Broad Enough? Sponsors Pleased With Narrower Praluent Label

Indication for cholesterol-lowering drug is narrower than Sanofi and Regeneron originally sought, but firms still see it as broad. Target patient population is estimated at 8-10 million patients, but sponsors are quick to say the number of actual users will be funneled down.

FDA approved Sanofi and Regeneron Pharmaceuticals Inc.'s Praluent (alirocumab), the first PCSK9 inhibitor in the U.S., July 24 with what the sponsors view as a broad label, though one that is narrower than requested in the U.S. and likely to be approved in Europe.

Praluent is indicated for patients with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease who are taking maximally tolerated doses of statins but still require additional lowering of their LDL-cholesterol.

Praluent's wholesale acquisition cost is approximately $14,600 per year.

The approval gives Sanofi/Regeneron a one month head-start in the PCSK9 market over rival Amgen Inc.'s Repatha (evolocumab), which has an Aug. 27 user fee deadline.

The Praluent sponsors said promotional efforts will begin July 27 and trade product will be available two days later.

Praluent, an injectable, comes packaged in pens and prefilled syringes in two doses, 75 mg and 150 mg. The drug is to be subcutaneously administered every two weeks.

The wholesale acquisition cost is $40 per day, or approximately $14,600 per year, making Praluent "the lowest priced patient-administered monoclonal antibody therapy on an annualized basis," the companies said in a release.

Broader Indication Snubbed

The indicated population encompasses approximately 8 million to 10 million people in the U.S., company representatives said on a same-day conference call.

"We do think we have a pretty broad label here, and I think the label sort of matches our clinical trial population," Regeneron President and CEO Leonard Schleifer said. "About 90% of the patients in our trial had clinical cardiovascular disease or were heterozygous FH. So the label matches fairly well."

However, the companies originally sought approval for a broader population that encompassed patients with primary hypercholesterolemia or mixed dyslipidemia, for use with statins or other lipid-modifying therapies and for monotherapy in statin-intolerant patients (see box).

Praluent's Indication
Sponsors' Original Proposal^1	FDA-Approved Label
Alirocumab is indicated for long-term treatment of adult patients with primary hypercholesterolemia (non-familial and heterozygous familial) or mixed dyslipidemia, including patients with type 2 diabetes mellitus, to reduce low-density lipoprotein cholesterol, total cholesterol, non-high-density lipoprotein cholesterol, apolipoprotein B, triglycerides, and lipoprotein (a), and to increase high-density lipoprotein cholesterol and apolipoprotein A-1. Alirocumab is indicated in combination with a statin, with or without other lipid-modifying therapy. Alirocumab is indicated as monotherapy, or as add-on to other non-statin lipid-modifying therapy, including in patients who cannot tolerate statins.	Praluent is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease, who require additional lowering of LDL-C. Limitations of Use: The effect of Praluent on cardiovascular morbidity and mortality has not been determined.
^1 Sanofi/Regeneron's briefing book for June 9 meeting of FDA's Endocrinologic and Metabolic Drugs Advisory Committee

With its focus on HeFH and secondary prevention in CV disease patients who cannot get to LDL-C goal on statins, Praluent's U.S. label is largely in line with the recommendations of FDA's Endocrinologic and Metabolic Drugs Advisory Committee.

At a June 9 meeting, the committee endorsed approval but recommended limiting use to patients with HeFH or at high CV risk whose LDL-C is not under control with other therapies (Also see "PCSK9 'Groundhog Day': Amgen’s Repatha Gains FDA Panel Backing In High-Risk Groups" - Pink Sheet, 10 Jun, 2015.).

Panelists said that given questions about the reliability of LDL-C as a surrogate for CV benefit with non-statins, they were not comfortable approving the PCSK9 inhibitor for low- and moderate-risk patients until an ongoing CV outcomes trials is completed (Also see "Praluent, Repatha Spur Rethinking On LDL-Cholesterol As A Surrogate Endpoint" - Pink Sheet, 15 Jun, 2015.).

Another over-arching concern at the committee review was that patients would be prematurely switched from, or dialed back on, statins, which have demonstrated CV benefits and a long history of safety, in favor of the PCSK9 inhibitors.

The U.S. label also is narrower than the indication Praluent is likely to receive in Europe.

Earlier on July 24, the European Medicines Agency announced that its Committee for Medicinal Products for Human Use had recommended approval of Praluent in a patient population that more closely resembled the sponsors' original proposal in the U.S. (Also see "Sanofi’s Praluent Closes Gap On Repatha In Europe, As GSK Gets Green Light For World’s First Malaria Vaccine" - Pink Sheet, 24 Jul, 2015.).

"It's a much broader label," in Europe, Schleifer said. The companies are expecting marketing authorization from the European Commission in late September.

Making The Case To Payers

While the U.S. label is estimated to encompass up to 10 million patients, company executives hastened to add the actual number of patients who will use PCSK9 inhibitors will be funneled down by numerous factors. These include Sanofi and Regeneron's own educational and promotional efforts to ensure that patients in the target population are receiving maximum tolerated statins and adhere to those drugs.

"Through our educational efforts, we could potentially limit the patient population for PCSK9 inhibitors," said Regeneron Senior VP-Commercial Robert Terifay.

Other factors that may reduce the size of the actual market include physicians' resistance to use of biological therapy for LDL-C reduction and reluctance to take on the responsibility for prior authorization, patients' unwillingness to inject themselves, and low urgency among physicians and patients to get LDL-C under control, Terifay said.

"We believe that with the availability of Praluent for use in appropriate patients, Regeneron and Sanofi will be bringing significant value to the health care system," Terifay said.

The efforts by Sanofi and Regeneron execs to tamp down expectations for broad use are a nod to insurers' concerns about the financial ramifications of paying for a new and expensive class of cholesterol-lowering therapies in a large patient population where the standard of care is dominated by low-cost generic stains.

Payers are expected to implement coverage restrictions and controls, such as step therapy and prior authorization, to ensure that only those patients with the hardest-to-treat forms of hypercholesterolemia get the drugs. Payers also are expected to use formulary leverage to drive price competition (Also see "Formulary Focus: PCSK9 Drug Prices May Lead Payers To Impose Coverage Restrictions" - Pink Sheet, 26 Jan, 2015.).

Even before the first PCSK9 was approved, the Pharmaceutical Research and Manufacturers of America rolled out a public relations campaign that pushes back on claims the drugs will be a financial drag on the health care system and used by tens of millions of people (Also see "PhRMA Countering PCSK9 Cost Concerns Ahead Of Launch" - Pink Sheet, 23 Jul, 2015.).

The Praluent sponsors said they believe that U.S. payers will be comfortable with the FDA-approved label and its focus on very high risk patients.

Priority Review Voucher Buys Time

While FDA's approval of Praluent as the first PCSK9 inhibitor in the U.S. was noteworthy, so was the lack of a same-day approval for Repatha.

Praluent represents the first successful redemption of a priority review voucher.

Although Sanofi/Regeneron submitted their BLA after that of Amgen, the Praluent sponsors secured a priority review, thanks to a voucher they bought from BioMarin Pharmaceutical Inc. for $67.5 million. The voucher allowed Praluent to leap frog Repatha in the regulatory review queue, putting its user fee date one month ahead of the Amgen drug.

Praluent represents the first redemption of a priority review voucher that resulted in a product approval. Novartis AG redeemed a voucher in its bid to add a gout indication to the label for Ilaris (canakinumab), but that effort resulted in a "complete response" letter.

There had been speculation that FDA might approve both PCSK9 inhibitors at the same time, given the advisory committee reviews of Praluent and Repatha occurred on back to back days and the drugs' user fees were not far apart.

However, such a move would have blunted the advantage Sanofi/Regeneron gained with the voucher purchase and may have reduced the value of such vouchers in the long-term.

Instead, Amgen appears to be on track for a late-August approval of Repatha with a label that will likely resemble that of Praluent (Also see "PCSK9 'Groundhog Day': Amgen’s Repatha Gains FDA Panel Backing In High-Risk Groups" - Pink Sheet, 10 Jun, 2015.).

In Europe, however, Repatha is ahead in the PCSK9 race, having received European Commission marketing authorization July 21 (Also see "Surprise As Amgen Passes Regeneron/Sanofi To First PCSK9 Inhibitor Approval" - Pink Sheet, 21 Jul, 2015.).