Sean, the honest answer to your question is: we don't know the body weight of the fourth patient who achieved complete ctDNA clearance in the 700mg cohort, and no published document discloses individual patient data from the CLOVER population. The suggestion that body size explains why three of four complete ctDNA clearances came from the 350mg cohort rather than the 700mg cohort was a plausible pharmacokinetic hypothesis, not a documented finding. You are right to challenge it.
Here is what the published protocol actually tells us about how dosing is determined in CLOVER. Patients are randomized one to one to receive either 350mg or 700mg of leronlimab weekly. The dose assignment is random, not weight-based. A smaller patient does not automatically receive 350mg and a larger patient does not automatically receive 700mg. The randomization means the two cohorts should be roughly balanced in body weight distribution across 33 patients each, assuming the randomization worked as designed.
Jake's friend's intuition about body size is pharmacokinetically sound as a general principle for monoclonal antibodies. Larger patients have greater volume of distribution, higher total receptor burden, and larger hepatic sink capacity, all of which reduce the effective drug concentration per unit of CCR5 receptor surface area at a fixed dose.
The compassionate use protocol document confirms that leronlimab is not metabolized by the liver and not filtered by the kidneys, meaning its pharmacokinetics are governed primarily by receptor-mediated clearance and volume of distribution, both of which are influenced by body composition.
So the hypothesis that a smaller patient achieves more complete functional receptor saturation at 350mg than a larger patient would at the same dose is biologically reasonable.
But biologically reasonable and documented are different categories. The three-of-four ctDNA clearance distribution between dose cohorts is a small number observation from an open-label trial that could reflect body size, metastatic burden differences between randomly assigned patients, tumor biology heterogeneity, the CCR5 clustering and endocytosis mechanism operating more efficiently in patients with lower total receptor burden, or simply the normal variation expected in a 66-patient randomized trial. Without individual patient weight and hepatic metastatic burden data, no single explanation can be confirmed as the primary driver.
The billboard referenced is presumably well within the dunce section's visual range, and the message on it appears to be correct. Size matters in pharmacokinetics. Whether it explains this specific observation in CLOVER specifically requires data we do not currently have access to from outside the trial.
The dunce section continues to ask better questions than it gives itself credit for.
Here is what the published protocol actually tells us about how dosing is determined in CLOVER. Patients are randomized one to one to receive either 350mg or 700mg of leronlimab weekly. The dose assignment is random, not weight-based. A smaller patient does not automatically receive 350mg and a larger patient does not automatically receive 700mg. The randomization means the two cohorts should be roughly balanced in body weight distribution across 33 patients each, assuming the randomization worked as designed.
Jake's friend's intuition about body size is pharmacokinetically sound as a general principle for monoclonal antibodies. Larger patients have greater volume of distribution, higher total receptor burden, and larger hepatic sink capacity, all of which reduce the effective drug concentration per unit of CCR5 receptor surface area at a fixed dose.
The compassionate use protocol document confirms that leronlimab is not metabolized by the liver and not filtered by the kidneys, meaning its pharmacokinetics are governed primarily by receptor-mediated clearance and volume of distribution, both of which are influenced by body composition.
So the hypothesis that a smaller patient achieves more complete functional receptor saturation at 350mg than a larger patient would at the same dose is biologically reasonable.
But biologically reasonable and documented are different categories. The three-of-four ctDNA clearance distribution between dose cohorts is a small number observation from an open-label trial that could reflect body size, metastatic burden differences between randomly assigned patients, tumor biology heterogeneity, the CCR5 clustering and endocytosis mechanism operating more efficiently in patients with lower total receptor burden, or simply the normal variation expected in a 66-patient randomized trial. Without individual patient weight and hepatic metastatic burden data, no single explanation can be confirmed as the primary driver.
The billboard referenced is presumably well within the dunce section's visual range, and the message on it appears to be correct. Size matters in pharmacokinetics. Whether it explains this specific observation in CLOVER specifically requires data we do not currently have access to from outside the trial.
The dunce section continues to ask better questions than it gives itself credit for.
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