FDA asks experts to weigh in on PCSK9 drugs' market reach for Amgen, Regeneron/Sanofi

After years of jockeying in the clinic with multiple trials aimed at carving out a lead role in developing a new class of LDL-lowering drugs, the blockbuster race between Amgen and a team from Regeneron ($REGN) and Sanofi ($SNY) for cutting-edge PCSK9 drugs comes down to this: back-to-back panel reviews to discuss the designated endpoint for cutting LDL as a surrogate for cardio benefits as well as the potential negative effect these new drugs could have on the massive demand for statins.

FDA reviewers today endorsed Amgen's ($AMGN) drug evolocumab--to be sold as Repatha--as an effective therapy, tracking its ability to slash levels of bad cholesterol. And while the agency flagged a concern for limited insight into the long-term safety of the high monthly dose, the FDA also didn't see any particular issue that couldn't be handled postapproval.

"Potential safety issues identified in this review could be adequately addressed in labeling and by appropriate monitoring and treatment by health care providers," says the review. "If evolocumab is approved, these issues (including pancreatitis) should be thoroughly explored in on-going studies."

Unlike almost all FDA reviews, though, safety and efficacy data aren't central to the discussion upcoming on Tuesday and Wednesday.

"The central issue regarding this application," notes Dr. James Smith, deputy director of the Division of Metabolism and Endocrinology Products at FDA's Center for Drug Evaluation and Research, in a carbon copy of his comments for Praluent (alirocumab, from Sanofi and Regeneron), "revolves around the following question: For what population(s), if any, does the LDL-C-lowering benefit of evolocumab exceed its risks to support approval?"

A whole generation of well-known statins, now cheap and easily available, has emerged with proven cardiovascular benefits for patients. Other LDL drugs, though, turned out to be controversial failures on CV outcomes. The FDA is fretting that an approval based on the LDL surrogate leaves it with no authority to demand a cardiovascular study. And regulators are alarmed over the impact these new drugs could have on statins, even though there are no proven CV advantages.

"One must consider whether labeling that specifically indicates a drug for 'statin-intolerant patients' could promote a condition that is not well-understood and encourage some patients to prematurely abandon statins, a class that has robustly established benefits on CV outcomes," explains the FDA. "Alternatively, language that indicates use in combination with 'maximally tolerated statin therapy' would recognize that, for some patients, maximally tolerated statin therapy may be no statin therapy at all."

Essentially, the two reviews are shaping up as a two-day discussion of endpoints and statin competition. While the reviews raise no direct threat to an approval, concentrating on labeling issues, the panels may go much further in terms of defining just how narrow these markets are--potentially limiting the blockbuster revenue that these three companies are chasing.

Analysts are seeing likely approvals ahead, but these issues could well influence peak potential.

"We think it's a positive that the documents didn't attempt to exclude patients from the label," UBS's Matthew Roden noted after the Praluent documents surfaced, "but it doesn't settle the debate on how big the class will be."

- here's the review