Becky Taub and Paul Friedman, the founders of Madrigal Pharmaceuticals, are heroes of mine.

They are leading the efforts of Madrigal Pharmaceuticals to develop the first treatment for NAFLD/NASH. That drug is called Resmetirom and is currently in phase 3 trials. Many observers think they will be the first to have a successful drug for fatty liver disease.

Shall we have a bit of fun before we look at the details?

Becky and Paul couldn't have known when they picked the name Madrigal that it would so perfectly describe the liver research world that they chose to work in.

Madrigal is a voice only, group singing style popular in the 17th century which features multiple voices singing different themes with a lot of elaborate point/counterpoint. The goal is to make what might seem like annoying noise become a pleasing ensemble instead. Think of it as vocal jazz of the Renaissance. The development of electronics, drums and guitars may not have advanced civilization, just an editorial comment because I'm old I suppose. Click on the image below for a taste of the art form.

OK enough fun, let's look under the hood. Resmetirom is a thyroid hormone agonist. Nothing about that makes sense does it? We are supposed to be talking about liver therapy so what is the deal with thyroid? The thing to remember about the liver is that it is a very complex chemical factory. There are constant comings and goings of a vast array of molecules that are processed or created by the liver and every part of the body is affected.  We have learned that the thyroid is involved in chemical exchanges with the liver which affect the way multiple important processes work.  This illustration will give you a glimpse of those processes and where Resmetirom acts. Click the image for a bigger version.

The details are too complex to go into in a blog like this but you can see that Resmetirom affects several of the key liver processes because it increases the effectiveness of the thyroid hormone which is what agonist means.  Something that depresses function is an antagonist. That big black figure is a mitochondria which is really very very tiny and several of them live inside liver cells but they are the power plants for the cell and therefore you. The illustration just emphasized how important to life they are. A lot of fatigue can be traced back to poor mitochondria functioning.

You might think of Resmetirom like a tuneup. By improving the thyroid hormone processes liver functions like fatty acid chemistry, cholesterol processing, and mitochondrial functions all improve and the liver is able to operate more efficiently. There are other effects too but you get the idea. We really like the multiple functionality of the drug and conceptually the approach has fewer safety risks than some more aggressive strategies.

You might be interested in what the research landscape looks like. Remember Madrigal is one of the leaders with a phase 3 trial underway and they are closing in on the bullseye.

Click on the image for a larger view, but if you look closely at the center ring you can see where Madrigal sits relative to all of the other companies trying to develop a liver therapy.

You might also note that they are one of only two firms working on the thyroid hormone strategy. As you think about what is to come, we know that Resmetirom alone will not be the complete answer but with the safety record they have shown so far I think it likely that when we finally get to combination treatments that really help us they will be part of that cocktail. In the meantime, if they are successful they may be an effective treatment for some subset of patients that will be identified by the testing. We look forward to the results of their phase 3 trial and hope that it proves that the early testing was correct and this can move forward with FDA.

In the midst of all the noise about liver disease research Madrigal may be the theme around which the other voices can combine to produce the harmony and the point/counterpoint of blending that the artistry of the Madrigal Choral means at its root and give us a transformational whole.