Hearts & Minds Blog
Investor Day and July Meetings RecapJuly 20, 2018
Hi, I’m Alex Schwartz and I recently joined Esperion as Head of Investor Relations. Prior to joining Esperion, I was a publishing analyst at Stifel Nicolaus, got an MBA in finance from Boston College, and was a trader at Schonfeld Securities. I will be focusing on providing knowledge on the LDL-C lowering market, cardiovascular drug development, and everything bempedoic acid as well as Esperion Therapeutics. Most recently, on July 10th, we hosted an Investor Day. A replay of the webcast is available here and the slides from Investor Day are available here. Following our investor Day, we spent a few days on the road meeting with investors. Below are key topics during these events.
- Upcoming bempedoic acid/ezetimibe combination pill readout in August
- Commercial relevance of 30% LDL-C Lowering
- Upcoming Study 2 bempedoic acid readout in September
- Dr. Plutzky and Dr. Underberg – Bempedoic acid dataset in 4000 patients and focus on bempedoic acid/ezetimibe combination pill
- Dr. Ference and Dr. Nissen – ACL genetic validation and CLEAR Outcomes
- Dr. Jenkins, Mr. Glickman, and Dr. Barlow – Insights into the regulatory process, the bempedoic acid opportunity, and payer research
Bempedoic Acid / Ezetimibe Combination Pill readout in August – expectation >30% LDL-C Lowering. During our investor day, we outlined our expectation that the bempedoic acid/ezetimibe fixed dose combination will achieve LDL-C lowering of 30% or more. In the days following the event, we were often asked “why do you expect >30% LDL-C lowering with bempedoic acid/ezetimibe combination pill?” Over the last few months, it has become clear that bempedoic acid lowers LDL-C by ~20% on low, moderate, and high dose statin therapy. Ezetimibe’s LDL-C lowering by comparison is inconsistent, and in the lower ‘teens’ when combined with various statins. For example, in combination with the most popular statin, atorvastatin/Lipitor, ezetimibe’s label notes an additional 12% LDL-C lowering when combined with the 20 mg dose, 11% LDL-C lowering when combined with the 40 mg dose, and only an additional 7% LDL-C lowering when combined with atorvastatin 80 mg. By comparison, in combination with another and significantly less-prescribed statin, simvastatin, ezetimibe’s label notes an additional 19% LDL-C lowering when combined with the 10mg dose, 10% LDL-C lowering when combined with the 20mg dose, and 18% LDL-C lowering when combined with simvastatin 40mg. In summary, for patients taking their maximally tolerated statin therapy, adding bempedoic acid’s consistent 20% LDL-C lowering on background statin therapy and ezetimibe’s “lower teens” LDL-C lowering suggests that the bempedoic acid/ezetimibe combination pill will be able to achieve >30% LDL-C on statin backgrounds.
Commercial Relevance of 30% LDL-C Lowering? An additional 30% LDL-C lowering alone gets >6 million patients to goal – highly compelling. At our Investor Day, physicians also commented that the main importance is the absolute change in LDL-C (as measured in mg/dL, and not just getting to a specific target) and actually changing overall LDL-C number. This brings bempedoic acid’s total achievable market to 12-13 million patients. This total achievable market corresponds to ASCVD and/or HeFH patients with elevated LDL-C that are on maximally tolerated statin therapy +/- ezetimibe. I also want to highlight that in previously completed clinical studies, the bempedoic acid/ezetimibe combination pill in patients with no statin background has achieved 48% LDL-C lowering and 40% hsCRP reductions This ability to deliver a “statin-like” efficacy benefit to patients utilizing a non-statin mechanism is extremely compelling. Almost 4 million patients in the US are considered statin intolerant (a subset of the 12-13 million total achievable market).
Study 2 – bempedoic acid’s second 52-week study. In September, we will announce results from our second 52week clinical study testing bempedoic acid versus placebo in patients on maximally tolerated statin therapy. This study is known as Study 2. This study is identical to Study 1 with two exceptions – it enrolled 779 patients (in comparison to Study 1’s 2,230 patients) and patients have >100 LDL-C baseline levels (in comparison to Study 1’s >70 LDL-C baseline levels). The primary endpoint is 12-week LDL-C lowering efficacy versus placebo, and key secondary endpoints include 24- and 52- week safety, tolerability and effects on LDL-C, HDL-C, non-HDL-C, total cholesterol, and triglycerides. While we are highly confident in our safety results to date, some investors are still concerned by Study 1’s perceived imbalance in the rate of unrelated fatal AEs and we have been getting questions on what Study 2’s blinded data show. Here’s what we have disclosed 1.) that it is almost certain that some patients enrolled in the study will die over the 52-week duration of the study given that there is a 1.8% one-year overall fatality rate for the general population aged 65-74 years in the U.S. (source: CDC’s Morbidity and Mortality Weekly Report). 2.) There have been no neoplasm-related patient deaths in Study 2.
Esperion Investor Day – Presentation Summaries
Dr. Jorge Plutzky – review of the Phase 2/3 data. Clinically, what’s important to Dr. Plutzky and physicians is the consistency of LDL-C lowering efficacy. In his view, bempedoic acid has achieved consistent efficacy added on to statins (20% LDL-C lowering – Study 1), added on to very low dose statins (28% LDL-C lowering—Study 3), and added on to no statin therapy (26% LDL-C lowering – Study 4). He noted the evidence for LDL-C lowering having benefits on risk of cardiovascular events is unequivocal and is very broadly accepted. In regards to safety, Dr. Plutzky suggested that looking at the global picture of assembling data is important (below), as looking too granularly at one study might be misleading. He was encouraged by a very similar balance between bempedoic acid and the placebo/active control. Finally, he noted that the percent change in LFTs is very similar to what’s seen with other lipid lowering agents.
Source: Esperion Therapeutics
Dr. Jamie Underberg – Clinical utility of the bempedoic acid/ezetimibe combination pill. We expect bempedoic acid/ezetimibe combination pill will provide an additional >30% LDL-C lowering in patients on background statin therapy. Previously, bempedoic acid/ezetimibe + atorvastatin 20mg achieved 64% LDL-C lowering. Looking at that waterfall plot below, Dr. Underberg noted that in waterfall plots for other studies, there will usually be some patients that cross above zero, i.e. their LDL-C levels increase. However, in this study, bempedoic acid/ezetimibe + atorvastatin 20mg provided a consistent and broad response importantly indicating safety, tolerability, and adherence.
Source: Esperion Therapeutics
In patients not on background statin therapy, bempedoic acid/ezetimibe achieves closer to 50% LDL-C lowering and is similar to what one might see with PCSK9 inhibitor monotherapy. In differentiation to PCSK9 inhibitor therapy, bempedoic acid also reduces high sensitivity C-reactive protein. A key point from Dr. Underberg is that the bempedoic acid/ezetimibe combination pill offers a non-statin, aggressive robust LDL-C lowering with complimentary mechanisms of action that’s well-tolerated and convenient for patients.
Dr. Jorge Plutzky and Dr. Jamie Underberg Q&A. The physicians saw the highest-risk patients as well as statin-intolerant patients as the most appropriate candidates for bempedoic acid therapy. In regards to the imbalance in deaths unrelated to study medication, the physicians pointed out that one should be informed by what’s driving these numbers and could be contributing or whether you’re being misled. Looking at the case-by-case analysis, the doctors were not concerned but of course want to continue to pay attention to it. Finally, there is nothing mechanistically that would make them concerned. Both physicians were comfortable with 52 weeks of exposure to bempedoic acid in our safety data and will take additional comfort with the longer term outcomes data.
Dr. Brian Ference – further genetic ACL validation. Dr. Ference conducted a naturally randomized CLEAR outcomes trial by using genetic variants in the ACL gene as instruments of randomization. The study involved more than 700,000 people and 105,000 cardiovascular deaths. ACL genetic variants are causally associated with lower risk of cardiovascular disease per unit lowering of LDL-C (below – top), the same as what is seen for HMG-CoA reductase (target of statins), NPC1L1 (target of eztimibe) and PCSK9s. Finally, after Dr. Ference examined more than 25,000 people with cancer, there appears to be no effect on the risk of any cancer or any specific kind of cancer, including lung cancer (below – bottom). These results are important as it suggests there is no neoplasm causality related to ACL inhibition.
Source: Ference BA, et al. 2018
Dr. Steve Nissen – LDL-C and hsCRP lowering and relevance to CLEAR Outcomes. During his presentation, Dr. Nissen clearly outlined the nearly linear (and independent) relationships of LDL-C as well as hsCRP as means to reduce cardiovascular risk. The Cholesterol Treatment Trialists Collaboration demonstrates that a 1 millimole per liter (or 39 milligrams) per deciliter) LDL-C lowering translates into a consistent 22% reduction in risk of CV events (below left). In addition, canakinumab and its recent positive CANTOS trial established that reducing elevated hsCRP (a marker of inflammation) is another method to benefit CV outcomes. While canakinumab did not lower LDL-C from baseline LDL-C at 48 months, hsCRP was reduced by 37% in the 150mg dose and led to a 15% reduction in risk of major cardiovascular events versus placebo (below right). As a result, both LDL-C lowering and now hsCRP reduction have been independently established to reduce CV event risk.
Source: Adapted from Lancet 2010: 376: 1670-81
My CLEAR Outcomes relative risk reduction calculations. Looking at prior cardiovascular outcomes trials, Esperion has designed its outcomes trial for heightened success. These key factors include: an expected ~135 mg/dL starting baseline LDL-C, 25-30% LDL-C lowering (patients enrolled are statin intolerant/on no background statin therapy), mean ~3.75 years on treatment (see accelerating separation in MACE curves with increasing duration), and hsCRP reduction in the bempedoic acid arm only (patients enrolled are statin intolerant/no background statin therapy). Based on Esperion enrolling patients with a baseline LDL-C of about 135 mg/dL, an expected lowering of about ~34-40 mg/dL (or 1 mmol/L –25- 30% LDL-C lowering by bempedoic acid in patients on no statin background therapy), and 3-4 years on treatment, suggests a relative risk reduction of ~20-22% in the bempedoic acid CLEAR Outcomes trial. This calculation is based on LDL-C lowering alone and does not factor in bempedoic acid’s secondary hsCRP properties. Esperion’s CVOT is >85% powered to detect ~14% relative risk reduction in the primary endpoint for bempedoic acid as compared with placebo.
Dr. Brian Ference and Dr. Steve Nissen Q&A. In regards to the perceived safety issues, Dr. Nissen believed that the number of fatal adverse event unrelated to study medication is so small that it’s just “noise” and was surprised that people are making a big issue out of it. He noted he cannot definitively say that there will never be a problem, but, as each additional month goes by with no announcement by the DMC, is comforting to him. In regards to LFTs, the REVERSAL trial (atorvastatin 80mg) had a 3.4% rate of LFT increases so bempedoic acid’s LFT elevation rate to date is a non-issue. In regards to the hypothetical cancer signal, Dr. Ference pointed out that statins and ezetimibe both had a cancer scare and it turned out there was no real evidence of an increased risk of cancer, based on both Mendelian randomization and clinical data.
Dr. John Jenkins – Insights into the FDA process. Dr. Jenkins provided insights into the FDA process for the company’s completing Phase 3 clinical development including: pre-NDA meeting, NDA submission, filing review, 74-day letter, mid-cycle communication, late cycle meeting, advisory committees, and regulatory action by PDUFA goal date. Dr. Jenkins also touched upon the proposed reorganization that will better assemble therapeutic areas together in the same division/office. Likely reviewing bempedoic acid’s NDA will be a newly created division that focuses on diabetes, dyslipidemia and obesity with the same team that has been reviewing bempedoic acid from the time of the IND. In addition, the FDA Amendments Act (FDAAA) of 2007 requires FDA to present all new molecular entities to an advisory committee (unless FDA determines that an advisory review is not needed). Historically, the Division of Endocrine and Metabolism usually convenes advisory committees for new molecular entities. Ultimately, the FDA utilizes the benefit-risk framework (below) to review applications, make more consistent decisions, and clearly communicate risk/benefit decisions. We expect to submit bempedoic acid as well as bempedoic acid/ezetimibe FDA combination NDAs no later than 1Q19 with a standard ~12 month review cycle.
Source: FDA Benefit Risk Assessment in Drug Regulatory Decision-Making
Mr. Mark Glickman – the Opportunity, the Providers, and the Patients. Mark Glickman, Esperion’s Chief Commercial Officer, tied epidemiologic data, prescription data, and bempedoic acid market research into the opportunity. More specifically, Mr. Glickman surveyed “product X” with cardiologists, endocrinologists, and primary care physicians and surveyed the need as well as likelihood to prescribe (product X=bempedoic acid). The doctors responded that 28%-29% of their patients would benefit from a new LDL-C lowering agent. This response is significant as it corresponds to the NHANES-based estimate that 29% patients are on statin but not at goal (~12-13 million patients). The top two responses for wanting a new agent were 1.) more efficacy to reach goals and 2.) for statin intolerant patients. These physicians perceived bempedoic acid as both a monotherapy or as an add-on, and as appropriate treatment for those with ASCVD or at high risk for ASCVD. Overall, the positive reaction to bempedoic acid’s profile translated into positive “likelihood to prescribe” ratings (bottom left) as well as into strong patient share numbers (bottom right).
Source: Esperion Therapeutics
Dr. Jane Barlow – Payer Perspectives. Dr. Jane Barlow focused her discussion on how payers are the managing the LDL-C landscape today as well as payer reactions to bempedoic acid. In her market research, Dr. Barlow conducted in-depth interviews with 25 payers that covered a total of 219 million U.S. Commercial, Medicare, and Medicare lives. In order to approve access to PCSK9 inhibitors, 100% of these payers require patients to be on maximally tolerated statin therapy, 48% also require having tried and failed ezetimibe, as well as 52% required a specialist to prescribe the PCSK9, or for primary care physcians to work in conjunction with a specialist to prescribe. While Repatha just added risk reduction data to their label, 24/25 payer plans had no change in coverage criteria. Dr. Barlow further noted despite Regeneron/Sanofi’s recent attempts to reduce Praluent net price in exchange for improved patient access, payers still have additional controls in place to manage PCSK9 inhibitor utilization. For example, while Praluent has a new $5,000/year (best case scenario) net price, patient out-of-pocket costs are calculated by the ~$14,000 wholesale acquisition cost (list price) and still total >$3000/year (below). Overall, we applaud Regeneron/Sanofi for reducing Praluent’s net price, however, it’s not in the same ballpark with bempedoic acid’s expected price – on a List price or net basis or on a co-pay basis. This point is important as Dr. Barlow’s interviews suggest price is a key factor in determining formulary positioning, steps in formulary, prior authorizations, and complexity in physician forms.
Dr. Jenkins, Mr. Glickman, and Dr. Barlow Q&A. In regard to formulary steps, Dr. Barlow noted that payers were comfortable stepping bempedoic acid before PCSK9 inhibitors given an appropriate price for bempedoic acid. A similar question arose as to whether payers will step ezetimibe before bempedoic acid. Dr. Barlow noted that 48% of payers surveyed have an ezetimibe step before PCSK9s and should a similar ezetimibe step be in place prior to bempedoic acid, it feeds into and supports the bempedoic acid/ezetimibe fixed dose combination. Mr. Glickman added that his goal is to not have any prior authorizations and any steps. In regard to how the FDA approaches product safety, Dr. Jenkins noted FDA looks at the safety database totality as well as recognized patient subgroups based on dose or duration of exposure. For the mortality imbalance, Dr. Jenkins expects FDA will examine and determine is there any pattern to cause these deaths or whether are they randomly occurring, and noted they were very small numbers. Finally, Dr. Jenkins would be surprised if the FDA asked for unblinded data from the ongoing CVOT. He further noted that the fact of the DMC not raising any concerns will provide the FDA some comfort on the safety of bempedoic acid.