Misiu--With the exception of the dosage issue, I'm actually pretty happy with the rollover protocol that Cytodyn is proposing for the mCRC trial. That protocol will safeguard trial participants by providing "ongoing access to leronlimab for those patients with CRC who continue to do well after 48 weeks on the parent study," and "will now offer leronlimab plus an ICI to those who progress on the parent study." (The quotes above and below are from the Scientific Supplement in the September Letter to Shareholders). You may not expect many of the patients to survive 48 weeks of leronlimab plus SOC... but the implication of the first part of the quote suggests the company does, or they wouldn't ask for that change.
The supplement goes on to say--
"These amendments will allow us to achieve multiple critical goals, including:
--Evaluate leronlimab as a stand-alone agent (in combo with SOC) in a 2nd tumor type.
--Prospectively evaluate the ability of two different leronlimab dose levels to induce PD-L1 expresion on CTCs in a solid tumor that is typically "cold"...
--Obtain biopsy tissue from patients with disease progression enrolling in the rollover protocol to correlate PD-L1 levels and changes in the tumor microenvironment on tumor tissue with PD-L1 expression on concurrently drawn CTCs...
--Evaluate the possibility of treating patients with a common and typically "cold" cancer with the combination of leronlimab and an ICI..."
I think the changes to the protocol protects patients while providing an incredible amount of vital information in a new indication for leronlimab that includes chemotherapy as part of the SOC. The detail and granularity of the Creativ Microtek data will inform and guide the way forward... and that in itself will save lives. Consider the implications in this paragraph from the Scientific Supplement:
"The decline in circulating tumor cells (CTCs) observed in most patients after as little as one dose of leronlimab was significantly associated with both progression-free and overall survival. Leronlimab's rapid and prognostically significant impact on CTCs, which appears to reflect activity within the primary tumor itself, provides important evidence of leronlimab's activity as a stand-alone agent. Confirming the full extent of leronlimab's activity on the primary tumor is on our short list of clinical priorities in the coming months."
Would we get the same kind of detailed information about stand-alone leronlimab--with SOC--in patients who were given an ICI when their PD-L1 numbers rose and they became eligible? Will we gain any relevant information about LL's affect on CRC metastasis? Maybe... But for those that are receiving 700mg and responding--why not let the original trial parameters play out and harvest all this clinically important data?
Towards the end of your post you write "Median overall survival in TNBC was 7.1 months. If he will not amend the CRC protocol to add ICIs, I suspect, we will not have many of our CRC patients to get to a new Rollover trial after this 12 months." I think you are flat out wrong here, taking mTNBC survival numbers and applying them to a different cancer indication entirely. We do have a more apt, apples-to-apples comparator--our basket trial included 5 mCRC patients with two partial responses, a single complete response, and a median overall survival of 15.4 months. Without any ICIs in the mix. I don't know if we will see any complete responses in our mCRC trial just because of the limited timeframe... but I suspect we will see several partial responses. And except for the sickest of the participants, I trust those that receive 700mg of leronlimab will survive the 48 weeks of the parent trial in better shape then when they started. And the sickest will probably progress and get the ICI earlier in the process... So why all the doubts? What problems are you seeing here that I am missing? Don't these protocol revisions give participants a real shot at life, even if they get a 350mg dose and progress?
What I don't understand is why a 525mg dose wasn't included in the trial. That dose demonstrated efficacy in the mTNBC patients even if it doesn't provide complete receptor occupancy. And if 525mg was not used for the first five in the safety cohort, why not replace the 350mg arm entirely with 525mg once the low dose was proven safe? It's the patients in the 350mg arm of our current trial that I most worry about, as we have no clue if the DSMB is going to bump them up to 700mg to increase their PD-L1 numbers... Or not.
At this point, the trial is underway and we still don't have approval for these modifications of the trial protocol... So I share some of your frustration there, on the timeline. On the other hand, Cytodyn needs to get this right, and make a presentation that cannot be denied. Which took a great deal of time and effort to deal with the bureaucracy and track down the necessary information. I don't think the "unassailable evidence" that is required was ready until this fall, at least in a format that would satisfy the FDA, from some of Dr Lalezari's recent public comments. So saying the meeting "should (have been) in May," without anything substantial to back up that conclusion... Well, that is the kind of thing I'd expect from Mazzy Star, not Misiu...
Lalezari is a pretty persuasive guy. And he's been running trials and dealing with the FDA for decades. I think he knows what it will take to convince them to change this particular horse in mid-stream. So give him some space to do his job... And hey, this is the FDA! Not known as a particularly nimble institution. Some of this may be related to their historical dysfunction and kowtowing to corporate influence. And since they are currently in turmoil, with lots of staff disruption and leadership changes, I suspect they are responsible for some if not a lot of this delay. And let's not forget Cytodyn's own history and responsibility for two lost years on clinical hold. While Nadar the person saved your son's life--if I got the story right--as CEO he also left the company in shambles and destroyed it's credibility. Cytodyn is still answering for his decisions on Wall Street, if not Washington. Worse still, he gave in to the FDA on the protocol for the severe covid trial and accepted two weeks instead of the necessary four it takes for leronlimab to calm that particular storm. He will soon be in jail for white collar crimes... but as far as I'm concerned, with the pandemic raging, that was a crime against humanity. Of course the FDA ultimately bears responsibility for not understanding why four weeks were necessary--were they really that stupid?)--(Oh Lordy--a bad flashback!). Oh my, what a long strange trip it's been... And yet here we are--so, so close...
I've always appreciated your posts; the caring and concern you express... but have recently noticed you are giving Dr Lalezari and Cytodyn a hard time. Stressed? I guess 10 years in Cytodyn could do that to a person. (I've got five years in myself, and would be hard-pressed to hold on for another five, if it came to the mismanagement of the Nadar years). But your comment in another recent post really rankled me. "I will never question our drug... What I am questioning is our management, for all of them this is only a second job." I think the last part--the dig about only a second job for all of them--was a cheap shot that doesn't account for the work and effort and stress Lalezari and the crew are under right now. I was offended. They are in that rare position where what they do in the next several weeks and months can literally make history and save millions of lives if they get this right. I'm sure they take that to bed with them every night, and wake up with it every morning. Not that they care about what is said on a stock message board... but I'm here on this board, and I do. There is always room for well-reasoned critique and debate... and even a rant every once in a while as needed. I hope you were just letting off some stress. But right now, as things are unfolding and the tension is rising, a little more space and respect for the Cytodyn crew would be appreciated.
With respect and appreciation,
--Sherlock57--
The supplement goes on to say--
"These amendments will allow us to achieve multiple critical goals, including:
--Evaluate leronlimab as a stand-alone agent (in combo with SOC) in a 2nd tumor type.
--Prospectively evaluate the ability of two different leronlimab dose levels to induce PD-L1 expresion on CTCs in a solid tumor that is typically "cold"...
--Obtain biopsy tissue from patients with disease progression enrolling in the rollover protocol to correlate PD-L1 levels and changes in the tumor microenvironment on tumor tissue with PD-L1 expression on concurrently drawn CTCs...
--Evaluate the possibility of treating patients with a common and typically "cold" cancer with the combination of leronlimab and an ICI..."
I think the changes to the protocol protects patients while providing an incredible amount of vital information in a new indication for leronlimab that includes chemotherapy as part of the SOC. The detail and granularity of the Creativ Microtek data will inform and guide the way forward... and that in itself will save lives. Consider the implications in this paragraph from the Scientific Supplement:
"The decline in circulating tumor cells (CTCs) observed in most patients after as little as one dose of leronlimab was significantly associated with both progression-free and overall survival. Leronlimab's rapid and prognostically significant impact on CTCs, which appears to reflect activity within the primary tumor itself, provides important evidence of leronlimab's activity as a stand-alone agent. Confirming the full extent of leronlimab's activity on the primary tumor is on our short list of clinical priorities in the coming months."
Would we get the same kind of detailed information about stand-alone leronlimab--with SOC--in patients who were given an ICI when their PD-L1 numbers rose and they became eligible? Will we gain any relevant information about LL's affect on CRC metastasis? Maybe... But for those that are receiving 700mg and responding--why not let the original trial parameters play out and harvest all this clinically important data?
Towards the end of your post you write "Median overall survival in TNBC was 7.1 months. If he will not amend the CRC protocol to add ICIs, I suspect, we will not have many of our CRC patients to get to a new Rollover trial after this 12 months." I think you are flat out wrong here, taking mTNBC survival numbers and applying them to a different cancer indication entirely. We do have a more apt, apples-to-apples comparator--our basket trial included 5 mCRC patients with two partial responses, a single complete response, and a median overall survival of 15.4 months. Without any ICIs in the mix. I don't know if we will see any complete responses in our mCRC trial just because of the limited timeframe... but I suspect we will see several partial responses. And except for the sickest of the participants, I trust those that receive 700mg of leronlimab will survive the 48 weeks of the parent trial in better shape then when they started. And the sickest will probably progress and get the ICI earlier in the process... So why all the doubts? What problems are you seeing here that I am missing? Don't these protocol revisions give participants a real shot at life, even if they get a 350mg dose and progress?
What I don't understand is why a 525mg dose wasn't included in the trial. That dose demonstrated efficacy in the mTNBC patients even if it doesn't provide complete receptor occupancy. And if 525mg was not used for the first five in the safety cohort, why not replace the 350mg arm entirely with 525mg once the low dose was proven safe? It's the patients in the 350mg arm of our current trial that I most worry about, as we have no clue if the DSMB is going to bump them up to 700mg to increase their PD-L1 numbers... Or not.
At this point, the trial is underway and we still don't have approval for these modifications of the trial protocol... So I share some of your frustration there, on the timeline. On the other hand, Cytodyn needs to get this right, and make a presentation that cannot be denied. Which took a great deal of time and effort to deal with the bureaucracy and track down the necessary information. I don't think the "unassailable evidence" that is required was ready until this fall, at least in a format that would satisfy the FDA, from some of Dr Lalezari's recent public comments. So saying the meeting "should (have been) in May," without anything substantial to back up that conclusion... Well, that is the kind of thing I'd expect from Mazzy Star, not Misiu...
Lalezari is a pretty persuasive guy. And he's been running trials and dealing with the FDA for decades. I think he knows what it will take to convince them to change this particular horse in mid-stream. So give him some space to do his job... And hey, this is the FDA! Not known as a particularly nimble institution. Some of this may be related to their historical dysfunction and kowtowing to corporate influence. And since they are currently in turmoil, with lots of staff disruption and leadership changes, I suspect they are responsible for some if not a lot of this delay. And let's not forget Cytodyn's own history and responsibility for two lost years on clinical hold. While Nadar the person saved your son's life--if I got the story right--as CEO he also left the company in shambles and destroyed it's credibility. Cytodyn is still answering for his decisions on Wall Street, if not Washington. Worse still, he gave in to the FDA on the protocol for the severe covid trial and accepted two weeks instead of the necessary four it takes for leronlimab to calm that particular storm. He will soon be in jail for white collar crimes... but as far as I'm concerned, with the pandemic raging, that was a crime against humanity. Of course the FDA ultimately bears responsibility for not understanding why four weeks were necessary--were they really that stupid?)--(Oh Lordy--a bad flashback!). Oh my, what a long strange trip it's been... And yet here we are--so, so close...
I've always appreciated your posts; the caring and concern you express... but have recently noticed you are giving Dr Lalezari and Cytodyn a hard time. Stressed? I guess 10 years in Cytodyn could do that to a person. (I've got five years in myself, and would be hard-pressed to hold on for another five, if it came to the mismanagement of the Nadar years). But your comment in another recent post really rankled me. "I will never question our drug... What I am questioning is our management, for all of them this is only a second job." I think the last part--the dig about only a second job for all of them--was a cheap shot that doesn't account for the work and effort and stress Lalezari and the crew are under right now. I was offended. They are in that rare position where what they do in the next several weeks and months can literally make history and save millions of lives if they get this right. I'm sure they take that to bed with them every night, and wake up with it every morning. Not that they care about what is said on a stock message board... but I'm here on this board, and I do. There is always room for well-reasoned critique and debate... and even a rant every once in a while as needed. I hope you were just letting off some stress. But right now, as things are unfolding and the tension is rising, a little more space and respect for the Cytodyn crew would be appreciated.
With respect and appreciation,
--Sherlock57--
22
