By Peter G. Traber, M.D. on February 11, 2016
I wrote recently about the need for non-invasive tests to replace liver biopsies in the evaluation of liver fibrosis due to various diseases, including NASH, and I also spent time exploring some of the non-invasive serum and imaging tests that are in development. I started this whole discussion by stating that it is difficult to assess liver function and the effect of fibrosis on liver function. As a result, we must rely on direct physical assessments like biopsy and imaging tests and indirect evaluations like serum tests, which attempt to provide insight into what is going on in the liver. Yet there are a number of potential approaches to testing actual liver function being developed, and we are evaluating one of these in the course of our own clinical trials.
For example, one of the functions of the liver is to extract bile acids out of serum and excrete them into the bile that then enters the intestine. A company called HepQuant, headed by Dr. Greg Everson, whom I’ve known for many years, has developed a test for this. A small intravenous dose of a non-radioactive labeled bile acid and an oral dose are administered to the patient and the test then measures how well the liver takes up this bile acid.
HepQuant has generated data that demonstrate a linear correlation between its test’s results and various measures of liver disease, such as degree of fibrosis. Unfortunately, the test wasn’t ready for use when we started our clinical trials, but the HepQuant test could be a very important endpoint in the future. [1]
Another function of the liver is to metabolize drugs. A 13C-methacetin breath test developed by Exalenz Bioscience measures the metabolism of a drug, and we are making use of this test in our NASH CX trial. Developers have been pursuing this approach for many years, but it has only recently come into clinical use. [2]
The concept behind the 13C-methacetin breath test is that the liver metabolizes a drug called methacetin into acetaminophen. We’re probably all familiar with acetaminophen, which is sold over-the-counter as Tylenol®. Methacetin has been available for a long time as an oral drug for pain relief, but it’s not in high demand now because people tend to use acetaminophen as a first choice. In metabolizing methacetin, the liver uses an enzyme called cytochrome P450 1A1 to remove a methyl group off methacetin, which results in acetaminophen.
The amount of cytochrome P450 in the liver is related to liver disease, and the amount decreases as the severity of the disease increases. The liver has a tremendous capacity for metabolizing drugs, but with a sufficiently sensitive test, even small changes in the metabolic capacity can be identified before they become a big problem.
In the Exalenz 13C-methacetin breath test, the methyl group on the methacetin has been tagged with a carbon-13 (13C) atom, rather than the normal carbon-12 atom. You may recall from chemistry class that carbon-14 is a radioactive form of carbon, but carbon-13 is not. The 13C-laced methacetin is given to the patient orally. The liver metabolizes the methacetin by knocking off the methyl group, which is turned into 13C-laced CO2 and passes through the blood stream to be exhaled. The patient wears a nasal cannula and breathes normally, and a machine measures the amount of carbon-13 that is excreted. The more that is excreted, the better the liver is working.
This is a functional measure of the metabolic capacity of the liver. Exalenz has shown a correlation between liver damage and cirrhosis and the 13C-methacetin metabolic capacity. They’ve also shown that it is related to patient outcomes.
As these two tests are further refined and evaluated, they could become important in diagnosing and monitoring the treatment of liver disease, because they aren’t just looking at the structure of the liver, but they actually give us a sense of how liver function is changing.
Between serum, imaging and functional tests, there may soon be a wide range of reliable and non-invasive tests available to us. Each of these tests measures different things, so they’re likely to be used in combination. I can envision using an imaging test to look at the structure of the liver and a functional test to determine liver function. In our NASH-CX trial, that’s why we have the hepatic venous pressure gradient (HVPG), liver biopsy, FibroScan® and the 13C-methacetin breath test from Exalenz. I will discuss HVPG and why we are using this test in a future Perspective.
Our clinical trials are testing GR-MD-02, but at the same time we’re also evaluating the relevance of certain non-invasive tests. From my perspective, this is something that all companies developing treatments for NASH and liver fibrosis should incorporate into the design of their clinical trials. No matter what the results for the candidate drugs, we should also take the opportunity to gain a better understanding of how the results of non-invasive tests correlate to the results of a liver biopsy and disease progression. That would add tremendous momentum in this area of medicine and with improved diagnosis, it would support the commercial sales of these drugs when approved.
- HepQuant products are investigational combination drug and in vitro diagnostic devices and have not yet been evaluated or reviewed by the U.S. Food and Drug Administration (FDA). They are not currently available for clinical or investigational use or commercial sale.
- The Exalenz breath test is not currently approved in the U.S. for the assessment of liver function.
These “CEO Perspectives” are a regular feature of our communication activities and may contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These statements relate to future events and use words such as “may,” “might,” “could,” “expect” and others. These statements include those regarding the hope that Galectin Therapeutics’ development program for GR-MD-02 will show that it can be both safe and effective in the treatment of liver disease, including NASH. For a discussion of additional factors impacting Galectin’s business, see the Company’s Annual Report on Form 10-K for the year ended December 31, 2014, and subsequent filings with the SEC. You should not place undue reliance on forward-looking statements. Although subsequent events may cause its views to change, management disclaims any obligation to update forward-looking statements.
