Esperion Therapeutics is a company based out of Ann Arbor, Michigan. Esperion was (re)launched by biotech mastermind Roger Newton in May 2008. The company was launched with the intent to treat cardiovascular diseases after it had secured a molecule, bempedoic acid, from Pfizer. Esperion sets itself apart from its competitors with a first-rate science team; a strong cash position; and a drug that is in late stage clinical trials. Bempedoic acid is now in a phase III program.
On January 25, 2017, Esperion Therapeutics announced that it had completed enrollment of ~2000 patients in its pivotal phase III long-term safety and tolerability study of bempedoic acid, CLEAR Harmony. The study was recently expanded to include high cholesterol patients already on the maximum tolerated dose of a statin of any kind. Esperion’s management explained that they expect the expansion of the study to support the company’s regulatory submission for the LDL-C lowering indication. Esperion now anticipates top-line results from the study in the second quarter of 2018 (previously projected as mid-2018). Furthermore, Esperion outlined a number of major milestones for 2017.
Complete Phase III Trial Recruitment
The completion of recruitment in CLEAR Harmony now moves our milestone focus to the recruitment efforts of Esperion for CLEAR Serenity, CLEAR Tranquility, CLEAR Wisdom, and the CLEAR Outcomes trials. Esperion announced that it plans to have all phase III trials fully enrolled by the end of 2017.I suspect that CLEAR Wisdom is next on Esperion’s list to meet patient recruitment goals. HoIver, due to the shorter timelines and smaller patient populations of CLEAR Serenity and CLEAR Tranquility, I wouldn’t be surprised if these two studies met their recruitment targets earlier than anticipated. Below is a table that briefly summarizes the CLEAR Program.
Esperion Therapeutics - CLEAR Program
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Phase III Program
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Study Duration
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Total Patients
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Est. Completion
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5 Years
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~12,600
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2022
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52 weeks
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1,950
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1Q-2018
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52 weeks
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750
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Mid-2018
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24 weeks
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300
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Mid-2018
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12 weeks
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225
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Mid-2018
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Launch of Phase II Trials
At the recent JP Morgan Healthcare Conference, Esperion Therapeutics outlined two phase II studies that it will initiate in the first half of 2017. One study will explore the benefit of combination therapy with bempedoic acid a PCSK9 inhibitor. The second study will explore the benefits derived from a triple combination therapy: bempedoic acid, a statin, and ezetimibe. Both of these studies will help bolster bempedoic acid and its potential to acquire a broad label. This is likely to make Esperion and bempedoic acid a much more palatable acquisition target for a large pharma that is interested in entering and/or maintaining its position in the cardiovascular space.
Combination with Ezetimibe
In its recent discussion at the JP Morgan Healthcare Conference, Esperion announced that it planned to deliver to investors a clinical and regulatory development plan for a combination of bempedoic acid and Ezetimibe (BA+EZ) in the first half of 2017. Esperion has been talking about doing a fixed dose combination since October, 2016, and I are now beginning to see the program take shape. Esperion plans to approach the FDA with an NDA for a fixed dose combination therapy in the second half of 2019. This timeline closely mirrors what Alan, a cardiovascular expert from BioWatch News, stated back in March of 2015 when discussing the 008 study.
“Unless the FDA has given guidance that it can indeed simultaneously approve both therapies, I think it's best to conservatively estimate that the combo tablet gets its approval decision within 90 days of the PDUFA for the monotherapy.”
I have not seen any specific guidance from the FDA regarding bempedoic acid as a combination therapy.
BA+EZ Efficacy & Safety
It has been some time since I last reported on BA+EZ efficacy and safety. Thus, I thought it wise to bring it back to the forefront for our readers. As evidenced in the chart provided below (courtesy of Esperion Therapeutics), the BA+EZ combination reduces LDL-C by almost 50% in statin intolerant patients. 
This is comparable to receiving a maximum dose of Rosuvastatin (taken once daily as a monotherapy) or evolocumab (given as a subcutaneous injection once every two Ieks). The combination has potential, but I will need to see follow-up studies that revalidate the efficacy and safety of the combo. A revalidation would be significant because it would provide Esperion with several unique options for bempedoic acid, including:
- An extended patent life
- The ezetimibe US patent expires in April, 2017
- A combo patent extends the protection to bempedoic acid. Especially
because the combo therapy is much more efficient than bempedoic acid as a mono-therapy.
- Potential for becoming standard of care?
The Lone CETP inhibitor and PCSK9i’s
The Lone CETPi
Recently, a number of CETP inhibitors have fallen off the lipid loIring rails due to an increase in cardiovascular events for those undergoing CETP therapy. There is currently only one remaining CETP inhibitor that is conducting phase III trials: Merck’s anacetrapib. Unlike torcetrapib, anacetrapib doesn’t appear to raise the levels of aldosterone or cortisol, which can lead to higher cardiovascular events due to a raise in blood pressure. Anacetrapib may appear to be gentler than torcetrapib, but I’m not convinced that it will significantly reduce cardiovascular events over a long period of time. A 2010 study of anacetrapib shoId higher levels of deaths due to cardiovascular causes than placebo. Further, death from any cause occurred in 11 patients in the anacetrapib treatment group vs. 8 in the placebo group. The results may appear grim, but I have leave the door of possibility open because anacetrapib does have some positive characteristics. In the 2010 trial, anacetrapib treated patients saw significantly less revascularization than placebo treated patients. Thus, it is possible that anacetrapib helps the body clear plaque buildup in arteries. Whether that will translate to significant, long-term reduction of cardiovascular events remains questionable. I anticipate results will become available sometime in 1Q-2017.
PCSK9i - The Injuncted
PCSK9i therapy is considered invasive and not cost-effective. A recent study that was published in JAMA concluded, “for PCSK9 inhibitors to be cost-effective at $100,000 per QALY, the annual drug costs would need to be reduced from $14,350 to $4,536 per patient or less.” Bempedoic acid is a small molecule and is therefore much cheaper to produce per unit than it is for PCSK9i. This is a considerable strength for Esperion because, assuming it’s approved, bempedoic acid will be able to compete on price right from the start. If bempedoic acid is paired with a generic statin and/or ezetimibe, the PCSK9 drugs will lose the cost and convenience argument. HoIver, PCSK9i drugs have the potential to reduce LDL-C levels quickly and drastically. In order for bempedoic acid to compete in this space, it will have to get close to the efficacy that has been exhibited by PCSK9i’s.
The PCSK9i space has gotten very interesting lately. On January 3rd, 2017, a federal judge denied Regeneron and Sanofi’s attempt to toss out a previous court ruling that concluded that Praluent violated Amgen’s patents of Repatha, Amgen’s PCSK9i. The new ruling prohibits Regeneron and Sanofi from selling Praluent in the United States. If this ruling Ire to be upheld on appeal, Amgen’s potential to take over the cardiovascular space will grow substantially. Regeneron and Sanofi still have the option to fight on through a federal appeals court or reach a settlement agreement with Amgen. Whatever the case, there will surely be further drama in the coming months as both companies have plans to release CVOT data soon.
Recently, the Glagov study, a study of Amgen’s Repatha, shoId that a PCSK9i paired with a statin has the potential for remarkable results . Glagov was not intended to be a cardiovascular outcomes study, but nevertheless measured cardiovascular events of patients. Results of Glagov shoId that a combination of evolocumab and a statin result in loIr cardiovascular events than placebo (these included nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, and coronary revascularization). Of all the treated patients with Repatha, only one patient exhibited signs of anti-Repatha antibodies, which suggests that Repatha might not face the same problems that plagued Pfizers bocicizumab .
Repatha CVOT Results
Today, Amgen announced that the FOURIER trial, a cardiovascular outcomes analysis of Repatha when paired with a statin, met its primary and secondary endpoints. The announcement stated that “Repatha significantly reduced the risk of cardiovascular events.” Amgen also announced that the EBBINGHAUS Study also met its primary endpoint, showing that Repatha has no effect on cognitive function. Amgen had a lot riding on this CVOT’s success. Amgen’s recent injunction against Regeneron and Sanofi’s sale of Praluent in the USA has helped to drive the sales of Repatha upward. I suspect February sales will continue to grow.
Amgen did not release specific data regarding the study, but plans to do so at the American College of Cardiology conference on March 17th, 2017. Strong CVOT results will likely eliminate doctor’s concerns about the PCSK9 drug class thereby causing them to prescribe treatment more frequently. Further, strong results will likely also open up the purse of insurance companies who are waiting to see if there are any long-term benefits from the treatment. Weak results would likely hinder Repatha sales. Support for the PCSK9i drug class would likely evaporate. However, previous data from the GLAGOV study suggests that this will not be the likely scenario. I expect overly positive results. Further, I suspect that Repatha’s FOURIER study will encourage the FDA to give its position on the LDL hypothesis - something crucial to the development of bempedoic acid.
The LDL Hypothesis
Esperion management claims bempedoic acid is not a replacement for statins or ezetimibe. Instead, management has stated that bempedoic acid is being positioned to complement these therapies. I think bempedoic acid is being positioned as the leading drug for reducing LDL-C. If Esperion can prove strong efficacy and safety in a double or triple combo, it will place a deep footprint in the cardiovascular space.
LDL reduction, alone, may not be the holy grail I once thought it was. In seeing the rise and fall of competitors in this space, I am convinced that LDL reduction is just a part of the story. In September, 2016, Alan (from BioWatch News) stated:
“The spirit of the law is crucial, not just the letter – How LDL reduction is achieved may be more important than the actual reduction. Are the especially pathogenic LDL subsets lowered?”
It is important to point out that the combination of bempedoic acid and ezetimibe reduces measures involving disease associated lipids, lipoproteins, and inflammation (LDL-C, LDL Particle Number, apolipoprotein B, total cholesterol, Non-HDL-C, HsCRP, Triglycerides). Furthermore, the combination of the two saw a modest increase in HDL particles, which are considered a predictor of reduced risk of coronary heart disease. The combination of ezetimibe and bemepedoic acid resembles that of PCSK9i therapy. However, PCSK9i treatment lacks one component that I consider to be a crucial piece of the puzzle, the reduction of inflammation (hsCRP).
“Statins reduce inflammation, PCSK9 drugs don’t. It’s no coincidence that the GLAGOV and FOURIER trials involves patients taking statins too.”
I believe Alan is dead on. PCSK9i’s are great at what they do, but they need help. Furthermore, I anticipate that we will see a greater number of patients that developed antibodies for the PCSK9 treatment over the course of the trial. Thus, the presentation to the FDA will be of great importance to Esperion investors.
Final Thoughts
The Esperion team still has a great deal of work ahead. Investors should remain vigilant in regards to future outcomes data being released as these data could have a profound impact on bempedoic acid’s future requirements with the FDA. I expect to hear more from Esperion when it delivers its 2016 earnings call in late February.
