Pfizer bets big on PCSK9 with 'massive' Phase III outcomes study

John Young, president and general manager of Pfizer's primary care business unit

By Tracy Staton and John Carroll

Tantalized by various megablockbuster projections for the PCSK9 field of cholesterol drugs, Pfizer ($PFE) has mapped out one of the most ambitious late-stage programs in the industry for RN-316. This week, the pharma giant spelled out plans for a massive cardiovascular outcomes trial to prove to regulators and payers alike that the drug not only works as advertised, but delivers real value to patients. And there are already plans to follow up on its first approval with a more convenient dosing regimen, outlining the company's lifecycle management expectations.

With the PCSK9 development program, Pfizer is trying to cover a lot of bases at once. The combination of trials testing RN-316's ability to lower "bad" cholesterol with cardiovascular outcomes trials will yield a mix of data Pfizer hopes to use to win over not only regulators, but payers. "The issue is, in this marketplace, we need trials constructed to demonstrate value to society and payers," Pfizer's John Young, president of the primary care business unit, said during the third-quarter earnings call on Tuesday.

One of the outcomes trials looks specifically at some very high-risk patients: those who've been unable to get their LDL cholesterol levels below 100, even with statin therapy. If RN-316--now dubbed bococizumab--can show itself effective at improving outcomes for that group, payers could see it as a money-saving bet. "Those patients really do represent a tremendous cost to the healthcare system," Young said during the third-quarter earnings call. "A positive outcome in that group would be very significant."

But the outcomes trials, which encompass 22,000 patients over a broad risk range, are also a hedge against skittish regulators. In years past--when Pfizer won approval for its megablockbuster statin, Lipitor, for instance--lowering LDL cholesterol was seen as a clear marker for lowering cardiovascular risks. Since then, several outcomes studies have weakened the case for a causal link between lowered LDL and lowered risk, and experts have questioned the use of a "surrogate marker" like LDL to prove a drug's worth to regulators. Young said LDL is a very well-established surrogate for cardiovascular risk, but for PCSK9 drugs, it's early days yet. For all the drugs in this new class, companies aren't yet certain what sort of data will be required for approval, he said.

"[T]here are indications from FDA that additional data may be required for a new class of cholesterol drug," Young said. "The program is designed to address the potential for regulators to require long-term cardiovascular outcomes and safety for approval."

The significance of Pfizer's move didn't escape analysts. In a note to investors, ISI's Mark Schoenebaum observed that Pfizer had "started massive PCSK9 Phase 3 programs (includes two large Ph3 studies)--we think PFE believes outcomes data needed for approval."

The outcomes effort also won't be ignored by Pfizer's major-league competitors. The Regeneron ($REGN)/Sanofi ($SNY) team released the first encouraging round of late-stage data on alirocumab just days ago. And researchers are planning a full slate of Phase III studies, with Amgen ($AMGN) also in the race.

The FDA has followed through on one promise for a higher bar on approvals: The agency had said that new diabetes drugs, in light of the controversy over heart risks with GlaxoSmithKline's ($GSK) Avandia, might have to be proven safe for the heart before they could win clearance for marketing. Early this year, Novo Nordisk ($NVO) found out the FDA was serious about that; The FDA declined to approve its new diabetes treatment Tresiba without more data on its safety.

So if the FDA raises the bar for cholesterol drugs--namely the PCSK9 class that's working its way through multiple Big Pharma pipelines--Pfizer wants to be ready. And the company believes its entry in the class will be a strong competitor.

In the PCSK9 field, "you can see emerging data suggesting some of the antibodies being very potent and some being intermediate," Mikael Dolsten, Pfizer's R&D chief, said during the call. "We were encouraged by the potent effect of our antibody."

As for dosing, Young said the program is now focusing on a two-dose-per-month schedule. After analyzing some Phase II research on bococizumab, the company decided the twice-a-month approach would be the optimal dosing schedule. Developing a once-a-month dose would come later, Dolsten said. The company is testing its delivery technology's ability to extend the drug's half-life and lower the volume of the required injection. "We think of it as a lifecycle management opportunity to explore once-monthly," he said. "That may include the Halozyme technology, for which we have an exclusive license in the PCSK9 class. The antibody itself at a high dose has the potential for once a month, but we would rather see a technology like this give it a really convenient opportunity."