Hypothesis & Questions in NASH trials. What is
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Posted On: 06/12/2022 9:30:16 AM
Hypothesis & Questions in NASH trials.
What is CLEARLY evident from the data is how well the 700mg LL did in improving the PDFF in the high CCR5 haplotype subgroup. PDFF was -27.88% In patients with increased CCR5, LL had the BEST efficacy in removing steatosis and liver fat, than in all other groups which had the typical CCR5 receptor distribution.
Could it be that in the haplotypes, the increased numbers of CCR5 receptors gives LL exactly what is necessary to overcome the dampening effects due to an increased fat presence?
It is understood, that in a patient with a high baseline cT1, say > 950 msec, a high concentration of scar tissue is present. In such a patient, the fibrosis is dense and therefore, the ratio of fat/fibrosis is lower than average. In patients whose baseline cT1 > 950, 350mg LL works very well in reducing fibrosis, (scar tissue).
When baseline cT1 is low, say < 800, then there will not be any scar tissue to even remove and the only thing measurable would be steatosis (fat). The ratio of fat/fibrosis would be much higher than normal and Leronlimab efficacy may be hindered with the excessive fat presence.
From looking at the data, it appears that in NAFLD and mild NASH, where the proportion of fat to fibrosis is above average, leronlimab's efficacy in removing scar tissue not as Robust as it is when the proportion of fat to fibrosis is less than average. Could fat impede leronlimab's efficacy?
In Moderate to Severe NASH, where the proportion of fat to fibrosis is lower than average, that is, where scar tissue and fibrotic density is increased, leronlimab's efficacy in removing scar tissue is enhanced.
We saw from the data that in the patients with baseline >950 msec, the NASH highly fibrotic patients, that leronlimab lowered their cT1 by 68 msec or nearly 2 stages of NAS with 14 weeks of treatment. In those same patients, leronlimab lowered their PDFF by 9.27%, which by itself, only lowers NAS by 1 stage in the same 14 weeks. There fore, when the ratio of fat/fibrosis is lower than average, 350mg leronlimab efficacy in removing scar tissue is twice as fast as it's efficacy to remove fat.
In patients with baseline >875 msec, with 350mg leronlimab dosing, the rate of fibrosis loss was -42 msec per 14 weeks while the rate of fat loss was -4.38% per 14 weeks. In this Moderate to Severe NAFLD group, the cT1 loss of -42 represents only 1 NAS stage improvement and the PDFF loss of -4.38% represents 1/2 NAS stage improvement. Here the ratio of fat/fibrosis approaches the average across all patients in the trial and leronlimab's overall efficacy in removing scar tissue is cut in half from its efficacy in the NASH patients where the ratio of fat/fibrosis is low, where scar tissue is high.
We saw that doubling the dose of leronlimab to 700mg did not double the results. We did see that the haplotype with increased CCR5 expression had significant steatosis reduction. Seems to me that with the increased quantity f LL, all the CCR5 receptors become saturated with LL and even additional quantities of LL do not benefit. With 350mg dosing, some of the CCR5 receptors may be left unbound. Testing the haplotype group, the number of CCR5 receptors increased, and the 700mg LL occupied them and the consequence was a significant tripling of the quantity of PDFF steatosis removed in the 14 weeks LL was given. In addition, in that same subgroup, cT1 was -45.4 msec which represents the loss of 1 NAS stage.
Possibly, it may not be the best to fully saturate CCR5 in NAFLD/NASH?
How well would 350mg LL of worked in the increased CCR5 haplotype had it been given in that subgroup?
Why was the increased CCR5 expression and therefore increase LL binding to CCR5 so effective in reducing PDFF and cT1 in that haplotype subgroup, especially in the 700mg dosing?
What would have happened had 350mg been dosed instead?
What is CLEARLY evident from the data is how well the 700mg LL did in improving the PDFF in the high CCR5 haplotype subgroup. PDFF was -27.88% In patients with increased CCR5, LL had the BEST efficacy in removing steatosis and liver fat, than in all other groups which had the typical CCR5 receptor distribution.
Could it be that in the haplotypes, the increased numbers of CCR5 receptors gives LL exactly what is necessary to overcome the dampening effects due to an increased fat presence?
It is understood, that in a patient with a high baseline cT1, say > 950 msec, a high concentration of scar tissue is present. In such a patient, the fibrosis is dense and therefore, the ratio of fat/fibrosis is lower than average. In patients whose baseline cT1 > 950, 350mg LL works very well in reducing fibrosis, (scar tissue).
When baseline cT1 is low, say < 800, then there will not be any scar tissue to even remove and the only thing measurable would be steatosis (fat). The ratio of fat/fibrosis would be much higher than normal and Leronlimab efficacy may be hindered with the excessive fat presence.
From looking at the data, it appears that in NAFLD and mild NASH, where the proportion of fat to fibrosis is above average, leronlimab's efficacy in removing scar tissue not as Robust as it is when the proportion of fat to fibrosis is less than average. Could fat impede leronlimab's efficacy?
In Moderate to Severe NASH, where the proportion of fat to fibrosis is lower than average, that is, where scar tissue and fibrotic density is increased, leronlimab's efficacy in removing scar tissue is enhanced.
We saw from the data that in the patients with baseline >950 msec, the NASH highly fibrotic patients, that leronlimab lowered their cT1 by 68 msec or nearly 2 stages of NAS with 14 weeks of treatment. In those same patients, leronlimab lowered their PDFF by 9.27%, which by itself, only lowers NAS by 1 stage in the same 14 weeks. There fore, when the ratio of fat/fibrosis is lower than average, 350mg leronlimab efficacy in removing scar tissue is twice as fast as it's efficacy to remove fat.
In patients with baseline >875 msec, with 350mg leronlimab dosing, the rate of fibrosis loss was -42 msec per 14 weeks while the rate of fat loss was -4.38% per 14 weeks. In this Moderate to Severe NAFLD group, the cT1 loss of -42 represents only 1 NAS stage improvement and the PDFF loss of -4.38% represents 1/2 NAS stage improvement. Here the ratio of fat/fibrosis approaches the average across all patients in the trial and leronlimab's overall efficacy in removing scar tissue is cut in half from its efficacy in the NASH patients where the ratio of fat/fibrosis is low, where scar tissue is high.
We saw that doubling the dose of leronlimab to 700mg did not double the results. We did see that the haplotype with increased CCR5 expression had significant steatosis reduction. Seems to me that with the increased quantity f LL, all the CCR5 receptors become saturated with LL and even additional quantities of LL do not benefit. With 350mg dosing, some of the CCR5 receptors may be left unbound. Testing the haplotype group, the number of CCR5 receptors increased, and the 700mg LL occupied them and the consequence was a significant tripling of the quantity of PDFF steatosis removed in the 14 weeks LL was given. In addition, in that same subgroup, cT1 was -45.4 msec which represents the loss of 1 NAS stage.
Possibly, it may not be the best to fully saturate CCR5 in NAFLD/NASH?
How well would 350mg LL of worked in the increased CCR5 haplotype had it been given in that subgroup?
Why was the increased CCR5 expression and therefore increase LL binding to CCR5 so effective in reducing PDFF and cT1 in that haplotype subgroup, especially in the 700mg dosing?
What would have happened had 350mg been dosed instead?
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