Hearts & Minds Blog
ACC Scientific Session Reflections: A Conversation Among Members of The Lipid Management TeamMarch 29, 2017
Last week The Lipid Management team attended the American College of Cardiology (ACC) 66th Annual Scientific Session in Washington D.C. where Dr. Brian A. Ference presented “Genetic Target Validation for ATP-Citrate Lyase Inhibition”, consisting of results from the Mendelian randomization studies conducted on the enzyme target of bempedoic acid, helping to further validate our therapeutic approach. Coupled with the highly-anticipated confirmation from the U.S. Food and Drug Administration (FDA) that our global pivotal Phase 3 program design can support approval for an LDL-C lowering indication, last week was an extremely eventful and important one in the development of bempedoic acid. I sat down with Tim Mayleben, president and CEO, and Dr. Mary McGowan, CMO, to discuss.
Marianne Andreach: What a whirlwind! What are some of the major highlights from ACC from your perspective?
Tim Mayleben: One of the most important outcomes from ACC this year was the further revalidation of the LDL-C hypothesis. In fact, at this point we should probably graduate the “hypothesis” to a “rule.”
Dr. Mary McGowan: FOURIER – Amgen’s CVOT for Repatha – showed a 15% reduction in risk for the primary endpoint, a 5-component MACE, and a 20% reduction in risk in 3-component MACE. Both key endpoints were met after only 26 months of therapy, with a P value of < 0.001. The collective results from FOURIER and SPIRE-2 demonstrate a clear and significant clinical benefit on top of statins. PCSK9i, statin and ezetimibe trials have all confirmed that lowering LDL-C results in CV risk reduction, and these observations are supported by data from recent Mendelian randomization studies in which variants in PCSK9 and variants in HMGCR were associated with nearly identical lower risks of cardiovascular events per unit reduction in LDL-C.
Marianne: FOURIER also reinforced that “mechanism matters” when it comes to LDL-C lowering.
Tim: Very much so! We know that LDL receptor-mediated LDL-C lowering results in CV risk reduction, equivalent to a unit or mg/dL reduction across drug classes. Like statins, bempedoic acid up-regulates expression of the LDL receptors and PCSK9is preserve LDL receptors. Dr. Ference’s Mendelian randomization studies demonstrated that ACL inhibitors, such as bempedoic acid, should reduce the risk for CV events by the same magnitude per unit change in LDL-C as statins, PCSK9is and ezetimibe.
Marianne: It is also important to highlight the ways in which CLEAR Outcomes is differentiated from FOURIER.
Dr. McGowan: Yes, CLEAR Outcomes and FOURIER differ in several important ways. First, patients enrolled in our study will have a much higher baseline LDL-C, will not be on a high-intensity statin and will be statin intolerant with target baseline LDL-C of between 100 mg/dL and 190 mg/dL. Patients enrolled in CLEAR Outcomes will inherently be at higher baseline risk as compared to FOURIER. Additionally, CLEAR Outcomes will have a much longer treatment duration with the last patient enrolled having a minimum of two years of therapy and an anticipated median therapy duration of 3.5+ years. Finally, bempedoic acid provides the added benefit of hsCRP reduction, similar to that seen in statins.
Marianne: Let’s move on to the announcement we made on the regulatory front. How did you obtain this clarity? Did FDA’s decision have anything to do with FOURIER?
Tim: Through regular and ongoing interactions with FDA, along with submission of key data supporting bempedoic acid, we were able to gain this exciting and positive confirmation on the pathway to approval for bempedoic acid for an LDL-C lowering indication. Written communication on this path forward was received from FDA just prior to ACC confirming the pathway to approval for bempedoic acid.
Dr. McGowan: The data submitted include positive results from Phase 1 and 2 clinical studies of bempedoic acid added on to high-dose statins (035/037) resulting in the inclusion of patients on any statin at any dose in our 52-week Phase 3 long-term safety study (Study 1) and in our Phase 3 LDL-C lowering study in patients with ASCVD and/or HeFH (Study 2); publication of the definitive manuscript on the mechanism of action of bempedoic acid in Nature Communications; and the aforementioned Mendelian randomization studies, providing genetic validation for inhibiting ACL to lower LDL-C and reduce cardiovascular disease risk. It is also notable to mention that Study 1 is now fully enrolled. This ~2200 patient study has been monitored since it’s initiation in January 2016 by our external Data Monitoring Committee (DMC). While the study remains blinded to Esperion, the DMC reviews are unblinded. With many patients reaching 52-weeks of treatment and now enrolling in our 78-week open-label extension study, we continue to be confident in the safety and efficacy of bempedoic acid.
Marianne: Were there any other important updates stemming from recent interactions with the FDA?
Dr. McGowan: We also reached agreement regarding the definition of statin intolerance for CLEAR Outcomes – “the inability to tolerate two or more statins, one at the lowest approved daily starting dose, due to an adverse effect.” In this cardiovascular outcomes trial (CVOT), both patients and investigators will provide written confirmation of statin intolerance and that both the investigator and the patient are aware of the benefits of statins in reducing the risk of cardiovascular events and death.
Marianne: So, where do we go from here?
Dr. McGowan: We plan to submit a new drug application (NDA) to the FDA by the first half of 2019 for an LDL-C lowering indication based on the successful completion of the global pivotal Phase 3 program for bempedoic acid. The proposed product label will include specific language for the use of bempedoic acid as an adjunct to maximally tolerated statin therapy in patients with hypercholesterolemia, specifically those at high cardiovascular disease (CVD) risk with atherosclerotic cardiovascular disease (ASCVD) and/or heterozygous familial hypercholesterolemia (HeFH) who require additional LDL-C lowering. We also plan to submit a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) by the first half of 2019 and expect the proposed product label would include use of bempedoic acid in patients with considered statin intolerant, as well as patients at high CVD risk with ASCVD and/or HeFH. By 2022, we expect to submit a NDA for a cardiovascular disease risk reduction indication to the FDA and a MAA to EMA upon successful completion of the CLEAR Outcomes CVOT.
Tim: We are very pleased to have achieved clarity from the FDA and continue to believe bempedoic acid has the potential to provide physicians with a complementary, convenient and cost-effective once-daily, oral treatment option for their patients with hypercholesterolemia who require consistent lowering of elevated LDL-C. We remain focused on completing the global pivotal Phase 3 program for bempedoic acid and reporting top-line results from our long-term safety and tolerability study by Q2 2018 and top-line results from our ongoing Phase 3 LDL-C lowering efficacy studies by mid-2018.