On Tuesday, the American Heart Association and the American College of Cardiology changed the guidelines for the use of LDL cholesterol-lowering statin drugs in patients at risk of heart disease or stroke. That change -- when considered next to an FDA panel's scathing rejection of Amarin's triglyceride-lowering drug Vascepa -- signals a shift in the way the field thinks about cardiovascular disease. With Amgen (NASDAQ:AMGN) , Regeneron (NASDAQ:REGN), Sanofi, Pfizer (NYSE:PFE), and a multitude of others on the verge of unrolling the next generation of cholesterol-lowering drugs, it's important to understand how these changes will impact the regulatory landscape.
The new guidelines
Previously, patients with elevated LDL cholesterol were prescribed statins, like Pfizer's Lipitor, and were given a target LDL blood concentration of 70 or 100 mg/dl, depending on the patient. That's no longer the case after several trials, including Merck's (NYSE:MRK) HPS2-THRIVE study of Tredaptive, showed no additional reduction in cardiovascular risk when LDL-lowering drugs were added to statins.
Now, doctors will focus much less on the lab numbers, and much more on the clinical outcome. Doctors will use a new risk calculator to determine if a patient is at risk of heart attack or stroke, and those patients will be prescribed statins continually regardless of achieving substantial reductions in LDL.
The guideline will have two impacts on currently approved drugs. First, it greatly increases the number of patients for which statins are indicated. According to The Wall Street Journal, the authors estimate that the new guidelines could double the number of patients who qualify for statins. That could benefit a company like AstraZeneca (NYSE:AZN), which boasts the only patent-protected statin in Crestor. Crestor is also one of the most potent statins, and it brought in $6.23 billion in 2012. That's good news for a company that could really use a boost.
On the other hand, the guidelines implicitly discourage the use of add-on therapies. Merck's(NYSE:MRK) Zetia, for example, reduces LDL cholesterol by blocking the absorption of cholesterol in the intestine, and is used in some patients who don't achieve their LDL goals on statins alone. While trials have shown a beneficial effect on LDL cholesterol when added to statin therapy, it has not been shown to significantly reduce the risk of heart attack or stroke in a clinical outcomes study. Merck is undertaking the IMPROVE-IT trial to prove that its Vytorin -- a Zetia/statin combo therapy -- does have a clinically relevant benefit, but until that trial reads out clinicians could cut back on Zetia/Vytorin prescriptions.
What about PCSK9 inhibitors?
This seems to be a question that keeps coming up since an FDA panel voted against recommending approval of Amarin's fish oil pill Vascepa, on the grounds that the clinical benefits of triglyceride reduction in moderate cases was unsubstantiated. In fact, it was an important topic of conversation in Amgen's quarterly conference call.
PCSK9 inhibitors lower LDL cholesterol by mimicking a naturally occurring mutation in individuals with remarkably low cholesterol. Trial results for Amgen's AMG145, Regeneron's alirocumab, and Pfizer's RN-316 have shown stellar results in mid-stage trials as statin add-ons and stand-alone monotherapies. The big question, though, is if the surrogate read-out of LDL reduction will translate into a benefit for patients.
If these drugs hope to supplant statins as the cholesterol kings, they'll have to earn their keep. In anticipation of a similar FDA panel response to Amarin, Amgen, Regeneron, and Pfizer are all undertaking long-term clinical outcomes studies. If the trials are positive, it will then be up to clinicians to weigh the benefits of the new drugs against the costs of transferring patients from oral statins to injectable PCSK9 inhibitors. If not, you can be sure they'll suffer the same fate as Tredaptive.
The bottom line
The shift in thinking at the American College of Cardiology coincides with a renewed demand from the FDA for trials demonstrating a real clinical benefit to patients. In turn, that could shift the landscape of cardiovascular therapies, both on the market and off. Investors should watch as the new dynamic unfolds, and bear in mind that surrogate markers for disease prevention don't always translate into real benefits for patients and investors.