Hearts & Minds Blog
Bempedoic Acid Mechanism of Action Paper Published in Nature Communications: Q&A with the AuthorsDecember 2, 2016
As you may have seen, Esperion scientists and collaborators recently published the definitive paper on the mechanism of action for bempedoic acid, “Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis,” in the journal Nature Communications. I sat down with authors and colleagues Narendra Lalwani and Steve Pinkosky to discuss our findings, highlights from our research and ultimately why this publication reinforces that “mechanism matters”.
Marianne Andreach: Briefly describe the findings and the importance of bempedoic acid’s mechanism of action over the course of the experiments and analyses that our team conducted.
Dr. Narendra Lalwani: The culmination of our research and the translation of our findings include two major components: 1) the scientific basis for how bempedoic acid works in the human body, and 2) the pharmacological efficacy of how bempedoic acid works in humans to lower LDL-C.
Science is constantly evolving, and we had previously published our early experience with in-vitro assays and in-vivo rodent models to identify and understand if we had a drug. Based on those historical in-vitro and in-vivo data, we postulated what could be going on biologically. Not all findings from animals translated directly to humans, as is common in drug research and development. This new manuscript articulates the mechanism by which bempedoic acid works in humans, specifically in the liver, and the pharmacological benefits associated with the drug.
Marianne: What were the highlights of this project for each of you?
Steve Pinkosky: The characterization and identification of the specific acyl-CoA synthetase (ACS) isoform that converts bempedoic acid to the active ATP citrate lyase (ACL) inhibitor was the most critical and impactful outcome from our research. The studies, outlined in the manuscript, that describe this finding provide the basis for how the mechanism of action of bempedoic acid is similar to statins, and importantly, how it’s differentiated.
Another highlight for me was working with our collaborators. The broad scope of this project required that we not only leverage the substantial internal expertise on cholesterol biology existing within Esperion, but that we also reach out to experts from various disciplines around the world to ensure we had access to the level of knowledge and resources needed to successfully execute these studies.
Dr. Lalwani: The research allowed us freedom to understand the benefit/risk properties and the differentiation between statins and bempedoic acid, in particular, to the benefit of lipid-lowering and the difference in risk of muscle-related side effects, and the significant role played by ACS throughout the process.
Marianne: What did we learn about ACL?
Dr. Lalwani: We learned that inhibition of ACL (an enzyme target) is a pivotal mechanism in cholesterol biosynthesis inhibition. Until recently, most of the research conducted was focused on the enzyme HMG-CoA reductase (the target of statins) and other historical attempts at researching ACL as a target over the years were not successful.
Over the course of our research at Esperion we identified bempedoic acid as a potentially successful drug – one that specifically targets ACL, focused only in the liver, and does this without causing toxicity. Bempedoic acid is “first-in-class” – that is, it’s the only drug targeting ACL inhibition that has progressed to this point in clinical development.
Marianne: It was noted that we were able to demonstrate that bempedoic acid is active only in the liver. Why is this so important?
Steve: Statin therapy has been tremendously successful in lowering LDL-C for many patients; but we now know that there is a subset of the population that cannot tolerate statins. For these patients, it is believed that statins inhibit cholesterol synthesis within muscle cells, resulting in pain, cramping and weakness. So these patients either stop taking their statin, or take less than they need to be optimally managed. If these patients cannot find other ways to lower their LDL-C, decades of clinical data suggest they are more likely to suffer from a major cardiac event.
Bempedoic acid engages a mechanism similar to statins, but through a liver-specific process that converts the bempedoic acid pro-drug into active drug. This way, bempedoic acid can reduce LDL-C through specific actions in the liver without causing problems known to result from engaging the same mechanism in muscles. This advantage explains how bempedoic acid can work to lower LDL-C in patients that are unable to tolerate statins.
Dr. Lalwani: To expand on that, cholesterol synthesis is required to sustain life. The liver is the most important organ that collects and ultimately manages cholesterol. The specificity of bempedoic acid for the liver shows that it works where it should, which we believe limits the potential for off-target toxicities such as the muscle-related side effects seen with statins.
Marianne: How is bempedoic acid mechanistically complementary to, and different from, existing LDL-C lowering therapies? You’ve mentioned statins, but also ezetimibe and PCSK9 inhibitors?
Dr. Lalwani: The common denominator for how all of these different therapies lower cholesterol is through the LDL receptor. Statins inhibit cholesterol biosynthesis and up-regulate LDL receptors through HMG-CoA reductase, an enzyme located two steps downstream from ACL. PCSK9 antibodies directly affect the LDL receptors found on the surface of liver cells, which help regulate the amount of LDL-C entering the bloodstream. Ezetimibe targets a different mechanism and works in the digestive tract to block absorption of cholesterol. Bempedoic acid has a complementary mechanism of action that targets the liver specifically through ACL inhibition, demonstrating the lowering of LDL cholesterol with reduced potential for muscle-related side effects, because it has no activity in skeletal muscle cells as previously discussed.
Marianne: What is the key takeaway from this paper on the clinical profile of bempedoic acid?
Steve: The key takeaway from the publication is that bempedoic acid’s mechanism of action is similar to that of statins – the most successful LDL cholesterol lowering drugs on the market. Bempedoic acid inhibits cholesterol synthesis and upregulates LDL receptors in liver cells. However, it is differentiated in one key way: bempedoic acid is inactive until it enters the liver where it gets converted to its active form by the enzyme, ACSVL1, an enzyme not found in skeletal muscle cells. Therefore, unlike statins, bempedoic acid cannot inhibit cholesterol synthesis in skeletal muscle cells or cause the associated side effects.
Marianne: How did Esperion’s work exploring the mechanism of bempedoic acid help us determine the relative contributions of inhibition of ACL and the activation of AMPK to inhibition of cholesterol synthesis, up-regulation of LDL receptors and reduction in LDL-C levels?
Steve: To determine whether AMPK played a role in the LDL cholesterol lowering effect of bempedoic acid, we had to first understand how it activated AMPK activity. We determined that bempedoic acid required the specific regulatory beta 1 subunit of AMPK to mediate its activation. We then used this information to select an AMPK knockout mouse model that would be insensitive to AMPK activation by bempedoic acid to cross with another genetic model that has elevated levels of LDL-C and functional LDL receptors, the APOE/AMPK beta1 double knockout mouse. This allowed us to compare the effects of bempedoic acid on liver LDL receptor expression and plasma LDL cholesterol in the presence and absence of AMPK activation.
Our studies showed that bempedoic acid increased LDL receptors and reduced LDL cholesterol even when AMPK was absent. Based on other published work, we also now know that, while rodents highly express AMPK beta 1 in liver, humans express very little. Therefore, it is very unlikely that any significant AMPK-dependent effects mediated by bempedoic acid will be observed in humans.
Dr. Lalwani: Beta 1 and ACS specificity show that if there is AMPK activation with bempedoic acid it will only be in liver cells, not in muscle cells. The historical concern with AMPK activation is the potential risk for toxicity in other tissues, specifically in cardiac muscle cells. Since bempedoic acid is only active in liver cells, it doesn’t have the potential to cause this toxicity.
Marianne: Do you think this paper and our work could renew interest in ATP citrate lyase as a target?
Dr. Lalwani: I’m confident that our work to understand ACL will renew interest in this target. As bempedoic acid reaches approval, people will fully realize the validity of ACL as a target for lipid lowering and we believe that there will be a lot of activity and interest within the industry in ACL inhibition.