Miljenko, many times in the past you have made me think quite hard about a biotech investment with you penetrating questions. Recently you have asked me to compare VK2809 to that of MGL-3196. I punted on that question, saying that I wanted only to compare the 12 week Ph2 data sets in NASH. But, I have been asked the same question by others, so I figured it might be useful to give an answer here as to why I am not comparing the data on the 2 compounds, at least not yet. So here goes.
I know Miljenko that you know much of the stuff I will summarize below, but I offer this at least for others to see my thinking on these compounds, and why I cannot compare them yet.
One highly interesting aspect of MGL-3196 is its potency, this is a complicated issue. Typically a drug candidate needs to be single digit nanomolar potency at its target, in this case the thyroid hormone beta receptor, a so-called nuclear hormone receptor, that when stimulated by a ligand, activates a broad gene expression response. But the MDGL drug has 2 unique properties that sets it aside from 'classical' drugs. First, in a recombinant thyroid hormone functional assay, it has an in vitro potency of two orders of magnitude lower potency. (In a function E coli THbeta assay with a reporter, I have seen EC50 values of 120 to 210 nM potency.) But secondly, it is taken up selectively into liver cells by a cell surface transporter, and due to its charge characteristics, it does not passively diffuse across the cell membrane either in liver or other tissues. So its discovery required the knowledge of 2 different structure-activity relationships, one for the transporter and the other for the THbeta target. Hence, the drug is liver specific, and its ability to be liver concentrated overrides its relatively low potency. That type of drug discovery is quite unique and clever. Similar general comments hold for Metabasis discovered 2809, but it appears from what I have seen that it may have greater in vitro potency, albeit not in an identical functional assay.
But that is at least one reason why I do not yet compare yet the VKTX compound to the MDGL compound. The in vitro potency values for the two compounds would be an apples to oranges comparison, as the assays were different. There are other potential limitations to compare the multiple dose Ph 1 results for both compounds. |
