I think there is a very good chance that the 350mg dose of leronlimab is going to outperform expectations in the preliminary results of the mCRC cancer trial we are all waiting for. There is some specific history with the 350mmg dose to back up this thought, as well as plenty of theory… which I’ll get into shortly. But if I’m right there will be a number of the 350mg patients with stable disease; perhaps even some with a partial response. This means we probably won’t get too many patients who progress at this date, and most likely we won’t see any—or few—who transition to the 700mg dose and/or receive an ICI. I don’t think many of us were expecting people were going to get an ICI this early in the process anyway, so I’m not going too far out on a limb here.
Why do I think the 350mg dose will outperform expectations? The general, generic reason is that leronlimab tends to make other drugs preform better… at least in the pre-clinical studies, and strong indications in the human HIV and retrospective cancer trials. Add to this Dr Fourqurean’s idea about treating the patient and not the disease via CCR5 inhibition, and you get the general observation among users that people feel better on leronlimab because it reduces inflammation. Specifically, in regards to colorectal cancer—which is often driven by IBD and colitis—leronlimab will likely help the general health of the gut, and the immune system’s response to cancers of the gut. The permeability of an inflamed gut and how that will affect metastasis is probably the big question. Will a 350mg dose be enough to make a difference?
From memory, I recall that the 350mg dose occupies 44% of available receptors. That dose was used in CD02, the Optimize Phase2b/3 trial back in the day that proved leronlimab’s utility as salvage therapy for those with Multidrug-Resisstant HIV. The trial parameters seem odd—one dose of 350mg leronlimab on top of the failing ART regimen, followed by a 24 week extension at 350 or 700mg doses. The primary end point was achieving ≥0.5 log 10 reduction in plasma HIV-1 RNA from baseline at the end of the 1-week double-blinded treatment period. The numbers weren’t outstanding—by per protocol analysis, 72% of patients on the 350mg dose achieved a >0.5 log reduction in plasma HIV RNA vs 24% on placebo. The abstract I read didn’t break down the 24 week extension by dose, unfortunately, but did conclude:
“Leronlimab resulted in significantly reduced plasma HIV-1 within 1 week after addition to failing antiretroviral therapy. After 24 weeks combined with an optimized background treatment, most participants had plasma HIV-1 RNA levels <50 copies per milliliter plasma, suggesting utility of leronlimab as a component of salvage therapy.” (https://pubmed.ncbi.nlm.nih.gov/39972543/)
The point here is—clearly measurable efficacy at the 350mg dose. In HIV patients. In TNBC we also have two out of four patients (who had follow-up scans to evaluate) that received 350mg of leronlimab increased their PDL-1 numbers significantly, with one out of four reaching the 400 threshold for ICI use. So we are likely to see some PDL-1 responders in the 350mg dose cohort… like, maybe one-third to one-half? And in the recent abstract on the Clover trial we have 3 out of 5 patients increasing PDL-1 but no information on what dose or the amount of increase. And at the City of Hope site we have 4 of 4 with decreases in CEA, CA19-9 and/or ctDNA after one week, the latter which correlates to improved survival in the previous clinical studies. My assumption is that most of those patients were dosed at 350mg (given the first five were all given that dose, and subsequent to that, “approximately 15 patients will be randomized 1:2 on 350mg and 700mg arms respectively in order to achieve an overall 1:1 treatment assignment…” (from the recent mCRC poster). That would be 7 out of the first 10 or 11 dosed at 350mg… with talk of good results in those first patients.
The other clinical benefit the 350mg dose might have in the trial is additive effects or synergy with avastin in terms of limiting angiogenesis. This will help limit the growth or even reduce existing tumors… and it could certainly help with controlling metastasis.
I’m tempted to roll out some of the 350mg numbers from the MASH trial… but I’ll spare everyone the confusion. However, the preclinical work in MASH did emphasize a reduction in fibrosis--in the liver and other organs--with leronlimab, and increasing fibrosis seems to be one of the ways in which cancer hides away from the immune system. One additional bit of theory to add to the mix—apparently, macrophages have memories, mediated by IFN-y signaling. We all know leronlimab increases IFN-y… so check this out:
“For their study, the researchers exposed cultured macrophages to IFNγ and then studied epigenetic changes in the cells’ genomes. They recorded thousands of shifts in immune-boosting enhancers that lasted for days after exposure. These shifts were only sustained because of continued signaling from minuscule amounts of IFNγ that remained attached to the macrophages.”
“Minuscule amounts of IFN-y.” Enough from a shot or two of leronlimab at the 350mg dose? Who can say? The authors of the study suggest their insights might be relevant to autoimmune diseases (ie, stop the signaling to suppress over-active immune memory) but I think it might be another MOA for leronlimab’s effects on cancer. More from the article:
“Recent studies of macrophages have shown that their memories rely on a cytokine signaling molecule called interferon gamma (IFNγ). When the immune system encounters a threat for the first time, IFNγ induces changes in macrophages’ DNA, exposing enhancer domains that pump up gene expression. The newly bolstered genes explain how the immune system can respond faster and more forcefully when it next encounters the threat. But researchers didn’t fully understand how the macrophages maintained this memory for so long after their exposure to IFNγ."
"Our new findings suggest that these changes in macrophages are actually readily reversible and do not inherently encode immune memory,” said University of California, Los Angeles (UCLA) microbiologist and study co-author Alexander Hoffman in a statement. “Instead, the cells are dependent on ongoing signaling from interferon gamma sequestered at or near the macrophage cell surface.”
https://www.the-scientist.com/lingering-immun...mory-74092
So, for all of the above reasons, I’m going to speculate that the 350mg dose is going to have a clinically-relevant effect on patients in the Clover trial. Will it obviate the need for an ICI at some point? No—except for a lucky few… perhaps. What it will likely do is keep people from progressing early on… I’m anticipating some stable disease in the 350mg cohort; perhaps with the avastin/leronlimab double-whammy on angiogenesis we will get some tumor shrinkage enough for some partial responses. The question is—will the 350mg dose be enough to tip the scales towards a 30% reduction in tumor size? Or enough to prevent a 30% increase in tumor size? The answer is… Probably not for the first question, and likely enough for the second. I do not think we will get many patients progressing and eligible for an ICI early on in the trial. Perhaps I’m wrong—MSS colorectal cancer is a bastard—but if some were hoping for a quick demonstration of what can happen when leronlimab is paired with an ICI… well, I think we will have to wait for that. But compared to a 350mg dose, the 700mg dose ought to do quite a bit better as far as tumor shrinkage and partial responses, along with a big boost in PDL-1 numbers. If the numbers are good—will Big Pharma bite? Will the FDA reward us with a BTD? And—will good but not dramatic numbers keep the shorts at bay? Those questions--who can say? I've got enough time to wait a few more months for mature data—and some ICI action! Coming soon... but probably not April.
Why do I think the 350mg dose will outperform expectations? The general, generic reason is that leronlimab tends to make other drugs preform better… at least in the pre-clinical studies, and strong indications in the human HIV and retrospective cancer trials. Add to this Dr Fourqurean’s idea about treating the patient and not the disease via CCR5 inhibition, and you get the general observation among users that people feel better on leronlimab because it reduces inflammation. Specifically, in regards to colorectal cancer—which is often driven by IBD and colitis—leronlimab will likely help the general health of the gut, and the immune system’s response to cancers of the gut. The permeability of an inflamed gut and how that will affect metastasis is probably the big question. Will a 350mg dose be enough to make a difference?
From memory, I recall that the 350mg dose occupies 44% of available receptors. That dose was used in CD02, the Optimize Phase2b/3 trial back in the day that proved leronlimab’s utility as salvage therapy for those with Multidrug-Resisstant HIV. The trial parameters seem odd—one dose of 350mg leronlimab on top of the failing ART regimen, followed by a 24 week extension at 350 or 700mg doses. The primary end point was achieving ≥0.5 log 10 reduction in plasma HIV-1 RNA from baseline at the end of the 1-week double-blinded treatment period. The numbers weren’t outstanding—by per protocol analysis, 72% of patients on the 350mg dose achieved a >0.5 log reduction in plasma HIV RNA vs 24% on placebo. The abstract I read didn’t break down the 24 week extension by dose, unfortunately, but did conclude:
“Leronlimab resulted in significantly reduced plasma HIV-1 within 1 week after addition to failing antiretroviral therapy. After 24 weeks combined with an optimized background treatment, most participants had plasma HIV-1 RNA levels <50 copies per milliliter plasma, suggesting utility of leronlimab as a component of salvage therapy.” (https://pubmed.ncbi.nlm.nih.gov/39972543/)
The point here is—clearly measurable efficacy at the 350mg dose. In HIV patients. In TNBC we also have two out of four patients (who had follow-up scans to evaluate) that received 350mg of leronlimab increased their PDL-1 numbers significantly, with one out of four reaching the 400 threshold for ICI use. So we are likely to see some PDL-1 responders in the 350mg dose cohort… like, maybe one-third to one-half? And in the recent abstract on the Clover trial we have 3 out of 5 patients increasing PDL-1 but no information on what dose or the amount of increase. And at the City of Hope site we have 4 of 4 with decreases in CEA, CA19-9 and/or ctDNA after one week, the latter which correlates to improved survival in the previous clinical studies. My assumption is that most of those patients were dosed at 350mg (given the first five were all given that dose, and subsequent to that, “approximately 15 patients will be randomized 1:2 on 350mg and 700mg arms respectively in order to achieve an overall 1:1 treatment assignment…” (from the recent mCRC poster). That would be 7 out of the first 10 or 11 dosed at 350mg… with talk of good results in those first patients.
The other clinical benefit the 350mg dose might have in the trial is additive effects or synergy with avastin in terms of limiting angiogenesis. This will help limit the growth or even reduce existing tumors… and it could certainly help with controlling metastasis.
I’m tempted to roll out some of the 350mg numbers from the MASH trial… but I’ll spare everyone the confusion. However, the preclinical work in MASH did emphasize a reduction in fibrosis--in the liver and other organs--with leronlimab, and increasing fibrosis seems to be one of the ways in which cancer hides away from the immune system. One additional bit of theory to add to the mix—apparently, macrophages have memories, mediated by IFN-y signaling. We all know leronlimab increases IFN-y… so check this out:
“For their study, the researchers exposed cultured macrophages to IFNγ and then studied epigenetic changes in the cells’ genomes. They recorded thousands of shifts in immune-boosting enhancers that lasted for days after exposure. These shifts were only sustained because of continued signaling from minuscule amounts of IFNγ that remained attached to the macrophages.”
“Minuscule amounts of IFN-y.” Enough from a shot or two of leronlimab at the 350mg dose? Who can say? The authors of the study suggest their insights might be relevant to autoimmune diseases (ie, stop the signaling to suppress over-active immune memory) but I think it might be another MOA for leronlimab’s effects on cancer. More from the article:
“Recent studies of macrophages have shown that their memories rely on a cytokine signaling molecule called interferon gamma (IFNγ). When the immune system encounters a threat for the first time, IFNγ induces changes in macrophages’ DNA, exposing enhancer domains that pump up gene expression. The newly bolstered genes explain how the immune system can respond faster and more forcefully when it next encounters the threat. But researchers didn’t fully understand how the macrophages maintained this memory for so long after their exposure to IFNγ."
"Our new findings suggest that these changes in macrophages are actually readily reversible and do not inherently encode immune memory,” said University of California, Los Angeles (UCLA) microbiologist and study co-author Alexander Hoffman in a statement. “Instead, the cells are dependent on ongoing signaling from interferon gamma sequestered at or near the macrophage cell surface.”
https://www.the-scientist.com/lingering-immun...mory-74092
So, for all of the above reasons, I’m going to speculate that the 350mg dose is going to have a clinically-relevant effect on patients in the Clover trial. Will it obviate the need for an ICI at some point? No—except for a lucky few… perhaps. What it will likely do is keep people from progressing early on… I’m anticipating some stable disease in the 350mg cohort; perhaps with the avastin/leronlimab double-whammy on angiogenesis we will get some tumor shrinkage enough for some partial responses. The question is—will the 350mg dose be enough to tip the scales towards a 30% reduction in tumor size? Or enough to prevent a 30% increase in tumor size? The answer is… Probably not for the first question, and likely enough for the second. I do not think we will get many patients progressing and eligible for an ICI early on in the trial. Perhaps I’m wrong—MSS colorectal cancer is a bastard—but if some were hoping for a quick demonstration of what can happen when leronlimab is paired with an ICI… well, I think we will have to wait for that. But compared to a 350mg dose, the 700mg dose ought to do quite a bit better as far as tumor shrinkage and partial responses, along with a big boost in PDL-1 numbers. If the numbers are good—will Big Pharma bite? Will the FDA reward us with a BTD? And—will good but not dramatic numbers keep the shorts at bay? Those questions--who can say? I've got enough time to wait a few more months for mature data—and some ICI action! Coming soon... but probably not April.
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