After a long first day of debating the merits of low-density lipoprotein cholesterol (LDL-C) as a surrogate endpoint for cardiovascular (CV) risk before endorsing Praluent (alirocumab, Regeneron Pharmaceuticals Inc./Sanofi SA) in general genetic heterozygous high-risk populations and higher risk secondary populations, the FDA's Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) reconvened Wednesday to review what many analysts predicted might be a more bruising battle in the protein convertase subtilisin/kexin type 9 (PCSK9) inhibitor class. However, FDA reviewer Eileen Craig was relatively kind to Amgen Inc. in describing efficacy and safety data for evolocumab, branded Repatha, to lower LDL-C in patients with primary hyperlipidemia and mixed dyslipidemia and in a second indication of patients 12 and older with homozygous familial hypercholesterolemia (HoFH).

Craig's presentation wasn't completely benign. Although FDA data didn't challenge the efficacy of evolocumab in lowering LDL-C and other lipid parameters across Amgen's clinical program, the agency raised concerns about the mixture of patients enrolled in pivotal trials, the limited dosing regimens proposed for the drug and the adequacy of the safety database.

Ironically, after all but one of a dozen public speakers – a mixture of clinicians, patients and advocates – passionately pleaded for more options to treat LDL-C, the afternoon session turned into a bigger debate over whether evolocumab might work so well that it could lower LDL-C to dangerously low levels. Committee members also worried aloud that physicians might reduce patient dosing regimens for statins, which have an abundant safety and efficacy track record, rather than for a drug just out of the gate without clearly predictable experience.

At the end of the day – literally – evolocumab received a ringing endorsement from the FDA committee members in HoFH, with the panel voting 15-0 with no abstentions to recommend FDA approval in the orphan indication. One after one, they cited the urgent need for additional treatment options for the serious disease, which strikes as early as childhood.

Panelists also largely supported the use of evolocumab to lower LDL-C in other patient populations, voting 11-4 to recommend approval of the drug, at a minimum, in heterozygous familial hypercholesterolemia, or HeFH. In comments after their vote, some committee members went further, signaling a desire to see evolocumab approved in patients with high or very high LDL-C that is not controlled by statins and who have correspondingly high CV risk and in patients who cannot tolerate statins.

Amgen still might not get the relatively broad label it's seeking for evolocumab, or even approval – EMDAC votes are not binding on the FDA's decision – but the company was optimistic following Tuesday's muddled discussion and Praluent vote. (See BioWorld Today, June 10, 2015.)

"It is clear from today's discussion with the FDA's Endocrinologic and Metabolic Drugs Advisory Committee that there is a critical need for additional treatment options for patients who are unable to control their high cholesterol despite currently available therapies," Amgen said. "Elevated LDL-C is recognized as a major risk factor for CVD, and approximately 33 percent of patients at high risk for CVD cannot adequately lower their LDL-C levels with statins and/or other currently approved lipid-lowering therapies. We look forward to continuing to work with the FDA as they complete their review of the biologics license application for Repatha, in hopes of bringing this important new medicine to patients with high cholesterol."

The company submitted its BLA to the FDA in August 2014, and its marketing authorization application to the EMA was accepted for review a month later. Earlier this year, Thousand Oaks, Calif.-based Amgen also submitted an application to Japan's Ministry of Health, Labour and Welfare. Evolocumab is being developed in Japan by a joint venture between Amgen and Tokyo-based Astellas Pharma Inc.

In the U.S., the drug's PDUFA date is Aug. 27.

'THIS MAY EVEN SET UP A BEST-CASE SCENARIO' FOR AMGEN

Following presentations Wednesday morning by Amgen and the FDA, the sometimes plodding EMDAC discussions meandered through the minutiae of sorting LDL-C from other components of total cholesterol and what that could mean for characterizing drugs in the PCSK9 class, for which data are still being collected. The dearth of long-term safety data and the prospect of approving evolocumab before results of a large cardiovascular outcomes trial, already under way, are reported was clearly unpalatable to some committee members.

One of the biggest naysayers, William Hiatt, professor of medicine in the division of cardiology at the University of Colorado School of Medicine, cited concerns echoed by others that approval of the drug could open the door to relatively wide prescribing on fairly skinny data.

"I agree with the panel that not much has turned up on safety concerns," Hiatt said. He added, however, that the limited exposure data collected to date "is a concern" in terms of assessing the drug's risk/reward benefit.

Still, several committee members openly praised Amgen for evolocumab's "thoughtful" development plan. And following the committee's recommendation to support Praluent the previous day, the votes came as little surprise. In a research note issued in the midst of the EMDAC discussions, RBC Capital Markets analyst Michael Yee correctly predicted a positive panel vote following "typical panel concern."

He also forecast a label that will encompass more than HoFH and HeFH.

"The fundamental AMGN call has been that there is at least a 50-60 percent-plus likelihood the labels will be broader than just familial Ho/HeFH and probably encompass and include 'higher risk' patients," Yee wrote, noting that the previous day's 13-3 vote to recommend Praluent for approval "gives the FDA freedom now to approve and they'll figure out the label but just want to hear the feedback from panelists in a public forum."

In a hot comment late Tuesday, following the first day of EMDAC, Piper Jaffray analyst Joshua Schimmer also observed that Amgen was "well positioned" for a bigger boost from the two-day panel than the Regeneron/Sanofi partnership.

"With no meaningful discussion on several of the points of differentiation between Repatha and Praluent (dosing interval, low dose/high dose option, injection devices, etc.), it's hard to get a sense of commercial positioning from the panel," he acknowledged. "However, AMGN is relatively well positioned with a larger CVOT trial set to read out potentially one year ahead of Praluent. This may even set up a best-case scenario for AMGN with premium pricing easier to procure for a narrower initial indication followed by a subsequent explosive label expansion. Therefore, we are comfortable with our estimates as we currently model revenue of $45M in 2015, $150M in 2016 and $600M in 2017."

Such projections may be mitigated by payers, however, which may have been the elephant in the room at the EMDAC. Although committee members barely skirted the issue of the cost of new cholesterol therapies compared to long-used statins, one public speaker zeroed in on pricing by noting that payers, not the FDA, now determine which patients are prescribed which drugs.

"We do acknowledge that the launch of the PCSK9 class probably will also be modest to start as payers will likely limit the drugs more than the FDA does," Yee conceded in his note.

Yee also weighed in on Esperion Therapeutics Inc., whose shares (NASDAQ:ESPR) sank 18.8 percent Wednesday, closing at $81.68 for a loss of $18.85. The Ann Arbor, Mich.-based company, which is grooming its cholesterol-lowering ETC-1002 (bempedoic acid) for statin-intolerant patients, reported significantly lower LDL-C vs. placebo in a phase IIb trial and expects to move into phase III in the second half of the year. (See BioWorld Today, March 18, 2015.)

But the drug's premise might run into a headwind at the FDA, given the tenor of the EMDAC conversations, in which panelists strongly endorsed the continued use of statins as first-line therapy and expressed wariness about the validation of LDL-C as a surrogate endpoint.

"LDL reduction as a surrogate heightens the belief that ESPR might need outcomes pre-approval, or would have a concerning panel too in the future," Yee wrote. "We acknowledge that risk but think a PCSK9 broad label would be a positive datapoint that FDA is OK with these LDL reduction drugs, and that would benefit ESPR."

He added, "Our call here is that ESPR is fine long term and the risk/reward is significantly asymmetric to the upside if it plays out like we think it should."