Yes ohm, completely agree that the disease is comp

Yes ohm, completely agree that the disease is complex. But my thinking was to simplify the administration of the medication as much as possible.

As the original trial was designed, 14 weeks long, I stuck with it. It was effective in some patients and possibly, many of the patients treated needed no further treatment after those 14 weeks concluded. But how would the physician know to take those patients off the medication?

Obtaining cT1 and PDFF MRI is expensive and to do that every 14 weeks of treatment is asking too much. Basing it off all biomarkers would be way too confusing for the average physician, so would a formula be necessary? Way too complicated.

My thinking was to consider exactly what Madrigal does. They of course just carry out their treatment unchecked for a year. I'm not a believer in that sort of treatment. I definitely prefer feedback confirming that the medication is working, especially if taking it for a year. Therefore the 14-week interval of checking seemed good with me. Treat for 14 weeks and then check.

But what to check. So, I looked at the heat map . Knowing what I know about the trial, that in general both the 350mg and 700mg HM treated groups were successful while the 700mg normal and Placebo groups were unsuccessful.

Taking that as more or less the gist of the trial, I looked back at the heat map. I wanted to see in which biomarkers were all the colors the same for the 350mg and 700mg HM and opposite those colors for both the 700mg normal and Placebo.

Well it only happens in T4, Thyroxine Free and only less so in Potassium. This is telling me that leronlimab is functioning well in these patients while both T4 and Potassium are elevated from baseline and not functioning when T4 is decreased or unchanged.

In the 700mg and Placebo, where the trial failed, we can assume leronlimab failed in those patients and what did T4 show? That it slightly decreased. So, when leronlimab was not functioning, T4 might be unchanged or even decreased from baseline. And why would T4 not be functioning in those 700mg treated patients? Because most of them likely had mild disease as I described Interpretation of NASH Prior to Liver Conference .
With the black coloring in the Placebo T4, that means no treatment is equivalent to no change in T4 even with worsening disease (in Placebo).

Potentially, an opposite marker to T4 could also be used. That is Tumor Necrosis Factor Receptor 2 where it is green (decreased) in all of 350mg and 700mg HM but red (increased) or black (unchanged) in 700mg normal and Placebo.

"In the 350mg treated group, Tumor Necrosis Factor Receptor 2 was reduced. TNFR2 plays a significant role in tumor cell growth as it has been found that the loss of TNFR2 expression is linked with increased death of associated tumor cells and a significant standstill of further tumor growth."

TNFR2

So, if this biomarker was chosen, physicians could measure it to see that when it is no longer decreased from baseline, then leronlimab is no longer functional.

Potassium sort of fits here, except for the dark in the 350mg column. I don't really understand the 350mg column anyway. Does it mean patients less than 875 but greater than 800 cT1? I think that is only 1 patient anyway.

So, I choose T4, because it is easy to measure, can easily be done at the end of every 14 week interval and is in line with what Madrigal is doing.

For a look at other biomarkers and how they behave with respect to NASH dosing BioMarkers in NASH trial

Certainly, at the end of the trial, another MRI to obtain cT1 and PDFF would be warranted.

As to why leronlimab stops functioning in mild disease, from NASH Interpretation

Quote:

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"The picture shown here:

https://www.nature.com/articles/s41577-021-00639-3/figures/1

really makes it clear that in early phases of NAFLD, the immune system is not even being activated or recruited. It is only in the later phases of NAFLD and then later into NASH when the immune system is recruited and activated.

It is only then, when leronlimab has effect.

In the 700 HM group, with many more CCR5 surface receptors on the hepatocytes, their binding to leronlimab may help the hepatocyte reduce the steatosis that occurs in the early phases of NAFLD with a NAS of 1 or 2. Whereas, with normal or low surface expression of CCR5, the binding of leronlimab to CCR5 is insufficient to cause any change within the hepatocyte b/c there just isn't sufficient quantities of CCR5 on the hepatocytes surfaces to effect any change in steatosis, but with 700 HM group, there are many more CCR5 surface receptors which are bound by leronlimab which effects an improved PDFF in the 700 HM group.

For patients who are stricken with more severe disease, cT1 > 950, the binding of leronlimab with the CCR5 receptors of the HSC affected intracellular communication and thereby thwarted scarring and fibrosis leading to improvements in cT1. As the level of disease became milder, the effectivity of the leronlimab dosing became lessened.

In the event the 17 700 normal group were relatively healthy, having a NAS of 3 or less, it would be like they were receiving Placebo, (which is what the heat map depicts). Just compare the vertical column of the Placebo to the vertical column of 700mg and they look identical. Why? because the 700mg patients had to be quite healthy to begin with. If you don't have the immune system being recruited and activated, then there is nothing for leronlimab to bind to. Since in this group, you only have normal CCR5 surface receptor quantity expressed on the hepatocytes, there is insufficient CCR5 quantity to effect any changes in steatosis. The 700 HM group showed that with increased CCR5 receptor expression, when bound to leronlimab, the PDFF was significantly reduced. In the case of cT1, giving 700mg in mild diseased had a positive effect on reducing the rate of fibrosis development and increasing the rate of scar tissue removal, but not nearly as effective as the rate observed in reduced dosing with more severe disease."

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