So, speaking of research, I took a look at the cit

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So, speaking of research, I took a look at the citations on that "Expanding the Therapeutic Perspective of CCR5 Blockade" article, and found a couple studies using maraviroc and cenicriviroc for NASH, MASH, MAFLD. I hadn't realized a CCR5 inhibitor had been studied in (I'll call it) MASH before...

Both failed to pass muster. In the AURORA Phase III trial utilizing cenicriviroc "The study did not demonstrate the efficacy of CVC for treating liver fibrosis."

In the MAVMET trial they tested maraviroc and/or metformin for MAFLD in HIV patients. Primary outcome was change in Liver Fat Fraction after 48 weeks with Mara. “Contrary to our hypothesis, neither Mara or Met, or the combination significantly reduced liver fat. They added the caveat that “Baseline levels of liver fat were lower than predicted.”

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I've read both studies long ago. Cenvriviroc preferentially binds CCR2 and is a weak binder of CCR5. Maraviroc has a receptor occupancy of 84%. So neither will be as effective as leronlimab especially when it comes to CCL5 (RANTES) which is a high driver of inflammation.

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Now, I know from Cytodyn’s study of LL in MASH (from the HEATMAP!) that it decreases inflammation in the liver, and reduces fat, but what are the indications that it can deal with fibrosis? Ohm—or any other knowledgable person out there—any data that would suggest a resolution in fibrosis?

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Straight from the trial, cT1 is a measure of fibrosis and and both cT1 and PDFF (fat) reduction were statistically significant with the 350mg dose and a combination of 350mg and the 700mg dose. It was not statistically significant in the 700mg dose possibly because of a skewed CCR5 delta 32 deletion patient population. That statistical significance was reached with only 22 patients in the drug arms is an excellent result when seeing that big pharma is running trial with hundreds or thousands of patients.

The current mouse NASH study will try to sort out why 700mg did not do as well as 350mg in the trial. This will probably be necessary for the FDA to allow a 350mg to 700mg dose escalation in a phase 3 trial rather than just a 350mg arm. Since none of the mice will have CCR5 deletions 700mg will show better results if my hypothesis of why the trial did not is correct.

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Principal PDFF and cT1 results follow:

PDFF percent change from baseline
Placebo: 9.85
Leronlimab 700 mg: 3.75 (P = 0.136 vs placebo, not significant)
Leronlimab 350 mg: -5.94 (P = 0.008 vs placebo)
Leronlimab 700 and 350 mg pooled: -1.09 (P = 0.014 vs placebo)

cTI absolute change from baseline
Placebo: 27.64
Leronlimab 700 mg: -2.73 (P = 0.059 vs placebo, not significant)
Leronlimab 350 mg: -24.38 (P = 0.021 vs placebo)
Leronlimab 700 and 350 mg pooled: -13.39 (P = 0.013 vs placebo)
https://www.natap.org/2022/EASL/EASL_70.htm

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Continuing on the NASH/MASH topic, and Cytodyn's place in the landscape, I am concerned the GLP-1 drugs are going to expand into indications like reducing liver fat and addressing general, low-grade inflammation.

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GLP-1 antagonists are very effective because of the high level of GLP-1 activation. High reduction in fat but also accompanying side effects. Leronlimab increases GLP-1 but as a secondary effect that would restore balance.

Fat is one of the drivers behind inflammation but not the only one. Genetics can play a part but environmental insults are a very big factor. It's not only how much you consume, but also what you consume. Lower dietary fiber and some additives can also increase inflammation. Then there's the other environmental effects - pesticides, air pollution, chemicals and even micro-plastics can drive inflammation. GLP-1 antagonists would have no effect on those factors unlike leronlimab.

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And this is the kind of thing that could keep me up at night...

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Now you can sleep a little better.