Cholesterol Drugs Haunted By Ghosts Of Past, Present, And Future

Please also see this preview of IMPROVE-IT: What You Need To Know About IMPROVE-IT

Cholesterol drugs, both new and old, are in the news again. There's a lot going on now but the picture won't really become clear until next month, when the results of a decade-old trial will finally be revealed. Briefly, here's what's happening:

• Two new trials presented fresh evidence that PCSK9s, the much discussed new class of cholesterol drugs, have powerful LDL-lowering properties.
• A new drug from Esperion, the phoenix of biotech companies, also showed promising results. The drug, ETC-1002, is a few years behind the PCSK9s in development but has some important theoretical advantages that may prove very important down the road.
• At the annual meeting of the American Heart Association in November the results of the IMPROVE-IT trial will be presented. The results of this trial, as I have argued in the past, may have a broad if not decisive impact on the future of the PCSK9s and ETC-1002.

 PCSK9: The Ghost of the Present

The Lancet yesterday published the results of two new studies showing that Amgen's evolocumab was effective in reducing LDL cholesterol in patients with familial hypercholesterolemia (FH), a genetic disposition to high LDL cholesterol levels. In Rutherford-2, injections of evolocumab in people with heterozygous FH resulted in impressive 60% reductions in their LDL levels compared with placebo. In Tesla Part B, people with the more severe and much rarer form of homozygous FH had a 31% reduction in LDL compared with placebo. Patients in both trials were also taking standard lipid-lowering therapies, including statins and ezetimibe.

These results should come as little surprise to anyone who has been following the development of the PCSK9s. There is now an abundance of trials showing that evolocumab and its rival,  Sanofi's and Regeneron's alirocumab, are extraordinarily effective at reducing LDL in a wide variety of patient groups and clinical situations.

It is widely believed that these drugs will gain FDA approval next year for use in FH patients and in statin-intolerant patients. (It should also not come as a Casablanca shock that there have been a host of studies in recent years showing that these conditions, once thought to be relatively rare, are in fact extremely widespread.)

But there is a minority opinion that holds that approval would be premature without solid long-term evidence showing that these drugs, which are potent monoclonal antibodies that require regular injections, are safe and will in fact reduce cardiovascular events. The PCSK9 advocates argue that the drugs should be approved for these "limited" populations, with broader approval in larger populations contingent on long term outcome studies. (At the end of August the first hint of outcomes data for alirocumab was presented, but this small-- there were only 46 cardiovascular endpoints-- post-hoc analysis of a trial neither designed nor powered to study outcomes won't satisfy critics.)

Esperion's ETC-1002: The Ghost of the Future

A few years behind in development is ETC-1002, a novel oral drug from Esperion. Even if you knew nothing about the drug the astonishing backstory behind Esperion would compel you to take a close look. Briefly, Esperion founder Roger Newton was one of the key players in the development of atorvastatin (Lipitor) at Pfizer. He then formed the first incarnation of Esperion, which Pfizer then subsequently bought for $1.3 billion in 2003. After Pfizer abandoned the projects Esperion had been working on Newton regained the company from Pfizer and eventually began serious development of ETC-1002.

ETC-1002 interferes with cholesterol synthesis and carbohydrate metabolism by inhibiting ATP-citrate lyase  and activating a complementary enzyme, AMPK. For now Esperion is focusing on its LDL cholesterol lowering effects and, following the strategy of the PCSK9s, hopes to gain an initial approval for patients who can't tolerate statins. But the drug's effects on carbohydrate metabolism leads to suspicions that ultimately the company may have much broader ambitions. Early results offer hints of important additional effects, including lowering blood pressure, lowering weight, and reducing inflammation. Unlike statins, which have caused controversy because they increase glucose, ETC-1002 may lower or have a neutral effect on glucose.

Yesterday Esperion announced positive top line results of a phase 2b trial evaluating the safety and efficacy of ETC-1002 alone and in combination with ezetimibe with ezetimibe alone in patients with high cholesterol levels with or without statin intolerance. The results (see below) show that ETC-1002 effectively lowers LDL by itself and in combination with ezetimibe. Perhaps even more intriguing, the reduction in inflammation, as measured by hsCRP, raises the hope of additional benefits, though of course at this point no one can say for sure what this may mean. The company also said that the drug was safe and well tolerated in the study.

Here is the change in LDL over 12 weeks:

Here is the change in hsCRP over 12 weeks:

Some people believe that in the long run ETC-1002 could steal much of the thunder from the PCSK9s, which so far have garnered the lion's share of attention. As a cheaper oral drug with multiple other potential benefits this seems plausible, but of course it is still far too early to tell whether this drug will be able to deliver on these hopes.

Esperion's CEO Tim Mayleben told FierceBiotech that it plans to enroll 4,000 patients in phase III studies by the end of next year, after meeting with the FDA. Mayleben said the company has the resources to perform these trials on its own but has received "significant inbound interest from potential partners."

IMPROVE-IT: The Ghost of the Past

As I have argued before, I think the fate of the PCSK9s and ETC-1002 may well hinge on the results of the highly controversial  IMPROVE-IT trial, which will finally be revealed on November 17 during the annual meeting of the American Heart Association.  IMPROVE-IT compared the effect on cardiovascular outcomes of the statin simvastatin with Vytorin (the combination of simvastatin and ezetimibe, manufactured by Merck) in more than 18,000 patients with acute coronary syndromes.

In case you're not aware, ezetimibe and IMPROVE-IT have been the subject of intense controversy for a long time now. Early on ezetimibe was criticized following its initial approval because although it had been shown to reduce LDL cholesterol there were no studies testing its long-term effects on cardiovascular outcomes. The drug became a huge best seller for Merck and Schering Plough and was often prescribed along with a statin as initial first-line therapy.

I won't here rehearse again the extremely complicated subsequent tale of this drug. Suffice it to say that now, 12 years after its approval, IMPROVE-IT will provide the first real evidence about the clinical benefits of ezetimbe. And it will also provide the first real evidence in the modern era about the role of LDL as a surrogate endpoint. Unlike statins, which appear to have multiple mechanisms of action, ezetimibe is a pure LDL-lowering drug. So IMPROVE-IT will provide vital new raw material to the debate about the reliability of surrogate endpoints in general and the independent importance of lowering LDL cholesterol in particular.

The key thing now is that if IMPROVE-IT meets its primary endpoint then the FDA will be far more inclined to accept LDL-lowering as a surrogate endpoint and the PCSK9 inhibitors may well gain early approval. On the other hand, if IMPROVE-IT does not meet its primary endpoint then this approval will be far more problematic, in my opinion.

In response to concerns that IMPROVE-IT may be negative some cholesterol experts-- including many with connections to industry-- have argued that IMPROVE-IT will not provide a definitive answer to the important questions about surrogates and LDL. They argue that the patients in IMPROVE-IT won't be able to show a beneficial effect because patients were not at high enough risk and that ezetimibe is not a potent enough drug to show benefit.

There may be some value to these points, but if IMPROVE-IT is negative it seems highly likely that FDA reviewers and FDA advisory panel members will be far more likely to cast a skeptical eye on LDL as a surrogate endpoint and new drugs that lower LDL but have not been shown to have a clinical benefit.

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