Hearts & Minds Blog
Help with Understanding Liver Function Test Increases: From the Lipid Management TeamMarch 11, 2018
We recently announced positive results from our first pivotal phase 3 study (Study 4 or the 048 study) of bempedoic acid. This was a significant milestone for our Lipid Management Team on our path of developing, gaining approval for, and commercializing bempedoic acid and the bempedoic acid / ezetimibe combination pill. I’m incredibly proud of our team!
In Study 4, bempedoic acid lowered LDL-cholesterol by 28%, reduced hsCRP by 33% and was observed to be safe and well-tolerated in 269 ASCVD or high-CV risk patients with elevated LDL-cholesterol who are considered statin intolerant and who were already taking ezetimibe and up to low or very-low dose statins.
There were no differences in the occurence of overall AEs, SAEs or muscle-related AEs between bempedoic acid and placebo – further reinforcing the favorable safety and tolerability profile that has been observed in prior clinical studies. We also reported that two patients (1.1%) in Study 4 had increases in a lab value that is routinely measured in clinical studies called a Liver Function Test (LFT) of greater than 3 times the upper limit of normal (3X ULN) repeated and confirmed (meaning the test was performed twice to confirm it was correct). This rate of LFT increases (1.1%) was within the range of our previously reported studies of bempedoic acid (which ranged between 0.0% – 1.2%) and well within the range listed in the FDA-approved labels of statins, Vytorin and ezetimibe (which ranged between 0.2% – 2.3%). Nevertheless, some of you have wondered about the significance of the LFT increases and as experts in the development of lipid regulating drugs, our Lipid Management Team wants to help put these LFT increases in context.
Below is a brief Q&A that we hope you find helpful.
What is an LFT and what is an LFT increase?
A liver function test is a blood test that measures certain substances including the enzymes alanine transaminase (ALT) and aspartate transaminase (AST) as well as the additional biomarkers such as bilirubin and alkaline phosphatase. These enzymes are primarily but not exclusively produced by the liver. An increase in a liver function test is when the level of AST and/or ALT is greater than the upper limit of normal. Because a variety of factors can contribute to an increase in an LFT, the measurement is often repeated within 7 days.
Why are LFTs measured in clinical studies of lipid regulating drugs?
LFT measurements are a standard safety measure in almost all drug development programs. In general, LFT increases occur infrequently, but they have been observed with the development and use of oral lipid regulating drugs. For these drugs, LFT increases typically occur within the first 12 weeks of initiating therapy. However, LFT increases with oral lipid regulating drugs have NOT been associated with liver injury and the protocol to address an LFT increase with these drugs, in clinical practice or clinical studies, is simply to withdraw drug therapy for a few days to a couple of weeks and then restart therapy. This has been highly effective and remains the industry standard.
What causes an increase in LFTs?
There are multiple and diverse causes for an increase in LFTs in humans. These can range from viruses (such as hepatitis viruses, herpes simplex virus), to alcohol intake, and a wide variety of diseases. Individual patient characteristics, particularly obesity leading to fatty liver, can also increase LFTs. Finally, there are a wide variety of approved drugs (including aspirin and acetaminophen), and even a number of herbal supplements, that have been shown to result in an increase in LFTs.
What is known about the approved lipid regulating drugs and increases in LFTs?
The liver is the primary site for controlling the production and metabolism of cholesterol in the body. It is not surprising, therefore, that many of the drugs developed and approved for managing cholesterol have activity in the liver and have been associated with increases in LFTs. This includes statins, fibrates and high doses of niacin. Statins are the most widely used of all LDL-C lowering drugs. The first statin was approved over 30 years ago and it’s estimated that over 100 million patients have been treated with statins worldwide. Statins work by inhibiting a key enzyme (HMG CoA Reductase) on the cholesterol synthesis pathway in liver cells. Statins have been associated with increased LFTs ranging from 0.2% to more than 2.3% of patients, depending upon the statin and related dose. More importantly, it has now been shown that while statins cause increases in LFTs infrequently, they are not associated with any serious liver-related side effects and over the years the testing requirements of LFTs for patients treated with statins have been significantly reduced. Today, there is no requirement to monitor LFTs for statins.
Can you provide some overall context for the LFT increases observed in the clinical program for bempedoic acid?
- Bempedoic acid, like statins, works in the liver and inhibits the production of cholesterol. It differs slightly from statins in that it targets a different enzyme (ATP Citrate Lyase) than statins, but on the same cholesterol synthesis pathway in liver cells. Bempedoic acid is currently in the final phase of testing in humans prior to submission for approval to the FDA.
- Among all of the completed clinical trials from the Phase 2 clinical program, a total of almost 800 patients were treated with bempedoic acid, most for 12 weeks. The rate of LFT increases in these patients was 0.5% (or roughly 4 patients out of nearly 800). This rate of 0.5% is at the low end of the range observed with statins (0.2% to 2.3%).
- Also like statins, there is no pattern as to which patients had increases in LFTs. As mentioned above, increases in LFTs may also be influenced by other external factors such as alcohol intake, certain illnesses or other drugs.
- The rate of LFT increases in a clinical program typically varies from study to study. In the bempedoic acid program specifically, the rate of LFT increases in individual studies has ranged between 0.0% (zero reports of LFT increases in most studies) to 1.2% (in the 08 study) and includes 1.1% in Study 4 (the 048 study). It is also typical with oral LDL-C lowering drugs that the LFT increases are not balanced between the treatment arms and the placebo arm – most LFT increases occur in the treatment arms for the reasons we outlined above.
Finally, below is some information from a review of blinded safety data in the on-going Phase 3 program of bempedoic acid that we think you’ll find helpful:
- As of this writing, a total of 3,623 patients have been enrolled in the bempedoic acid Phase 3 program, which includes an estimated 2400+ patients treated with bempedoic acid.
- 3,009 patients are in Studies 1 and 2, which are 52 weeks in duration and randomized 2:1 to bempedoic acid versus placebo. All patients in these two studies have ASCVD and are on a background of maximally tolerated statin therapy, including 50% on high intensity statins.
- The overall estimated blinded rate of LFT increases in the bempedoic acid Phase 3 program, which assumes all increases occur in treatment arms, and includes the recent Study 4 results, is ~0.55%.
- One caveat: the rate of LFT increase can vary between now and the end of the Phase 3 program since three of the trials have yet to be fully completed. Additionally, these numbers and data will be “cleaned” as each individual study is completed and reports out. The “cleaning” of data (fixing errors or discrepancies in the database before the database is locked and the trial is unblinded) may also impact the final observed rate.
- Based on the available blinded safety data highlighted above, combined with our prior experience developing oral lipid regulating drugs, we remain highly confident in the safety and tolerability profile of the bempedoic acid franchise.
Final Note: As of this date, there have been no reports of LFT increases > 3X ULN repeated and confirmed in the bempedoic acid / ezetimibe combination pill study. In the Open Label Extension Study of Study 1 (over 1400 patients enrolled), there has been one report of an LFT increase.