My suspicion that the 350mg dose of leronlimab would “outperform expectations” in the initial look at data in the mCRC Clover trial was based on results from earlier clinical trials of leronlimab in MultiDrugResistant HIV (CD02 and CD03). In those trials the 350mg dose was used extensively, with significant biological activity. Writing about CD02 and CD03 in a paper entitled “Antibody-based strategies in HIV therapy” by Kufel (2020) we find: “After a single 5 mg/kg IV dose (350mg for a 70-kg patient), CCR5 receptor coating was observed for >60 days. More than 85% of receptor occupancy was observed through day 29 at 5 and 10 mg/kg…” Even though the 350mg dose is sub-optimal, I thought it might be worth speculating upon what this dose might do in a) the specific indication of mCRC, and b) combined with the specific anti-cancer agents Avastin and Lonsurf. And behind these specific speculations lies Geoffrey Fourqurean’s insight that CCR5 inhibition helps treat the whole person/whole patient by helping to resolve chronic inflammation, which in the gut seems to drive CRC (the IBD connection). And you can add leronlimab’s salutary effects on liver health and metastatic burden to this line of thought as well.
I am NOT implying the 350mg dose of leronlimab will outperform the 700mg dose over the course of the trial. No way--I'm not stupid. But will that 85% receptor occupancy add any clinical benefit in mCRC? In the CD03 study, which tested the three doses we are familiar with, Kufel observes that “More than 90% of subjects who received 700mg achieved viral suppression without any increased safety risk for up to 12 weeks, compared with 71% and 44% with 525mg and 350mg, respectively.” So we have biological/molecular effects, and clinical benefit, in HIV with the 350mg dose. Will that dose translate to mCRC... Will it provide a 44% increase in clinical benefit, or something comparable?
The initial reductions in ctDNA from the Kasi poster are substantial and impressive. And if Ken Chowder is right, all of those patients were on 350mg. My question would be—are these numbers going to be durable? Are the gains going to last? A decline in ctDNA is supposed to be predictive of longer PFS and OS… but is that going to be true for the 350mg dose? No data yet… but I’m going to speculate that this is where the 700mg dose should start to separate itself from the lesser dose. And of course the PDL-1 numbers should also be much better with 700mg. Just a feeling here… but I’m going to say we are going to get a lot of stable disease with the 350mg dose... for a while, anyway. Maybe some partial responses. Which suggests that in the year-long duration of the trial… not a lot of the patients will progress, so we won’t get to see many examples of leronlimab and an ICI in action. More likely with patients who continue on the drug beyond the trial's end date. And we will see extensive use of the leronlimab/ICI combo—with optimal dosage—in the TNBC EAP.
I am thinking the 350mg dose of leronlimab might boost the anti-angiogenic effect of avastin quite a bit... which could explain the excellent reduction in ctDNA numbers. Avastin seems to work quickly on its own… I asked AI if avastin would work rapidly to reduce ctDNA, and how that reduction might play out. She said “Evidence suggests bevacizumab can begin to affect tumor vascularity within 24 hours to a few days, but significant reductions in circulating tumor DNA (ctDNA) or radiographic tumor shrinkage are usually observed in the 4-to-8 week range rather than within the first two weeks.” And later, “6-8 weeks… is the typical time frame to see a decrease in ctDNA for patients responding to treatment.” Will 85% receptor occupancy of CCR5 add something to that? Something is reducing that ctDNA, and historically speaking, it sure ain't Avastin or Lonsurf. Some kind of synergy at work… or perhaps just an additive effect? That would be my rank speculation at this point… but considering the 350mg dose shouldn’t really be preforming as well as it seems to be, rank speculation is in order.
In the third-line setting, the rational for both Lonsurf and Avastin seem to be cancer-management rather than curative intent. AI suggests “In third line mCRC, partial responses to Avastin combined with chemo are considered uncommon, while complete responses are rare. Instead of tumor shrinkage, Avastin’s primary role in late line treatment is to achieve stable disease and prolong progression-free survival (tumor control).” So ORR is an excellent primary endpoint for the trial; not only is it low-hanging fruit, but any tumor shrinkage and leronlimab should unquestionably get credit for it. And tumor shrinkage should result in clinical benefit to patients. Like better PFS and OS numbers. The excellent ctDNA data from the initial results makes me hope for some great ORR numbers… Like 3 out of 5, anybody?
Let me re-emphasize that I see a lot of stable disease in the 350mg cohort, and a significant number of partial responses in the 700mg cohort. Which likely means we are probably not going to see a lot of progression within the trial’s one year timeframe… which means not a lot of people getting an ICI and saved in the kind of dramatic fashion that gets investors excited. Maybe some, but who knows? And as yet we hear nothing of the DSMB moving people from 350 to 700mg, or PDL-1 numbers rising to the point where an ICI is mandated. But of course it is early. As noted, the EAP program in TNBC should give us plenty of drama… of the feel-good, lifesaving kind. And soon! Meanwhile, the huge amount of data from the mCRC trial will give the oncology community plenty of data and insight into how to use leronlimab in real-life settings. No wonder Kasi is gushing about Clover. The irony of this trial might be that at half the optimal dose we could have the numbers to beat the SOC and get approved! Probably won't happen... But with leronlimab crazier things have.
One final thought—if there is some kind of synergy between avastin and leronlimab… perhaps that puts Roche more in play as a potential partner. If they are not already, since clearly leronlimab works with Tecentriq and seems to reduce it's side effects. Avastin is part of the SOC for many cancers... so there is a solid rationale there. Just add 700mg of leronlimab to the SOC... while spending most of your research budget on testing combinations with leronlimab, Tecentriq and/or a safer ICI. Hey, I’m still in the For God's Sake Anybody But Merck Or Gilead Camp--but that’s just me.
Kufel article (Antibody-based strategies in HIV therapy)
https://pmc.ncbi.nlm.nih.gov/articles/PMC7546180/
Chen (A pilot study to determine the timing and effect of bevacizumab on vascular normalization of metastatic brain tumors in breast cancer)
https://pmc.ncbi.nlm.nih.gov/articles/PMC4944505/#Abs1
I am NOT implying the 350mg dose of leronlimab will outperform the 700mg dose over the course of the trial. No way--I'm not stupid. But will that 85% receptor occupancy add any clinical benefit in mCRC? In the CD03 study, which tested the three doses we are familiar with, Kufel observes that “More than 90% of subjects who received 700mg achieved viral suppression without any increased safety risk for up to 12 weeks, compared with 71% and 44% with 525mg and 350mg, respectively.” So we have biological/molecular effects, and clinical benefit, in HIV with the 350mg dose. Will that dose translate to mCRC... Will it provide a 44% increase in clinical benefit, or something comparable?
The initial reductions in ctDNA from the Kasi poster are substantial and impressive. And if Ken Chowder is right, all of those patients were on 350mg. My question would be—are these numbers going to be durable? Are the gains going to last? A decline in ctDNA is supposed to be predictive of longer PFS and OS… but is that going to be true for the 350mg dose? No data yet… but I’m going to speculate that this is where the 700mg dose should start to separate itself from the lesser dose. And of course the PDL-1 numbers should also be much better with 700mg. Just a feeling here… but I’m going to say we are going to get a lot of stable disease with the 350mg dose... for a while, anyway. Maybe some partial responses. Which suggests that in the year-long duration of the trial… not a lot of the patients will progress, so we won’t get to see many examples of leronlimab and an ICI in action. More likely with patients who continue on the drug beyond the trial's end date. And we will see extensive use of the leronlimab/ICI combo—with optimal dosage—in the TNBC EAP.
I am thinking the 350mg dose of leronlimab might boost the anti-angiogenic effect of avastin quite a bit... which could explain the excellent reduction in ctDNA numbers. Avastin seems to work quickly on its own… I asked AI if avastin would work rapidly to reduce ctDNA, and how that reduction might play out. She said “Evidence suggests bevacizumab can begin to affect tumor vascularity within 24 hours to a few days, but significant reductions in circulating tumor DNA (ctDNA) or radiographic tumor shrinkage are usually observed in the 4-to-8 week range rather than within the first two weeks.” And later, “6-8 weeks… is the typical time frame to see a decrease in ctDNA for patients responding to treatment.” Will 85% receptor occupancy of CCR5 add something to that? Something is reducing that ctDNA, and historically speaking, it sure ain't Avastin or Lonsurf. Some kind of synergy at work… or perhaps just an additive effect? That would be my rank speculation at this point… but considering the 350mg dose shouldn’t really be preforming as well as it seems to be, rank speculation is in order.
In the third-line setting, the rational for both Lonsurf and Avastin seem to be cancer-management rather than curative intent. AI suggests “In third line mCRC, partial responses to Avastin combined with chemo are considered uncommon, while complete responses are rare. Instead of tumor shrinkage, Avastin’s primary role in late line treatment is to achieve stable disease and prolong progression-free survival (tumor control).” So ORR is an excellent primary endpoint for the trial; not only is it low-hanging fruit, but any tumor shrinkage and leronlimab should unquestionably get credit for it. And tumor shrinkage should result in clinical benefit to patients. Like better PFS and OS numbers. The excellent ctDNA data from the initial results makes me hope for some great ORR numbers… Like 3 out of 5, anybody?
Let me re-emphasize that I see a lot of stable disease in the 350mg cohort, and a significant number of partial responses in the 700mg cohort. Which likely means we are probably not going to see a lot of progression within the trial’s one year timeframe… which means not a lot of people getting an ICI and saved in the kind of dramatic fashion that gets investors excited. Maybe some, but who knows? And as yet we hear nothing of the DSMB moving people from 350 to 700mg, or PDL-1 numbers rising to the point where an ICI is mandated. But of course it is early. As noted, the EAP program in TNBC should give us plenty of drama… of the feel-good, lifesaving kind. And soon! Meanwhile, the huge amount of data from the mCRC trial will give the oncology community plenty of data and insight into how to use leronlimab in real-life settings. No wonder Kasi is gushing about Clover. The irony of this trial might be that at half the optimal dose we could have the numbers to beat the SOC and get approved! Probably won't happen... But with leronlimab crazier things have.
One final thought—if there is some kind of synergy between avastin and leronlimab… perhaps that puts Roche more in play as a potential partner. If they are not already, since clearly leronlimab works with Tecentriq and seems to reduce it's side effects. Avastin is part of the SOC for many cancers... so there is a solid rationale there. Just add 700mg of leronlimab to the SOC... while spending most of your research budget on testing combinations with leronlimab, Tecentriq and/or a safer ICI. Hey, I’m still in the For God's Sake Anybody But Merck Or Gilead Camp--but that’s just me.
Kufel article (Antibody-based strategies in HIV therapy)
https://pmc.ncbi.nlm.nih.gov/articles/PMC7546180/
Chen (A pilot study to determine the timing and effect of bevacizumab on vascular normalization of metastatic brain tumors in breast cancer)
https://pmc.ncbi.nlm.nih.gov/articles/PMC4944505/#Abs1
33
