This is Tim Mayleben – CEO of Esperion Therapeutics with some thoughts I wanted to share. Please read on if you’re interested.
First, a little history. Esperion Therapeutics was founded by my good friend and colleague, Roger Newton. You may remember that Roger was the co-discoverer and product champion for Lipitor, the best-selling LDL-cholesterol lowering drug in history (+$125 billion in worldwide revenue and counting). He was also the founder and CEO of the original Esperion. I was COO and CFO there. Roger and I have been great friends and business partners for almost 20 years. To provide a bit more history, in November 2003, just before our company was acquired by Pfizer for $1.3 billion and where our lead product was ApoA-I Milano/ETC-216, this article was published in Forbes (http://www.forbes.com/forbes/2003/1124/273.html). Roger also founded the current Esperion back in 2008 and I helped him spin bempedoic acid/ETC-1002 out from Pfizer, a drug that Roger and our team discovered at the original Esperion. Bempedoic acid is in Phase 3 clinical trials as I write this.
What should you know about me? I’m in my mid-fifties and have six kids, one of which currently serves our country in the US Army. I work very long hours and my significant other makes sure everything else in our life is balanced. I own a lot of shares of Esperion – most of which I’ve purchased with my own money. I’ve never sold a single share of our stock. I’m both financially and personally committed to the long-term success of bempedoic acid and Esperion – more on my personal commitment below. When our stock ran up over $100/share last spring, neither I, nor any of the Esperion leadership team, sold a single share of stock. I am committed to the long-term success of Esperion. I believe that the investors that entrusted us with their money should profit first – and many – though not all yet, have. I don’t ask my team to do anything I wouldn’t do. I believe in leading by example. I believe in telling it like it is.
Drug development is expensive. To support bempedoic acid, we’ve raised almost $450 million since 2008 – most of it since Esperion went public in June 2013. Drug development is also what I call a “long game”; success is not measured in days, weeks or months – success is measured in years. There are countless ups and downs and wins and losses along the way. It’s a lot of work. Your team has to be super-smart, super-experienced, and, yes, lucky sometimes, too. It takes grit. It takes persistence. It takes resiliency, especially when things don’t go your way. Most of all it takes team work. I constantly remind our team that “drug development is a team sport.” Even with some of the smartest people in the world working in our industry, success is still measured in low percentages according to industry statistics (https://www.bio.org/media/press-release/new-study-shows-rate-drug-approvals-lower-previously-reported-0). At Esperion, we’ve assembled a team that is among the most successful and experienced in developing lipid regulating drugs anywhere in the world. We work incredibly hard. We are passionate. We are committed to the success of bempedoic acid and Esperion. We believe we’ve stacked the percentages in favor of both bempedoic acid and Esperion.
Our industry – the pharmaceutical industry – is highly regulated. The US Food and Drug Administration (FDA) decides how drugs should be developed and which drugs are approved in the US. In Europe, it’s the European Medicines Agency (EMA). In some therapeutic areas, the guidelines for the development and approval of drugs are consistent year in and year out. In other therapeutic areas, the guidelines have gone from clear and certain to unclear and uncertain at times. For example, the development and regulatory approval of antibiotics in the US went through an extended period of uncertainty and change (see http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4378521/). As a result, the development of innovative antibiotics was temporarily stifled. More recently, the regulatory uncertainties have been lifted with new regulatory guidelines, and our industry has responded by racing to develop much-needed, innovative antibiotic therapies. Similarly, diabetes drug development went through a period of regulatory uncertainty in the last decade (see http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4522876/). Based on this, many experts believe that the development of innovative diabetes drugs was temporarily stifled; meanwhile diabetes is reaching epidemic proportions in the US.
The development and approval of LDL-cholesterol lowering drugs in the US may be approaching a period of uncertainty as we recently learned from the FDA that it can’t predict if LDL-cholesterol lowering will continue to be a surrogate endpoint for the approval of new LDL-cholesterol lowering drugs in the US in the future. The FDA may have had this uncertainty for several years now, including the period leading up to the announcement of the positive IMPROVE-IT results in November 2014. Nevertheless, as we saw in the summer of 2015, FDA approved two new LDL-cholesterol lowering drugs using LDL-cholesterol lowering as a surrogate endpoint. Let me be clear: no one, including Esperion, knows if LDL-cholesterol lowering will continue to be an accepted surrogate endpoint; but history certainly suggests it will continue to be an accepted surrogate for approval.
In the face of potential US regulatory uncertainty, we are navigating what we believe is the most optimal path to approval. What are we planning to do? We’re creating options for the submission and approval of bempedoic acid in the US – and moving rapidly forward with our plans for global approval, starting with the EU. Since LDL-cholesterol lowering may remain a surrogate endpoint in the US, we’re going to run our Phase 3 clinical studies for up to 52 weeks to demonstrate that bempedoic acid is safe and well-tolerated – the traditional standard for approval in the US and around the world. We expect to submit the results from these Phase 3 studies to both US FDA and EMA – in approximately 3,000 patients – by 2019. If FDA determines that LDL-cholesterol lowering is no longer an approvable surrogate endpoint in the US, we will have our large outcomes study already ongoing and we expect to submit the completed results from this study by 2022, if not earlier. We are preparing for any future changes in the regulatory terrain and are working to create options for bempedoic acid, despite potential future regulatory uncertainty.
Our drug, bempedoic acid, has, delivered robust, positive results in all completed clinical trials. It’s an oral drug that’s convenient to take; and we believe it will be cost-effective. It lowers LDL-cholesterol – the bad cholesterol – by 30% and hsCRP, a key marker of inflammation, by up to 40%. We say it works like a statin, but with reduced potential to cause muscle-related side effects (it’s estimated that about 10% of patients – 3.5 million in both the US and Europe and 8 million worldwide – who are prescribed statins can’t take statin drugs, or can’t take the dose of a statin needed to get their LDL–cholesterol under control). No other company is focusing so intently on these patients and working so diligently to address their needs. We have a definition for statin intolerance for our global clinical trials, though we may not see the term we use today to identify these patients – “statin intolerance” – used in product labeling. And that’s OK. We and global regulators will work to come up with the right term(s) to use for labeling in the future. It’s a subtle point, but an important one.
Bempedoic acid has also been shown to work well, and is well-tolerated, in combination with other popular oral, LDL-cholesterol lowering drugs like Lipitor and Zetia. In our completed Phase 1 and 2 clinical trials, bempedoic acid has done everything that we wanted and expected it to do: in addition to lowering LDL-cholesterol and reducing hsCRP, it has been well-tolerated by all kinds of patients, especially those who can’t tolerate statins; it appears safe, too. For a chronic therapy – one that many patients will take for the rest of their lives – that’s critically important.
But we don’t yet know everything about bempedoic acid, which is why we have ongoing clinical trials. The combination of statins and bempedoic acid has mildly increased blood drug levels in combination with statins. We have not been concerned by this because we have a very deep knowledge of the cholesterol biosynthesis pathway – more than 30 years of experience with the pathway in many cases – but we don’t yet have the clinical data to support our confidence. We are data-driven, and in keeping with our commitment to transparency, are collecting the necessary clinical results to support our understanding of bempedoic acid.
Esperion is working to change the world. We want to help those patients that can’t take statins. In a twist of fate, one of them is my significant other. Here is her story: she just turned 55, and last year she went for a physical – something that probably, like many of you, she hadn’t done for many years. She eats well, and looks to be in very good health – but we found out her LDL-cholesterol hovered near 190 mg/dL (this is considered quite high!). From working with Roger over the years and now, more recently, with Dr. Mary McGowan (Esperion’s CMO), we knew her cholesterol was too high, so she was prescribed a statin (10mg of Lipitor, of course!) by her doctor. Within three days she began suffering from extreme muscle aches and muscle stiffness. She couldn’t get out of the bathtub. She quit taking Lipitor and called her doctor. As has been experienced by many other patients, her doctor told her to “get over it” and keep taking her statin. Needless to say, she didn’t. And she didn’t go back to that doctor. High LDL-cholesterol typically doesn’t make anyone feel bad and she felt fine once she stopped taking Lipitor. But we both knew her cholesterol was too high – and if she didn’t do something, we could all suffer dramatically. I experienced a tragic loss early in my own life; my dad died of a heart attack caused by high LDL-cholesterol and atherosclerosis, leaving my mom to raise six kids alone.
Several months passed after my significant other abandoned her physician and her statin regimen to find another doctor, and she received a new referral in May. She had her cholesterol tested again and it was still around 190 mg/dL. This time she asked for Crestor and her doctor agreed and prescribed that for her. She filled the prescription and started taking 5 mg of Crestor that same month. After only three days, the muscle pain returned again. Her doctor lowered the effective dose by telling her to take the drug every-other-day – and still the muscle pain persisted. After just one week, she stopped taking Crestor. Her cholesterol remains elevated and she sees her doctor again this month – and will probably try Zetia. Unfortunately, Zetia will likely only lower her cholesterol by 15 – 20% and she will need something more.
My point in telling you this personal story is that it’s very similar to the stories of many other patients with whom I’ve met or who have written to me to say they can’t and won’t take statins. These patients and their physicians want to lower their elevated LDL-cholesterol. But since they can’t take statins – they don’t have enough good options. They are not well-served with the currently available therapies. We expect to change that.
Here’s how I think about Esperion and bempedoic acid: we know we have an oral drug that lowers LDL-cholesterol. We have a very “accessible” therapy – as Dr. Christie Ballantyne has said, it’s “patient friendly, physician friendly, and payer friendly.” Bempedoic acid is a drug discovered by an Esperion team led by one of the most successful lipid drug developers in history, Roger Newton. It’s been safe and well-tolerated in almost one thousand patients. We don’t know everything about bempedoic acid – but we’re running the final clinical trials to find out what we don’t yet know – long-term safety and tolerability, and how bempedoic acid works with the highest doses of statins. We have the money we need to complete our Phase 3 trials and prepare us to submit the results for global approval for an LDL-cholesterol lowering indication by 2019. We’re navigating the unknown future US regulatory terrain and creating all the right options for Esperion, bempedoic acid and our investors. In the meantime, we have a clear regulatory path to submission in Europe – a market that is equal in size to the US market. We believe we have positioned Esperion and bempedoic acid for success no matter how the future regulatory terrain changes.
Looking even further into the future, will bempedoic acid be prescribed and reimbursed when it’s approved for LDL-cholesterol lowering? No one knows for sure. The historical precedent for an oral, non-statin LDL-cholesterol lowering drug, Zetia, suggests yes (Zetia has recorded more than $50 billion in global revenue since its approval for LDL-cholesterol lowering). Much has been made of the lack of commercial success of the PCSK9 drug class. We are strong supporters of this drug class, but continue to believe these expensive, injectable drugs will eventually be commercially successful by serving the needs of the most severely ill patients.
We at Esperion are stepping rapidly and thoughtfully into the future; and making sure that we communicate clearly as the clinical development and regulatory future unfolds. To paraphrase Margaret Meade: “Never doubt that a small group of thoughtful committed people can change the world. Indeed, it is the only thing that ever has.”
I encourage you to stay tuned. We are working hard for patients who can’t and won’t take statins. We’re working hard to give physicians a new, oral accessible LDL-cholesterol lowering drug. We’re confident that if we get it right for patients and physicians, our investors will be enormously rewarded.