Just some comments on the extraordinary meeting yesterday (mostly taken verbatim from conference).
Starting with Dr. J : "During the April investor call, I made two important assertions. First, that CytoDyn was transitioning from a company built on faith and a few ifs into a company with solid and unassailable clinical data. Second, I asserted that leronlimab was delivering results in the clinic at the outer edge of what I thought was even possible. Today, I stand fully behind both of those statements and remain more confident than ever that our investors' patience will soon be rewarded."We have two tracks: the "standalone" as a cancer therapy unto itself, which would then be either used as monotherapy or in combination with standard of care and also as in the prime and pair paradigm, where we use leronlimab to prime a tumor, disrupt a tumor microenvironment, allowing intrusion of the host immune system, causing the cancer, in a defensive way, to express PD-L1, and then pairing leronlimab with a checkpoint inhibitor, which then defeats the PD-L1 attempt to beat back the invading immune system.
We will have data where the primary endpoint will be the calculated objective response rate, which includes all patients that are either complete responders or patients that have a 30% decrease in the largest diameter of their target lesion and a number of secondary exploratory endpoints such as partial response, stable disease, meaning they didn't quite reach the 30% decrease in tumor diameter, as well as progression- free and overall survival, additionally, we're following PD-L1 levels on circulating tumor cells and evaluating the efficacy of leronlimab now given in a rollover phase to patients with progression who have now increased their dose of leronlimab to 700 mg and added in the checkpoint inhibitor pembrolizumab, to follow them during the randomized phase of this study.
The majority of patients in CLOVER had three prior lines or more, and, some of these patients, four, fifth, six, and even nine prior lines. Data in the 28 patients in whom we have a baseline specimen that was obtained within seven days of the baseline visit, as well as a follow-up specimen indicates that at week two, we are seeing a median decrease of 86% across all the patients. Dr. J believes that that is a result that has not previously been shown in colon cancer. The efficacy that we're seeing based on DNA is being driven largely by leronlimab, but it's actually also being driven by leronlimab dose.
Note: Natera has a database of 140,000 samples. It was a big surprise for me that it is possible to compare CLOVER with LONGSURF (not exactly apples to apples but a valid comparison by its contrast) !!!
It turns out that even relatively low levels of CCR5 expression in the tumor microenvironment are associated with profound, deep, and rapid declines in circulating tumor DNA. This is golden for us.
About three-quarters of the patients who had scans at week eight demonstrate shrinkage or are classified as having stable disease. In this patient population, now fourth-line patients with CRC, that is very important towards the primary end point. repeat: three-quarters either shrinkage or stable !!!!
According to Dr. Aniline DNA changes take place sooner than with imaging (weeks to months) and tend to be very prognostic. Well, we knew that.
Also, there are observations of increased PD-L1 levels in the majority of patients. No better news for Prime and Pair
A real-world meta-analysis of real-world data showed that the overall response rate with bev and LONSURF (TAS-102) was actually closer to 3%. That is the bar with which the FDA will be judging leronlimab for our application. More telling DNA and early responses appear more dramatic, steeper, and faster than SUNLIGHT (TAS 102 + bevacizumab), where 90% of the patients had only failed two lines of therapy, and they even had about 5% of patients who had only failed one line of therapy and where it is unclear how many of those first-line failure patients actually contributed partial responses to their conclusion of a 6% overall response rate.
So, basically the bar for CLOVER is very low, and we will surpass it even whith patients with several (fourth, fifth, six and even nine) previous lines in our study.
The very critical information is that LONSURF monotherapy had a median increase of 22%, and the LONSURF plus bev had a median decrease of 55%.
Let me so bold as to ask the following question, which one treatment is better: the one with median decline of 55.2% (mean 22%) or the one with 93.2% (mean 87.44%) with much more serious, pre-treated patient cohort ?
No wonder Dr. Aniline said “I think pretty stunning in terms of the performance” and: “we both agreed we had never seen metastatic response from ctDNA like we have seen in this cohort of patients” (talking about the 12 from CLOVER trial). This is what (rightly) created the collective shiver at the team at CytoDyn.
Dr Kasi was specific: “When patients hear the term that we're going to do LONSURF, TAS-102, or trifluridine with bevacizumab, that's pretty much is a sign that we're running out of options. Same goes for fruquintinib, regorafenib. The response rate, no matter what study you look at, is no more than a single percentage point. They've all been FDA approved because they prolong survival, but they don't necessarily provide clinical meaningful benefit to the point of partial responses or stable disease”. Wholly cow!!! (my comment).
And DR. J as well: “That data clearly demonstrates deeper and more rapid DNA declines in the majority fourth-line or later CLOVER patients who received leronlimab with the backbone, compared to Natera's historic database of third-line patients who received the backbone alone. That analysis should remove any doubt about the robust anti-tumor activity of leronlimab as a standalone agent when added to standard of care in patients with colon cancer”.
Finaly my conclusion: we will beat by far the standard of care. Period. The only question is: how will the deep decline of ctDNA we have measured translate in actual tumor shrinkage and how many patients will have a 30% decrease in the largest diameter of their target lesion (primary point) ? We will know in San Francisco.
Now, one way or another, the FDA (and BP) will have a very hard time ignoring a treatment that is much superior to the current standard of care.
I say we have a working drug and is just matter of time before we see our Leronlimab out there helping patients.
Now, all this leaving out the huge potential of the Prime and Pair approach that requires a complete different chapter.
For all those that have cars (or better, trucks) this is a good time to check the shock absorbers, reinforce if necessary, and use the reverse gear (not an investment advice) !!!
Starting with Dr. J : "During the April investor call, I made two important assertions. First, that CytoDyn was transitioning from a company built on faith and a few ifs into a company with solid and unassailable clinical data. Second, I asserted that leronlimab was delivering results in the clinic at the outer edge of what I thought was even possible. Today, I stand fully behind both of those statements and remain more confident than ever that our investors' patience will soon be rewarded."We have two tracks: the "standalone" as a cancer therapy unto itself, which would then be either used as monotherapy or in combination with standard of care and also as in the prime and pair paradigm, where we use leronlimab to prime a tumor, disrupt a tumor microenvironment, allowing intrusion of the host immune system, causing the cancer, in a defensive way, to express PD-L1, and then pairing leronlimab with a checkpoint inhibitor, which then defeats the PD-L1 attempt to beat back the invading immune system.
We will have data where the primary endpoint will be the calculated objective response rate, which includes all patients that are either complete responders or patients that have a 30% decrease in the largest diameter of their target lesion and a number of secondary exploratory endpoints such as partial response, stable disease, meaning they didn't quite reach the 30% decrease in tumor diameter, as well as progression- free and overall survival, additionally, we're following PD-L1 levels on circulating tumor cells and evaluating the efficacy of leronlimab now given in a rollover phase to patients with progression who have now increased their dose of leronlimab to 700 mg and added in the checkpoint inhibitor pembrolizumab, to follow them during the randomized phase of this study.
The majority of patients in CLOVER had three prior lines or more, and, some of these patients, four, fifth, six, and even nine prior lines. Data in the 28 patients in whom we have a baseline specimen that was obtained within seven days of the baseline visit, as well as a follow-up specimen indicates that at week two, we are seeing a median decrease of 86% across all the patients. Dr. J believes that that is a result that has not previously been shown in colon cancer. The efficacy that we're seeing based on DNA is being driven largely by leronlimab, but it's actually also being driven by leronlimab dose.
Note: Natera has a database of 140,000 samples. It was a big surprise for me that it is possible to compare CLOVER with LONGSURF (not exactly apples to apples but a valid comparison by its contrast) !!!
It turns out that even relatively low levels of CCR5 expression in the tumor microenvironment are associated with profound, deep, and rapid declines in circulating tumor DNA. This is golden for us.
About three-quarters of the patients who had scans at week eight demonstrate shrinkage or are classified as having stable disease. In this patient population, now fourth-line patients with CRC, that is very important towards the primary end point. repeat: three-quarters either shrinkage or stable !!!!
According to Dr. Aniline DNA changes take place sooner than with imaging (weeks to months) and tend to be very prognostic. Well, we knew that.
Also, there are observations of increased PD-L1 levels in the majority of patients. No better news for Prime and Pair
A real-world meta-analysis of real-world data showed that the overall response rate with bev and LONSURF (TAS-102) was actually closer to 3%. That is the bar with which the FDA will be judging leronlimab for our application. More telling DNA and early responses appear more dramatic, steeper, and faster than SUNLIGHT (TAS 102 + bevacizumab), where 90% of the patients had only failed two lines of therapy, and they even had about 5% of patients who had only failed one line of therapy and where it is unclear how many of those first-line failure patients actually contributed partial responses to their conclusion of a 6% overall response rate.
So, basically the bar for CLOVER is very low, and we will surpass it even whith patients with several (fourth, fifth, six and even nine) previous lines in our study.
The very critical information is that LONSURF monotherapy had a median increase of 22%, and the LONSURF plus bev had a median decrease of 55%.
Let me so bold as to ask the following question, which one treatment is better: the one with median decline of 55.2% (mean 22%) or the one with 93.2% (mean 87.44%) with much more serious, pre-treated patient cohort ?
No wonder Dr. Aniline said “I think pretty stunning in terms of the performance” and: “we both agreed we had never seen metastatic response from ctDNA like we have seen in this cohort of patients” (talking about the 12 from CLOVER trial). This is what (rightly) created the collective shiver at the team at CytoDyn.
Dr Kasi was specific: “When patients hear the term that we're going to do LONSURF, TAS-102, or trifluridine with bevacizumab, that's pretty much is a sign that we're running out of options. Same goes for fruquintinib, regorafenib. The response rate, no matter what study you look at, is no more than a single percentage point. They've all been FDA approved because they prolong survival, but they don't necessarily provide clinical meaningful benefit to the point of partial responses or stable disease”. Wholly cow!!! (my comment).
And DR. J as well: “That data clearly demonstrates deeper and more rapid DNA declines in the majority fourth-line or later CLOVER patients who received leronlimab with the backbone, compared to Natera's historic database of third-line patients who received the backbone alone. That analysis should remove any doubt about the robust anti-tumor activity of leronlimab as a standalone agent when added to standard of care in patients with colon cancer”.
Finaly my conclusion: we will beat by far the standard of care. Period. The only question is: how will the deep decline of ctDNA we have measured translate in actual tumor shrinkage and how many patients will have a 30% decrease in the largest diameter of their target lesion (primary point) ? We will know in San Francisco.
Now, one way or another, the FDA (and BP) will have a very hard time ignoring a treatment that is much superior to the current standard of care.
I say we have a working drug and is just matter of time before we see our Leronlimab out there helping patients.
Now, all this leaving out the huge potential of the Prime and Pair approach that requires a complete different chapter.
For all those that have cars (or better, trucks) this is a good time to check the shock absorbers, reinforce if necessary, and use the reverse gear (not an investment advice) !!!
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