The market competition now playing out in the payer space between Sanofi/Regeneron Pharmaceuticals Inc.'s Praluent (alirocumab) and Amgen Inc.'s Repatha (evolocumab) began with a pre-approval race to see which PCSK9 inhibitor could secure US regulatory approval first.

Throughout the drugs' clinical development and review, sponsors of both PCSK9 inhibitors looked for regulatory advantages that might give them an edge and ensure they got the quickest possible approval from FDA.

Agency review documents reflect unsuccessful attempts by both products' sponsors to persuade FDA that their LDL-cholesterol-lowering drugs merited priority approval in their own right. In the case of Amgen, its requests for breakthrough therapy designation also fell on deaf ears.

Reviews of the first two PCSK9 inhibitors are a lesson in how regulatory mechanisms can become a factor in heated competition to be first in class.

To get the upper hand, Sanofi and Regeneron ultimately resorted to purchasing a priority review voucher to ensure faster agency consideration of Praluent.

Once it became obvious that the priority review voucher would allow Praluent to pass the earlier-filed Repatha in the regulatory queue, Amgen began making inquiries of FDA about advisory committee scheduling and labeling parity between the two products.

In the end, Praluent won approval a month ahead of Repatha due to the eight-month priority review provided by the voucher, while Repatha trudged along under the 12-month review track for new molecular entities.

The two drugs came to market with similar indication statements – for use as an adjunct to diet and maximally tolerated statin therapy for treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease who require additional lowering of LDL-C – that were substantially narrowed from the sponsors' original requests ([A#14150724005] and [A#14150827010]).

Repatha received an additional claim for patients with homozygous familial hypercholesterolemia (HoFH), a use that Sanofi and Regeneron did not study for Praluent.

The reviews of the first two PCSK9 inhibitors are a lesson in how regulatory mechanisms can become a factor in the heated competition to be first in class.

Review Challenges For Both Sponsors

That Praluent and Repatha proceeded along highly parallel tracks for most of their late-stage development and review is graphically illustrated in an interactive timeline of key milestone dates (see related story, [A#00151221012]).

The sponsors of both products encountered similar challenges and risks in bringing their compounds through the regulatory process. These included partial clinical holds shortly after IND submission, and FDA's repeated statements that whether the drugs could be approved solely on the basis of an LDL-C-lowering endpoint prior to completion of cardiovascular outcomes trials would be a review issue.

In addition, significant review issues for both agents arose following BLA submission that potentially could have delayed regulatory approval.

Just a month before approval, Sanofi and Regeneron faced "urgent" requests from FDA for information about a possible case of drug-induced liver injury. The companies also found themselves negotiating the terms for a late-issued post-marketing requirement for a pregnancy study in the review's last days.

Meanwhile, Amgen had to quickly conduct a new pharmacokinetics/pharmacodynamics study to bridge between two formulations of evolocumab, all the while knowing that the agency might not be able to review the data in the initial review cycle.

[Editor's note: These review challenges for Praluent and Repatha will be examined in more depth in future Drug Review Profile stories about the PCSK9 inhibitors.]

Seeking A Hook For Priority Review

A common theme that emerges from the review documents is both sponsors' strong desire for a priority review for their respective applications.

For Amgen, one cornerstone of its argument for a faster review appears to have been its HoFH data. Evolocumab received orphan drug designation for HoFH in September 2013.

In written questions ahead of its April 2014 pre-BLA clinical meeting with FDA, Amgen laid out its case for a shorter review timeline.

"Since evolocumab is intended to treat a serious medical condition for which an unmet medical need still exists … and based on the efficacy … and safety … data that demonstrate that evolocumab may provide a significant improvement in the treatment of subjects with primary hyperlipidemia and mixed dyslipidemia and HoFH, Amgen considers that a priority review designation is appropriate with submission of the BLA," the company said.

Amgen asked whether FDA agreed that evolocumab "may meet the requirements for a request for priority review designation?"

FDA's preliminary written response to the question was neutral, with the agency saying only that "a determination for priority review designation will be made following submission of the BLA."

Amgen did, in fact, request a priority review of the BLA submitted Aug. 27, 2014. The application included data from a placebo-controlled trial in 49 HoFH patients and an ongoing, open-label extension trial with 96 patients.

Nevertheless, FDA informed Amgen ahead of the 74-day letter, which is a communication of filing review issues, that a priority review would not be forthcoming.

During an Oct. 24 teleconference convened by FDA to discuss concerns about Amgen's formulation bridging data, the review division addressed the priority review issue.

"Before ending the call, the division also informed the firm that, unrelated to the bridging issues, the division has made the decision that the application would be reviewed under a standard review timeline," the teleconference minutes state. "The observed treatment effect on LDL-cholesterol among patients with HoFH was simply not compelling enough compared with alternative therapies to warrant a priority review."

HoFH data were "simply not compelling enough compared with alternative therapies to warrant a priority review," FDA told Amgen.

Although part of the discussion on this issue is redacted from the minutes, they conclude: "The firm stated their understanding."

In an Aug. 24 memo, FDA clinical reviewer Eileen Craig put evolocumab's treatment effect in HoFH into perspective with that of existing therapies for the rare genetic condition.

In the placebo-controlled HoFH trial, evolocumab significantly reduced LDL-C from baseline to week 12 by 31% compared to placebo; the mean change from baseline with evolocumab was -23% compared to +8% in the placebo group, the review states.

Craig said this rate of LDL-C reduction was similar to that previously observed with statin therapy in combination with Merck & Co. Inc.'s intestinal cholesterol absorption inhibitor Zetia (ezetimibe), and somewhat greater than was seen with statin monotherapy – specifically, AstraZeneca PLC's Crestor (rosuvastatin) – or Genzyme Corp.'s Kynamro (mipomersen), an oligonucleotide inhibitor of apolipoprotein B-100 synthesis that is subcutaneously injected.

However, the evolocumab-induced LDL-C reduction was less than that seen with Aegerion Pharmaceuticals Inc.'s Juxtapid (lomitapide), an oral microsomal triglyceride transfer protein inhibitor that produced mean and median changes in LDL-C from baseline of -40% and -50%, respectively. Evolocumab's LDL-C-lowering effects also were less than the approximately -50% change from baseline observed with LDL apheresis, Craig said.

Do We Have To Use The Voucher?

Review documents indicate that Sanofi and Regeneron also were coveting a priority review.

In July 2014, the companies spent $67.5m to purchase BioMarin Pharmaceutical Inc.'s voucher as a means for guaranteeing a short review for Praluent Also see "How Much Is A Priority Review Worth? $67.5 Million, Sanofi/Regeneron Say" - Pink Sheet, 11 August, 2014..

However, it appears the Praluent development partners wanted to first ensure that a priority review would not be granted on merit alone before committing the valuable voucher.

In written questions ahead of a Sept. 4, 2014 pre-BLA meeting, Sanofi/Regeneron tried to make their own case for priority review of alirocumab, regardless of the voucher.

"It is the sponsor’s position that alirocumab represents a first-in-class therapeutic with demonstrated safety and efficacy in patients suffering from hypercholesterolemia (familial and non-familial) who are unable to achieve sufficient lowering of their LDL-C with currently available lipid lowering therapies (including statins). As such it treats a serious condition (elevated LDL-C in patients with increased CV risk) and, if approved, would provide a significant improvement in effectiveness," the meeting minutes state.

"Therefore, the sponsor intends to request priority review at the time of submission of the BLA," the minutes continue. "Does the agency have a position on priority review for the BLA? Can you please share your thoughts on this topic?"

In its pre-meeting written response, FDA said: "We are aware of your intent to use your priority review voucher (PRV) for this application, which would allow for a priority review. If you choose not to use this PRV for this application, then a determination for priority review designation will be made following submission of the BLA."

Praluent's sponsors wanted to know whether they could get a priority review without using their voucher.

Sanofi and Regeneron also asked whether it would be acceptable to bundle both Praluent dosage forms – a pre-filled syringe and a pre-filled pen – into a single application, as was the companies' preference. Alternatively, if the dosage forms were not bundled and were submitted as separate applications, the companies asked whether FDA would assign priority review to both applications or only one.

FDA confirmed that a single, bundled application would be acceptable. In a case where an original application is split, "priority review may or may not be granted for both split original applications, depending on the reason for the split," the agency responded.

Amgen's Breakthrough Bid Falls Through

Priority review was not the only expedited regulatory pathway targeted for the PCSK9 products.

FDA twice denied Amgen's request for breakthrough status, first on Feb. 12, 2014, and again on Aug. 13, 2014, according to review documents. The latter denial came two weeks after Sanofi/Regeneron announced they had purchased BioMarin's voucher with intent to use it for Praluent, and two weeks before Amgen submitted the Repatha BLA.

Agency documents do not indicate the basis for the breakthrough requests or the reasons why they were denied by FDA. In response to questions from "The Pink Sheet," Amgen said: "We felt Repatha would address an unmet need for patients who did not have effective options to address their elevated LDL."

Given FDA's finding that the HoFH data did not support a priority review, it seems likely that these data also served as the basis for the breakthrough requests and were deemed insufficient for the designation.

There is no indication in FDA review documents that Sanofi/Regeneron similarly sought breakthrough designation for alirocumab. A Sanofi spokeswoman said the company would not discuss its regulatory strategy.

Questions Around Parity

By the time of Amgen's mid-cycle review teleconference with FDA on Feb. 12, 2015, Sanofi and Regeneron had already disclosed that the Praluent BLA was accepted for filing and received a priority review, with the July 24 user fee date coming one month before the goal date for Repatha.

Minutes from the mid-cycle meeting suggest Amgen wanted to know where its application stood vis a vis Praluent.

The minutes reference a question about advisory committee scheduling asked by Steven Galson, senior VP-global regulatory affairs at Amgen and a former director of FDA's Center for Drug Evaluation and Research.

Repatha was tentatively scheduled for an advisory committee review on June 10. "In response to questions from Dr. Galson, the division stated that we are not at liberty to discuss applications of other sponsors, including the scheduling of potential advisory committee meetings for such applications," the minutes state.

Concerns about parity across products also arose during Amgen's late-cycle teleconference with FDA, which was held on May 28, 2015, two hours after Sanofi and Regeneron had their late-cycle meeting.

"In response to a comment from the firm, the agency responded that considerations with regard to consistency in labeling across PCSK9 products would be considered to the extent possible, as appropriate, but each application is independent," the minutes from the Amgen meeting state.

PCSK9 Sponsors Looked For Regulatory Advantages In Race To Market

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