The utility of the 350mg dose of leronlimab in the Clover trial is great news for patients getting that dose in the trials… But it does fly in the face of the general understanding that 700mg provides full receptor occupancy and is the superior dose. Part of the reason that the smaller dose is effective—especially early on—is clearly the synergy with Avastin and Lonsurf. And in the April AARC poster we learn that at least one of the patients was 71 pounds, which means that pound for pound, the one getting the 350mg dose is receiving the equivalent of a higher dose/more receptor saturation than heavier patients (and the mean weight of participants in the trial is something on the order of 156 lbs, so there are likely some smallish patients in the trial). So these factors may explain individual responses to the lower dose… But they probably don’t explain the class effect we are seeing unfold before our eyes.
This kind of apparent inconsistency bothers me… And with so much at stake, it keeps me up at night. But in the literature, there are two other examples of leronlimab’s efficacy at the smaller dose. That would be in the MASH trial, where the 350mg dose reduced liver fat significantly. And in the early HIV studies, where that dosage was used frequently and successfully. So what gives?
I’ve been reading up on some of the earlier HIV studies, and came across on the Chang article from 2022, where I think we find the answer. The paper dived deeply into “the virological and immunological consequences of leronlimab” in both humans and rhesus macaques, and most importantly for this discussion, in both doses. It’s right there in plain sight in the abstract; couched in the language of science, but right there. And a lot of us apparently missed it.
Here’s the relevant quote: “All five human participants transitioned from daily combination ART to self-administered weekly subcutaneous (SC) injections of 350mg or 700mg Leronlimab and to date all participants have sustained virologic suppression for over seven years. In all participants, Leronlimab fully occupied CCR5 receptors on peripheral blood CD4+ T cells and monocytes.” “Peripheral blood” was the phrase that tripped me up; I didn’t get that what they were talking about was—basically—receptor occupancy in the bloodstream. If you re-phrase it slightly you get “Leronlimab fully occupied CCR5 receptors on CD4+ T cells and monocytes in the bloodstream.” That makes more sense to my non-medical mind. And it tells me that the 350mg dose works just fine in the bloodstream… even if it doesn’t have the oomph to penetrate tumors or CCR5-saturated organs like the liver. Or ferret out HIV reservoirs in places like lymph nodes, for that matter. So Cytodyn appropriately started to utilize the higher doses—including 525mg—in various studies. And the rest is going to be in the history books!
If this is true… what are the implications? I’d like some of the finer scientific minds of the board to weigh in on this, but it is my sense that the 350mg dose is good at stopping the recruitment of new CCR5+ immune cells to the CCL5 party, wherever that is. In other words it can stop immune cell trafficking, because the immune system relies on the circulatory system to get around. I’d say in HIV, MASH, and CRC, the lower dose turns out to be pretty good at stopping immune cells from gravitating towards and piling on whatever organ (or tumor) is the medical target. And if the vascular system is the target—think atherosclerosis—the 350mg dose should be very effective. Think stroke or TBI recovery! And hematological cancers? So many diseases haven’t been studied with leronlimab… so we are learning this shit on the fly and figuring it out as we go. But this is clearly just the start of something huge…
This train of thought might very well answer the questions that came up from the MASH trial. I put that question to AI… But that response is probably better served by another post. I’d like to finish up with a few thoughts on what this might mean for the 350mg cohort in the Clover trial. Simply put, I would expect a great deal of stable disease, along with some partial and complete responses, and an exemplary Disease Control Rate. 80s or 90s maybe? The reality is the 350mg dose can’t storm the CRC tumor’s shield like the 700mg dose can, and apparently it can’t get deep into the liver. But it can stop/control metastasis, because metastasis relies on the vascular system to get around. And the MASH trial told us leronlimab reduces liver fat, which is very helpful in CRC. But who knows—Lalezari’s comment about it’s unclear whether the higher dose will catch up or outperform the lower dose… well, that still blows my mind. We are learning this shit on the fly and figuring it out as we go.
The synergy of leronlimab with Bev and Taz in CRC seems like it is really off the charts. That’s what the ctDNA numbers tell us. What is crazy is, if we get an ORR that triples the SOC, and get a DCR in the 80s, with some kind of long survivor tail—to be determined later—leronlimab could very well be approved based on the 350mg cohort all by itself! I suspect the 700mg cohort will do better, which means a superior ORR and some Complete Responses in the mix… we will know soon enough. But the implication here is MSS CRC changing from a death sentence to some kind of chronic but manageable disease. And we haven’t even started to talk about the increase in PD-L1 and the addition of an ICI to the mix, which clearly is the province of the 700mg dose.
Look, I could be wrong here. But thinking about the effectiveness of leronlimab based solely on full occupancy at 700mg misses an important part of the picture. And that would be the implications of full occupancy of CCR5+ immune cells in the bloodstream with the 350mg dose. Clearly there are salutary effects with the 350mg dose in CRC as we are seeing in the Clover trial. But that dose could do wonders for atherosclerosis and cardiovascular/heart disease. Can’t wait to see that… though Cytodyn is pretty busy with solid tumors right now… As they should be.
https://pubmed.ncbi.nlm.nih.gov/35358290/
(Chang abstract, 2022)
This kind of apparent inconsistency bothers me… And with so much at stake, it keeps me up at night. But in the literature, there are two other examples of leronlimab’s efficacy at the smaller dose. That would be in the MASH trial, where the 350mg dose reduced liver fat significantly. And in the early HIV studies, where that dosage was used frequently and successfully. So what gives?
I’ve been reading up on some of the earlier HIV studies, and came across on the Chang article from 2022, where I think we find the answer. The paper dived deeply into “the virological and immunological consequences of leronlimab” in both humans and rhesus macaques, and most importantly for this discussion, in both doses. It’s right there in plain sight in the abstract; couched in the language of science, but right there. And a lot of us apparently missed it.
Here’s the relevant quote: “All five human participants transitioned from daily combination ART to self-administered weekly subcutaneous (SC) injections of 350mg or 700mg Leronlimab and to date all participants have sustained virologic suppression for over seven years. In all participants, Leronlimab fully occupied CCR5 receptors on peripheral blood CD4+ T cells and monocytes.” “Peripheral blood” was the phrase that tripped me up; I didn’t get that what they were talking about was—basically—receptor occupancy in the bloodstream. If you re-phrase it slightly you get “Leronlimab fully occupied CCR5 receptors on CD4+ T cells and monocytes in the bloodstream.” That makes more sense to my non-medical mind. And it tells me that the 350mg dose works just fine in the bloodstream… even if it doesn’t have the oomph to penetrate tumors or CCR5-saturated organs like the liver. Or ferret out HIV reservoirs in places like lymph nodes, for that matter. So Cytodyn appropriately started to utilize the higher doses—including 525mg—in various studies. And the rest is going to be in the history books!
If this is true… what are the implications? I’d like some of the finer scientific minds of the board to weigh in on this, but it is my sense that the 350mg dose is good at stopping the recruitment of new CCR5+ immune cells to the CCL5 party, wherever that is. In other words it can stop immune cell trafficking, because the immune system relies on the circulatory system to get around. I’d say in HIV, MASH, and CRC, the lower dose turns out to be pretty good at stopping immune cells from gravitating towards and piling on whatever organ (or tumor) is the medical target. And if the vascular system is the target—think atherosclerosis—the 350mg dose should be very effective. Think stroke or TBI recovery! And hematological cancers? So many diseases haven’t been studied with leronlimab… so we are learning this shit on the fly and figuring it out as we go. But this is clearly just the start of something huge…
This train of thought might very well answer the questions that came up from the MASH trial. I put that question to AI… But that response is probably better served by another post. I’d like to finish up with a few thoughts on what this might mean for the 350mg cohort in the Clover trial. Simply put, I would expect a great deal of stable disease, along with some partial and complete responses, and an exemplary Disease Control Rate. 80s or 90s maybe? The reality is the 350mg dose can’t storm the CRC tumor’s shield like the 700mg dose can, and apparently it can’t get deep into the liver. But it can stop/control metastasis, because metastasis relies on the vascular system to get around. And the MASH trial told us leronlimab reduces liver fat, which is very helpful in CRC. But who knows—Lalezari’s comment about it’s unclear whether the higher dose will catch up or outperform the lower dose… well, that still blows my mind. We are learning this shit on the fly and figuring it out as we go.
The synergy of leronlimab with Bev and Taz in CRC seems like it is really off the charts. That’s what the ctDNA numbers tell us. What is crazy is, if we get an ORR that triples the SOC, and get a DCR in the 80s, with some kind of long survivor tail—to be determined later—leronlimab could very well be approved based on the 350mg cohort all by itself! I suspect the 700mg cohort will do better, which means a superior ORR and some Complete Responses in the mix… we will know soon enough. But the implication here is MSS CRC changing from a death sentence to some kind of chronic but manageable disease. And we haven’t even started to talk about the increase in PD-L1 and the addition of an ICI to the mix, which clearly is the province of the 700mg dose.
Look, I could be wrong here. But thinking about the effectiveness of leronlimab based solely on full occupancy at 700mg misses an important part of the picture. And that would be the implications of full occupancy of CCR5+ immune cells in the bloodstream with the 350mg dose. Clearly there are salutary effects with the 350mg dose in CRC as we are seeing in the Clover trial. But that dose could do wonders for atherosclerosis and cardiovascular/heart disease. Can’t wait to see that… though Cytodyn is pretty busy with solid tumors right now… As they should be.
https://pubmed.ncbi.nlm.nih.gov/35358290/
(Chang abstract, 2022)
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