Hearts & Minds Blog
Setting the Record Straight: The Facts About Bempedoic AcidMay 22, 2017
We recently became aware of comments published containing misinterpretations or intentionally inaccurate statements regarding Esperion and bempedoic acid. As the press release we issued referenced, we generally do not comment on these types of communications. However, as lipid management experts we are compelled to set the record straight about Esperion, bempedoic acid, and our fixed-dose-combination.
Bempedoic Acid Clinical Development and Need for Additional Treatment Options
We have conducted the most robust clinical development program for an LDL-C lowering therapy in recent memory; over 1,000 patients enrolled across 18 completed studies to date (by comparison, the pcsk9i Phase 2 programs included an average of less than 500 patients treated in the related Phase 2 programs) to minimize Phase 3 development risk. In LDL-C lowering drug development, 12-week studies are now standard for both Phase 2 and Phase 3 efficacy studies, and were used extensively by the pcsk9i sponsors. For additional context, the Phase 2 LDL-C lowering efficacy studies for the statins were between four and six weeks in duration, and Phase 3 studies for statins were between six and 24 weeks in duration.
There remains a very high unmet need – with millions of patients and their physicians as well as payers still looking for convenient, cost-effective, once-daily oral therapy options. Two years after commercial launch, total pcsk9i prescriptions are less than 10,000. For context, there are approximately 40 million patients in the US taking LDL-C lowering drugs of which approximately one-third – or 13 million patients – are not at their LDL-C lowering goal. Patients, physicians, and payers all note two factors limiting access and commercial uptake of pcsk9is’ at this stage: 1) high cost and high co-pays, and 2) a relatively inconvenient dosing regimen which requires bi-weekly or monthly injections while still taking once-daily oral statin therapy. Bempedoic acid and the fixed-dose combination (with an efficacy profile comparable to PCSK9i monotherapy of approximately 50% LDL-C lowering with added hsCRP lowering of over 25%) has the potential to provide a cost-effective, convenient, once-daily oral therapy solution to these high unmet needs.
Payers have acknowledged that there is still an unmet need for new LDL-C lowering therapies. They have indicated a preference for less costly oral therapies and continue to reserve the use of pcsk9i’s for the highest risk patients. Active utilization management by payers to minimize the use of expensive biologics to reduce elevated LDL-C has proven to be a significant barrier to access for pcsk9i’s. The cost of a pcsk9i’s to a PBM as well as the inconvenience of a bi-weekly or monthly injectable therapy added on to an oral therapy has resulted in less than 10,000 patients in the US currently being treated with pcsk9i’s.
Expectations for Use of Bempedoic Acid Upon the Successful Completion of Phase 3 and Beyond
Our strategy continues to be to develop bempedoic acid and our fixed-dose-combination of bempedoic acid + ezetimibe (BA+EZ) as convenient, cost-effective, once-daily oral LDL-C lowering therapies for ASCVD and/or HeFH patients who need additional LDL-C lowering, and that are complementary to the existing oral standard-of-care therapies. The expected label language for the initial LDL-C lowering indication in the US is below:
- Bempedoic acid (ETC-1002) is indicated as an adjunct to diet and:
- Maximally tolerated statin therapy for treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease, who require additional lowering of low density lipoprotein cholesterol (LDL-C)
- The effect of bempedoic acid on cardiovascular morbidity and mortality has not been determined
- Statin intolerant patients will only be included in the initial LDL-C lowering indication label in Europe. However, statin intolerant patients will be included in the subsequent cardiovascular disease risk reduction indication submission upon successful completion of the CLEAR Outcomes trial in 2022.
FDA has acknowledged that there are patients that can’t or won’t take statins. For instance, in the FDA Briefing Document for the alirocumab Advisory Committee meeting, dated June 9, 2015, on page 8 of 370, the FDA reviewer says that “language that indicates use in combination with “maximally tolerated statin therapy” would recognize that, for some patients, maximally tolerated statin therapy may be no statin therapy at all.”
Bempedoic Acid Mechanism of Action and Supporting Genetic Validation Results
Esperion has worked extensively with the cardiology team at the Cleveland Clinic to design a robust cardiovascular outcomes trial (CVOT). The CLEAR Outcomes CVOT is enrolling ASCVD and/or HeFH patients with elevated LDL-C who are also considered statin intolerant. These patients are taking less than the lowest starting dose of a statin or no statin at all. It is expected that the mean baseline LDL-C level for these patients will be ~135 mg/dL because these patients will not have benefitted from prior statin therapy (e.g., equal to or greater than approved daily starting doses of statins).
To gain additional insight into the potential for success of the CLEAR Outcomes CVOT, Mendelian randomization studies were conducted by a team, led by Dr. Brian Ference, to genetically validate ATP Citrate Lyase inhibition (ACLi), the enzyme target of bempedoic acid. Results from the Mendelian randomization studies presented at ACC in March 2017 demonstrated that genetic variants of ACL have the same effect on the risk for cardiovascular events per unit change in LDL-C as variants that mimic the effects of HMG-CoA reductase (statins), pcsk9i’s and NPC1L1 (ezetimibe). Dr. Ference and colleagues concluded that an ACL inhibitor such as bempedoic acid should reduce the risk of cardiovascular events by the same amount as statins per unit reduction in LDL-C.
The importance of genetic validation of targets for LDL-C lowering and cardiovascular disease risk reduction through Mendelian randomization studies was highlighted at the pcsk9i’s EMDAC meetings in June 2015. Mendelian randomization studies have previously provided genetic target validation for several LDL-receptor-mediated LDL-C lowering therapies including HMG-CoA reductase, the enzyme target of statins, NPC1L1, the enzyme target for ezetimibe and pcsk9i’s and have been published in scientific literature over the past 20 years.
Published in November 2016 in Nature Communications was research conducted by Esperion elucidating the bempedoic acid mechanism of action. Bempedoic acid works two steps up from HMG-CoA reductase in the cholesterol biosynthesis pathway; specifically targets ATP Citrate-Lyase (ACL); is focused only in the liver; and does this without apparent off-target effects. We, and most lipid experts, know that statin use is not limited by the capacity of the cholesterol biosynthesis pathway but by the tolerability of the statins at higher doses. Recall, for example, that simvastatin was tested at doses much higher than the current maximum approved dose of 40 mg, including at least 160 mg. The pathway has considerable additional capacity even at the highest approved doses of the most potent statins. The ability of bempedoic acid to reduce LDL-C by an incremental 20-24% on top of statins illustrates this point because when you double a statin dose, you only reduce LDL-C by a further 6% (the “Rule of Six”). The ability of bempedoic acid to achieve this incremental reduction would be roughly equivalent to 3-4 doublings of the statin dose. The maximum LDL-C lowering with bempedoic acid (and statins) is achieved within 2 – 4 weeks of initiating therapy. Both statins and bempedoic acid show 100% of their LDL-C lowering benefit within 2-4 weeks, so the dosing durations of the studies in Phase 2 can be considered predictive of the LDL-C lowering in Phase 3 where there is longer follow up.
Bempedoic Acid High-Dose Statin Study Results and Overall Integrated Patient Safety Overview
Through more than 1,000 patients enrolled in the Phase 1 and 2 clinical studies, less than 1% of patients have experienced elevated liver transaminases. In the course of the entire Phase 2 program (more than 1,000 patients, most on therapy for 12 weeks), less than 1% of patients on bempedoic acid or in combination with bempedoic acid showed an increase in AST/ALTs. This compares to statins, which have reported AST/ALT elevation rates of 1 – 3%. Note that safety results will vary from study to study, but we and regulators appropriately review these data in the context of the entire program. Note also that single LFT elevations are not considered as AEs, they are required to be repeated and confirmed.
Looking forward, Esperion has a Data Monitoring Committee (DMC) for bempedoic acid, providing oversight for both our ongoing global pivotal Phase 3 program and the ongoing CLEAR Outcomes CVOT. The DMC meets quarterly. All safety data are regularly reviewed by the DMC. We previously completed a very robust Phase 2 program with bempedoic acid in over 1,000 patients. No safety signals have emerged.
In the 035 study, the “real-world” setting for the use of bempedoic acid and statins in actual patients – hypercholesterolemic patients – including the highest dose of one of the most potent statins (80 mg atorvastatin) – showed that the “to-be-marketed” tablet formulation of bempedoic acid had no effect on the Cmax (0%) and a de minimis effect on the AUC (29%) of atorvastatin. In addition, bempedoic acid demonstrated a 22% incremental LDL-C lowering on top of 80 mg of atorvastatin. The 007 study was completed in 2013 with a not-to-be-marketed capsule formulation of the drug and with an escalating dose trial design, both of which are no longer relevant.
Recognizing the complexity of drug development related to determining “bio-equivalence” [e.g., for generics], FDA guidance suggests that drugs are considered to be “bio-equivalent” if the AUC is between 0.80 and 1.25 of the reference drug. As noted earlier, the AUC of atorvastatin is 1.0 when dosed alone and 1.29 when dosed in combination with bempedoic acid. This is well within the range of “bio-equivalence”. More importantly bempedoic acid is well within the range of safety, and the Cmax of atorvastatin is no different when dosed alone or in combination with bempedoic acid. For context, physicians in practice generally consider the Cmax to be more predictive of adverse events and, as noted above, there was no effect of bempedoic acid on the Cmax of atorvastatin.
Study 035 was a double-blind, placebo-controlled study. These types of studies are designed to account for unexpected results in the treatment groups. The LDL-C lowering of bempedoic acid was 22% using the industry-accepted practice of reporting placebo-corrected results. The appropriate interpretation of the results from this small study is that you have to assume that what happened in the placebo control group also happened in the treatment group – and absent treatment with bempedoic acid, we would have seen an increase in LDL-C in the treated group – likely from dietary non-compliance in all patients. For additional context, note that the results from the evolocumab Study 1 in the Repatha label also showed an increase in LDL-C levels in the placebo control group of 7%.
There were five AEs in the 035 study placebo group – and 16 AEs in the treated group. Further, there was one treatment-related AE in the placebo group and seven treatment-related AEs in the treated group. None of the AEs were serious. However, note that the study included only 60 patients and there were no trends in AEs. Importantly, there were no serious AEs in either group.
In the 008 study, note that patients who are statin intolerant would be expected to have, and report, more muscle-related adverse events. Discontinuation from statin therapy because of muscle-related adverse events defines statin intolerance. SAEs are common in Phase 2 studies of any investigational therapy in any therapeutic area. There are a number of events all clearly noted on our 008 disclosure tables as NOT related to treatment. Note that “relatedness” is determined by the investigator and only reported by Esperion. The specific data generated with bempedoic acid in Phase 2 show that all but one of the SAEs was not associated with therapy. The “sudden death” in the 008 study was considered to be possibly related because there was an un-witnessed death of a high-CV-risk patient who had already completed the study and had prior CV events. The results of the autopsy and post-mortem testing were never made available; therefore due to the temporal nature of the death, the potential role of bempedoic acid could not be excluded by the investigator.
Note also that AEs are most appropriately evaluated over the entire Phase 2 program – 1,000 patients worth of data – which we have done. Regulators don’t accept “cherry picking” of safety data – either positive or negative. Safety data are looked at across the entire breadth of the program and patient exposures as part of an integrated summary of safety that will be part of the NDA submission.
We have reported the safety results from all our studies using “industry standard” methodologies. All of our studies have been clearly and completely published in highly regarded, peer-reviewed journals, including the duration of therapy for each study. We have progressively assessed bempedoic acid as monotherapy, added on to low-, moderate- and high-doses of the four most commonly prescribed statins (atorva, rosuva, simva and prava), added on to ezetimibe, across multiple patient populations ranging from hypercholesterolemic patients, to diabetic hypercholesterolemic patients, to hypertensive hypercholesterolemic patients and patients considered statin intolerant across multiple Phase 1 and 2 studies. Data presented in the October 2016 announcement of the 035 results did not include safety data from the previously completed 014 study. However, updated tables pulled from the appendix of the corporate slide deck are below. These data have been publicly available for several months with clear labeling of data sources.
Financial Outlook and Expectations
The total cost of the Esperion CVOT (“CLEAR Outcomes”) is estimated to be approximately $250 million. This is a five to six year study so the total cost will be incurred over that time period. Furthermore, based on our regulatory announcement in March, we are confident that the global pivotal Phase 3 program will support the bempedoic acid and the fixed-dose combination global regulatory submissions for an LDL-C lowering indication by the first-half of 2019 and expected approval by the first-half of 2020. With cash on hand to deliver top-line data from the entire Phase 3 program, the company is well capitalized to continue to create substantial value for the bempedoic acid and fixed-dose-combination programs and our shareholders.
Opportunities for Bempeodic Acid Partnership
We have regular and on-going discussions with multiple potential partners. We are the lipid management experts and have deep and successful experience developing LDL-C lowering drugs and, being very well-capitalized, we haven’t needed a development partner. We have over $200 million in cash at March 31, 2017, which will fund the company into 2019. Finding the right commercial partner(s) for the bempedoic acid and fixed-dose-combination programs is our #1 business priority. However, we will only partner on terms that are in the long-term interests of Esperion’s shareholders and that truly maximize the long-term revenue potential of bempedoic acid and our fixed-dose-combination or doublet pill programs.
External Events on the Horizon
As with FOURIER, we (and other lipid management experts) remain confident that the ODYSSEY Outcomes study will readout as positive in 1H 2018 and demonstrate once-again that “mechanism matters” when it comes to LDL-C lowering and the reduction of cardiovascular disease risk. Like statins, bempedoic acid up-regulates expression of the LDL receptors; and pcsk9i’s preserve LDL receptors. Therapies that impact the LDL receptor have consistently demonstrated over the past almost 40 years that they reduce cardiovascular disease risk. As FOURIER also demonstrated, duration of therapy in cardiovascular outcomes trials matters (e.g., shorter duration of therapy results in lower reported CV risk reduction); the patients in FOURIER had a mean duration of therapy of only 26 months. By comparison, it’s estimated that the duration of therapy in ODYSSEY Outcomes will be approximately 36 months. For additional context, the duration of therapy expected in CLEAR Outcomes is approximately 42 – 45 months.
Three CETP inhibitors have previously failed in Phase 3 clinical trials, most recently evacetrapib in October 2015. The CETPi class has, unfortunately, not met expectations and, among other issues, the mechanism for lowering LDL-C is still not understood. Even if the results of REVEAL (the anacetrapib CV Outcomes trial) are positive, this drug has extremely long tissue residence times which many experts believe could severely limit its commercial potential. Based on the Silverman et al paper from JAMA (October 2016), it is acknowledged that not all LDL-C lowering mechanisms result in CV risk reduction. Based on available data, it is understood that LDL-C lowering through the LDL receptor is expected to reduce CV disease risk. Mendelian randomization studies have shown that inhibition of HMG-CoA reductase (statins), NPC1L1 (ezetimibe), pcsk9 and ACL (bempedoic acid) reduces LDL-C and reduces cardiovascular disease risk. CETP inhibition on top of statins has not been demonstrated to be predictive of CV risk reduction.
While we can’t predict the future, we remain confident that LDL-C lowering will remain an accepted regulatory surrogate for cardiovascular disease risk reduction – as it has been for the past more-than 40 years.
Expected Bempedoic Acid Catalysts
In March we announced initiation of a non-registrational Phase 2 triplet oral therapy study of bempedoic acid 180 mg + ezetimibe 10 mg + atorvastatin 20 mg to explore the safety, tolerability, and the LDL-C lowering potential of these complementary, convenient and cost-effective once-daily oral therapies. Bempedoic acid has been dosed with ezetimibe; bempedoic acid provides 30% LDL-C lowering and ezetimibe provides 18% LDL-C lowering for a total of 48% LDL-C lowering when combined. Bempedoic acid has been administered with all approved doses of atorvastatin and provides approximately 22% incremental LDL-C lowering. Atorvastatin and ezetimibe have been dosed together previously and the label for ezetimibe shows 37 – 54 % LDL-C lowering with atorvastatin alone (10-80 mg) and 7 – 16% incremental LDL-C lowering (the incremental 7% LDL-C lowering is in combination with atorvastatin 80 mg) with ezetimibe. Our triplet oral therapy study is the natural evolution of having studied each of the doublet combinations previously. The study is fully enrolled, the last patient/last visit will occur this month, and we remain confident in the study design with top-line results to now be announced next quarter (Q3 2017).
Next month we have plans to announce our clinical development and regulatory strategy for development of the fixed-dose-combination of bempedoic acid + ezetimibe (BA+EZ). Expectations for this product are based on previously conducted studies which demonstrated an approximate 50% LDL-C lowering and > 25% hsCRP reduction. Importantly, the doublet pill is a convenient, oral, once-daily LDL-C lowering drug that will be cost-effective. Bempedoic acid and the fixed-dose-combination are positioned as complementary to both statins and to ezetimibe, the standard of care LDL-C lowering therapies. Furthermore, bempedoic acid administered as monotherapy has consistently shown 30% LDL-C lowering in clinical trials conducted to date which is far superior to Zetia (ezetimibe) alone which is typically shows 15%-18% LDL-C lowering.
As previously announced, top-line results from all four global pivotal Phase 3 safety and efficacy studies will be released starting in the second quarter of 2018.
This post contains forward-looking statements that are made pursuant to the safe harbor provisions of the federal securities laws, including statements regarding the regulatory approval pathway for bempedoic acid, the therapeutic potential of, and clinical development plan for, bempedoic acid, including the Company’s timing, designs, plans, and announcement of results regarding its global Phase 3 long-term safety and tolerability program and CVOT for bempedoic acid, and the Company’s expected cash and liquidity position and outlook. Any express or implied statements contained in this post that are not statements of historical fact, including interpretation of guidance given by the FDA, may be deemed to be forward-looking statements. Forward-looking statements involve risks and uncertainties that could cause Esperion’s actual results to differ significantly from those projected, including, without limitation, changes in the FDA guidance for regulatory approval, delays or failures in the Company’s studies, including risks regarding the FDA’s interpretation of the Company’s clinical trial results, the risk that U.S. Food and Drug Administration may require additional studies or data, that Esperion may need to change the design of its Phase 3 program, that positive results from a clinical study of bempedoic acid may not be sufficient for FDA approval or necessarily be predictive of the results of future clinical studies, particularly in different or larger patient populations, that existing cash resources may be used more quickly than anticipated, that Esperion’s global Phase 3 long-term safety and tolerability program for bempedoic acid may not produce sufficient safety or tolerability results or show meaningful change in LDL-C, that the CVOT may not demonstrate that bempedoic acid leads to cardiovascular risk reduction or other key lipid measures of patients, if approved that Esperion’s product could have labeling restrictions that impact its marketing and adoption, or the risk that other unanticipated developments or data could interfere with the scope of development and commercialization of bempedoic acid, and the risks detailed in Esperion’s filings with the Securities and Exchange Commission. The FDA guidance described in this post was given as of a specific date and the FDA could change its position on the clinical endpoints or other standards for review/approval. You are cautioned not to place undue reliance on the forward-looking statements, which speak only as of the date of this post. Actual results could differ from those described therein. Esperion disclaims any obligation or undertaking to update or revise any forward-looking statements contained in this post, other than to the extent required by law.