In October 2013, Pfizer (PFE) began a series of Phase 3 studies for bococizumab. The company intends to dose over 22,000 patients in separate trials sorted by risk type and indication. This monoclonal antibody (MAB) is one of an emerging class of therapies that lower cholesterol through inhibition of proprotein convertase subtilisin/kexin type 9, an enzyme mercifully abbreviated to PCSK9.

Why PCSK9 is a target
Low density lipoprotein cholesterol, the "bad" kind that's often referred to as LDL-C, is typically removed from the bloodstream after attaching to LDL receptors on the surface of liver cells. PCSK9's natural function is to regulate the amount of circulating cholesterol by marking LDL receptors for destruction after they carry LDL-C into a liver cell. In theory, any drug that inhibits this enzyme should also lower circulating LDL-C, which in turn should lower a patient's risk of heart attack.

Taking the "mono" out of monoclonal
Pfizer is not alone in the race to develop a monoclonal antibody to inhibit PCSK9. Amgen (AMGN -0.56%) has had some luck with two Phase 3 trials involving its PCSK9 inhibitor, evolocumab. In December 2013, Amgen announced its MAB met its primary endpoint of reducing LDL-C at 52 weeks in a study of 901 hyperlipidemia patients.

This data was no doubt followed by a sigh of relief at Amgen. The study is just one of 13 Phase 3 trials with a combined enrollment of over 28,000 patients.

So far, Amgen has been quiet about the details of the Phase 3 study. Results from several Phase 2 trials have shown it to be roughly as effective as Pfizer's bococizumab, however.

In May 2010, Regeneron Pharmaceuticals (REGN 0.84%), while partnered with Sanofi (SNY 0.77%), was the first team to show that the inhibition of PCSK9 could significantly lower cholesterol levels in humans. In mid-October 2013, the team was also the first to present Phase 3 data showing it to be highly effective with relatively low dosages over a period of 24 weeks. This was just the first of 12 Phase 3 trials with an expected total enrollment of over 23,000 patients.

During the study, 103 patients self-administered an initial low dose of alirocumab every two weeks for the first eight weeks. If LDL-C remained above the threshold of 70 mg/dL after eight weeks then the dosage was raised. The majority of patients didn't require the increased dosage, which is a pretty good sign.

Late, but hungry
Although Pfizer is late to the feast, it appears to have brought the biggest appetite. It's series of Phase 3 studies includes two dedicated cardiovascular outcomes trials. The company's competitors have limited the scope of their trials to test for surrogate markers to prove the efficacy of their compounds. In other words, Pfizer will wait five years to see how many of its patients suffer heart attacks or stroke. In an attempt to file their new drug applications faster, Pfizer's competitors appear to be limiting their observations to reductions of LDL-C and blood pressure.

Will it be necessary?
In November 2013, the American College of Cardiology and the American Heart Association updated their cholesterol therapy guidelines. The groups recommend physicians continue prescribing standard therapies like statins over fancy new drugs. The sole reason, it seems, boils down to long-term familiarity.

This was great news for Pfizer, but terrifying to its competitors. Luckily for Amgen and Sanofi, a deputy director in the drug and research branch of the FDA, Eric Colman, soothed their nerves. Apparently, PCSK9 approval decisions will remain based largely on the reduction of LDL-C and blood pressure.

That isn't a promise that's etched in stone, however. Coleman also mentioned Merck's Vytorin trial. The FDA might change its mind, depending on results from the IMPROVE-IT trial. This is a two-and-a half year trial of non-statin therapy Vytorin combined with Simvastatin, comparing it against Simvastatin alone to measure the rate of heart attack and stroke. If the statin plus non-statin therapy doesn't significantly decrease the rate of cardiovascular events, the FDA will probably change its mind. This would force Pfizer's competitors to also include cardiovascular outcomes trials before filing their new drug applications. As a result, Pfizer could find itself in the lead.

Fortune favors the bold
Pfizer might be late to the party, but I can't help but be impressed by its bold move to differentiate itself from the competition. The company's full cardiovascular outcomes trials are likely to be far more expensive than its competitors' Phase 3 programs. Given the reluctance of doctors and payers to adopt new expensive therapies without long term proof safety and efficacy, however, it has a good chance of paying off in the long run. On top of that, if regulators change their minds then Pfizer and its investors will be laughing all the way to the bank.