Ohm: Alzheimer's is one of my favorite possible in

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Ohm: Alzheimer's is one of my favorite possible indications too. My question about it is the brain blood barrier. We know that a good percentage of Leron can get through the BBB and counter inflammation there. But wouldn't we run into the same questions/problems w Alzheimer's that we've encountered with Glioblastoma, where (possibly) we might need to refigure the dosage or up the number of treatments because the amount of Leron that gets through is to a degree lessened? In other words, we might have to do a couple of Phase II trials to get to the results necessary to advance that indication. Or do you think that problem is not relevant to Alzheimer's? TIA.

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I don't have the data so I can only suggest possibilities. More frequent dosage to increase levels of leronlimab may be needed. It's possible that the the lower permeability of the mouse blood brain barrier may be the cause. It may be entirely something different that the data may reveal if enough of it is released.

The percentage of receptor occupancy for leronlimab in the brain is 70%. I looked for brain receptor occupancy of maraviroc for comparison with no success. Maraviroc has been shown to effect a broad range of Alzheimer's markers.

This is the paper listing leronlimab occupancy -

https://journals.plos.org/plospathogens/artic...10396-g004

I had thought that CCR5 occupied maraviroc may still allow binding of ligands due to it simply changing the shape of the CCR5 receptor and that just may be the case. It potentially has greater BBB penetration being small molecule, but only 84% occupancy in non-cerebral CCR5. If it is somewhat ineffective against blocking ligands than leronlimab should be more effective in the brain.

From the paper listed above -

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Currently, maraviroc is the only FDA-approved CCR5 inhibitor for HIV. In a 10-day monotherapy study, twice-daily 300 mg maraviroc reduced viral load by 1.84 log10. A similar reduction of 1.83 log10 was observed from a single Leronlimab injection of 5 or 10 mg/kg , which is the approximate dosage range used to treat participants in our study based on their individual average weights (4.34–11.76 mg/kg). While both drugs are CCR5-targeting and show similar efficacy in short-term use, the difference in their mechanism of action allows maraviroc-resistant HIV to continue infecting maraviroc-occupied CD4+CCR5+ T-cells, perpetuating the development of ARV resistance.

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