading, and you will see that there is no other conclusion that can be drawn except that the drug works and that a statistical anomaly should not condemn thousands of people to their deaths.
Clinical Trial Results
CytoDyn’s headline number was a 24% reduction in the mortality rate in the mechanically ventilated critical patient population, but there was no p value! The question is why was it not statistically relevant? The answer is simple, because they only had 62 patients total in both arms of the critical trial. That means at best they had 20 evaluable patients in placebo, and maybe only 5 over 65 making it almost impossible to reach statistical significance in this sub-population. For this group they simply have to do another trial to get more data, but here is the bright spot. In this critically ill patient population they shortened the time to recovery by 6 days and had statistical relevance (p=.005). Not only does this help clear up the ICU it dramatically impacts the cost of critical care which UCLA Doctor Otto Yang estimates is $25,000 per day. Approval of this drug is going to save the American taxpayer a ridiculous amount of money per critical patient.
What is so significant about the last statistic is that the company announced it almost has the green light to start another trial for 140 critically ill COVID-19 patients with the endpoint of length of hospital stay. If any readers believe in statistics, this p=.005 means that when they finish this next trial they will likely meet their primary endpoint of length of hospital stay and be a shoe in for approval. This approval could be worth tens of billions factoring in label extension and be the quickest pathway to approval. In a recent interview with Dr Been, the CEO of CytoDyn indicated his consultants think the clinical trial could be done in as little at 3-4 weeks because all the infrastructure and clinical trial sites were enrolling over 20 daily toward the end of the trial.
Taking into account the age adjustment Pourhassan also said:
“If that age adjustment was allowed to be done for that population (critical) which is not allowed, so we didn't present it, but if we did, we would have had 40% better mortality” - Nader Pourhassan - CEO CytoDyn
The biggest disappointment in the handling of this clinical trial rests with the Data Safety Monitoring Committee (DSMC). Their role is to ensure that a drug which has promise meets its primary endpoints. It has the power to recommend an adjustment to the primary endpoint at interim analysis. They are the ones that recommended the company to finish the trial and they estimated the company was likely to hit its primary endpoint of mortality. Just so we are clear not one drug has ever hit its primary endpoint in COVID-19 for mortality, not dexamethasone, not Remdesivir, or more recently tocilizumab. CytoDyn was slated to be the first and had they changed the endpoint like the DSMC recommended in so many other trials, leronlimab would have hit its endpoint of reducing the time out of the hospital by 6 days and been statistically significant. Approval would have likely been this week had they simply recommended they change the primary endpoint to what everyone else was doing, but the DSMC made a huge blunder that could ultimately cost tens of thousands of American lives.
The good news is that this blunder of the DSMC could be undone by the interim chief of the FDA. Janet Woodcock, the new chief, has the power to look at secondary endpoints. CytoDyn gave them a huge statistically significant endpoint in a massive subpopulation of their study. There were 384 in the modified-intent-to-treat (mITT) group. In Dr Been’s interview viewers learned that there were 309/384 (80.4%) that used “commonly used COVID-19 treatments.” The bottom line is that the subgroup, which represents 80% of the clinical trial, was statistically relevant and met the primary endpoint with a p=.0319. In other words they crushed the endpoint.
There was also a subset of dexamethasone alone to see how it did in comparison to combination therapy with leronlimab. While it's unclear how big this subpopulation is, the data is statistically significant with a p=.0552. The analysis of the secondary endpoints with the age adjusted analysis permitted by the FDA also revealed “numerical superiority over the placebo group, with some secondary endpoints approaching statistical significance.” The most widely used drug in COVID-19 is dexamethasone, and this study revealed combination therapy with leronlimab improves outcomes without any side effects. It too was statistically relevant.
More news is expected out of CytoDyn. They expect to announce the severe trial results and the results from the Open Label Extension. They also have an executive summary of the data being readied for an 8-K filing. The CEO also talked of major news with Health Canada and the MHRA which is the United Kingdom's regulatory agency. In fact, CytoDyn just announced they got an www.cytodyn.com/newsroom/press-releases/detail/503/cytodyn-to-file-acce…">https://www.cytodyn.com/newsroom/press-releases/detail/503/cytodyn-to-f…">accelerated rolling review and an Interim Order (IO). For those unfamiliar with Health Canada’s IO, its equivalent to an EUA. The company announced they were given the green light to file it. It would allow the importation of a drug like leronlimab contingent on CytoDyn conducting a clinical trial. For any investors reading this it means revenue from Health Canada could be days to weeks away for CytoDyn. Investors are also expecting a NASDAQ uplisting once the company lands an EUA from a country or revenue.
FDA Action Plan
The FDA currently has the top line results of the severe to critical clinical trial for leronlimab and gave CytoDyn guidance to pursue a quick 140 patient clinical trial for critical patients with an endpoint of time of hospitalization. The trial missed its primary endpoint by a hair due to a data anomaly where more critical patients over the age of 65, which have a mortality rate of approximately 75%, were placed in the active arm of the trial. This inadvertent move inordinately reduced the overall mortality of the placebo arm of the trial. Instead of facing a historical placebo mortality rate of 35% the company was more likely facing a 23% mortality rate. The deaths not reported in the placebo arm dramatically shifted the scales, and in spite of the overwhelming clinical twist of fate the clinical trial still met its endpoint! The FDA knows how to adjust for these anomalies, but with 10’s of thousands of American lives hanging in the balance will they do the right thing of approving an EUA?
At this point in the pandemic it will be interesting to see if the newly anointed FDA chief follows her own guidance which was released in www.fda.gov/media/137926/download">https://www.fda.gov/media/137926/download">February 2021 on page 11. For critically ill patients the FDA is suggesting an endpoint of 60 days not 28 days for critical patients. They are also recommending time to sustained recovery as a primary endpoint. CytoDyn also announced this weekend the discharged alive endpoint at Day 28. It showed leronlimab was 166% better than the placebo arm with a 28% probability of walking out of the hospital versus an 11% chance of walking out of the hospital. Since all this data is being tracked in the clinical trials setting it will be interesting to see what transpires over the coming days.
If this top line news circulates in clinician circles that lerononlimab works and is no longer available for their patients under the Open Label Extension (OLE) arm, there could be an incredible outcry for an immediate EUA. Some might not realize that an OLE is just a stopgap measure enacted by the FDA for clinicians to give a drug the FDA believes could be approved and causes no harm while getting more information supportive of the trial. For the clinicians that have seen the 40% reduction in mortality adjusted for age, it is reasonable to suspect that will be knocking down the FDA’s door demanding an EUA approval versus seeing the death that will transpire over the coming 90 days waiting for the trial to finish enrollment. If an EUA isn’t granted almost immediately Janet Woodcock can almost be assured of a congressional investigation as the clinicians write their congressmen.
This clinical trial data is a homerun for the planet. This is why Canada, Great Britain, Brazil, and the Philippines are racing to approve the drug. If the FDA moves too slowly, these other countries may sell out CytoDyn’s immediate supply of leronlimab leaving the United States without any protection. In the www.youtube.com/watch?v=Xduqr2uDkSw">https://www.youtube.com/watch?v=Xduqr2uDkSw">interview with Dr. Been, the CEO, Nader Pourhassan indicated that the www.cytodyn.com/newsroom/press-releases/detail/502/cytodyn-to-hold-webc…">https://www.cytodyn.com/newsroom/press-releases/detail/502/cytodyn-to-h…">conference call on Monday March 8th at 4PM EST would address one of their most pressing issues, which they believe is supply. Apparently, the company is not the slightest bit worried about FDA approval and the missed endpoint because the data is squarely in their corner and they have multiple international partners desperately looking for a solution and quite frankly don’t need the bureaucracy of the FDA to start generating revenue.
Closing Thoughts
There was a mistake in age stratification of about 10 patients in a 384 patient clinical trial that could decide the fate of the future treatment of COVID-19. The Data Safety Monitoring Committee was lax in assuring the clinical trial met its primary endpoint and ultimately its charter to protect patients. With https://covidtracking.com/data/charts/us-currently-hospitalized">40,000 COVID-19 hospitalizations in the United States and a drug that saves 1 out of every 4 treated it's hard to believe the FDA would be willing to condemn 10,000 people to death over the coming month because they didn't give a EUA of a perfectly safe drug that does no harm. The additional trial of 140 patients seems like a C- level executive’s response. Janet Woodcock is due to get a flood of emails Janet.Woodcock@fda.hhs.gov">mailto:Janet.Woodcock@fda.hhs.gov">Janet.Woodcock@fda.hhs.gov if she doesn’t quickly make a top level executive decision regarding leronlimab. A EUA just feels like the right thing to do in a time like this. Leronlimab has unequivocally proven that it takes dying off the table and brings it back into flu-like proportions and should be approved post haste.
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