An FDA advisory committee will meet June 9 to discuss the breadth of indication for Sanofi and Regeneron Pharmaceuticals Inc.'s lipid-lowering injectable agent Praluent (alirocumab), including whether the PCSK9 inhibitor is appropriate for patients purported to be "statin intolerant."

In draft questions released June 5, FDA asks the Endocrinologic and Metabolic Drugs Advisory Committee whether alirocumab's efficacy in lowering LDL-cholesterol is sufficient to substitute for demonstrating a reduction in cardiovascular clinical outcomes in one or more populations, including patients with different degrees of CV risk, familial versus non-familial etiologies of hyperlipidemia, and use with or without concomitant statins.

The agency poses one voting question to the committee: whether Sanofi/Regeneron have sufficiently established that alirocumab's LDL-C-lowering benefit exceeds its risks to support approval in one or more patient populations, and if so which ones.

"We remind you that under the current regulatory pathway, [the sponsors] would not be required to successfully demonstrate an effect of alirocumab on CV outcomes after an approval based on changes in LDL-C," FDA's draft voting question states.

No Question About LDL-C-Lowering Efficacy …

The Praluent meeting will kick off a two-day advisory committee session on the PCSK9 inhibitors, with Amgen Inc.'s Repatha (evolocumab) slated to go before the same panel June 10 ([A#14150429002]).

Over the course of the two days, the discussions should help inform what labeling will look like for the early entrants in this new class of lipid-lowering agents, pending the results from large, ongoing CV outcomes trials Also see "PCSK9 Mechanism Lends Confidence Ahead Of Outcomes Data" - Pink Sheet, 23 March, 2015..

Given the already intense competition in this category between Sanofi/Regeneron and Amgen, with more entrants making their way through the pipeline, breadth of initial indication – and any differences in indication between the PCSK9 inhibitors – could have important commercial ramifications.

Even though Sanofi/Regeneron submitted their BLA after Amgen, the alirocumab review is being expedited thanks to a priority review voucher the sponsors bought from BioMarin Pharmaceutical Inc. for $67.5 million Also see "How Much Is A Priority Review Worth? $67.5 Million, Sanofi/Regeneron Say" - Pink Sheet, 11 August, 2014..

The alirocumab user fee date is July 24, while the goal date for evolucumab, which is undergoing a standard review, is Aug. 27.

FDA's briefing document appears to raise no questions about alirocumab's ability to lower LDL-C across the Phase III program's 10 double-blind, randomized trials. Five trials were placebo-controlled and five used Merck & Co. Inc.'s intestinal cholesterol absorption inhibitor Zetia (ezetimibe) as an active control.

"The sponsor’s primary analysis … demonstrated that alirocumab was associated with decreases in calculated LDL-C of 36% to 61% from baseline, and statistically significant treatment differences of 39% to 62% as compared to placebo … and 24% to 36% as compared to ezetimibe," clinical reviewers Julie Golden and Mary Roberts said. "Maximal LDL-C-lowering efficacy was observed at week 4 and persisted for the duration of the trials."

FDA is instead turning to the advisory committee for input on whether LDL-C lowering, in the absence of data on CV clinical outcomes, is enough to support approval, and if so in which population of patients.

"The central issue regarding this application revolves around the following question: For what population(s), if any, does the LDL-C-lowering benefit of alirocumab exceed its risks to support approval," wrote James Smith, deputy director of the Division of Metabolism and Endocrinology Products.

… But Worries About Endpoint Reliability

Sanofi/Regeneron are seeking a broad indication for Praluent, including use in combination with statins or other lipid-lowering treatments and as monotherapy. However, an addendum to the companies' briefing document reflects a narrower monotherapy indication – a revision made in response to the agency's comments in its background document (see box).

Praluent's Proposed Indication

Sanofi/Regeneron's addendum makes a one-word revision to its original proposed indication (change indicated by strikethrough text):

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 (LDL-C), total cholesterol (Total-C), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (Apo B), triglycerides (TGs), and lipoprotein (a) [Lp(a)], and to increase high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-1 (Apo A-1).
Alirocumab is indicated in combination with a statin (HMG-CoA reductase inhibitor), with or without other lipid-modifying therapy (LMT).
Alirocumab is indicated as monotherapy, or as add-on to other non-statin LMT, ~~including~~ in patients who cannot tolerate statins.

Central to the question about indication and target population is the agency's concerns that alirocumab and other PCSK9 inhibitors will be used in lieu of statins – the tried and true lipid-lowering agents that were approved on the basis of LDL-C lowering but have since developed extensive data on CV outcome benefits and long-term safety.

The prospect that PCSK9 inhibitors might be used in place of statins is particularly worrisome given growing uncertainty about the reliance of lipid parameters to serve as surrogate markers for clinical benefit, FDA briefing documents state, recounting some of the high-profile failures of lipid-altering agents to demonstrate an improvement in CV outcomes Also see "New Cholesterol Guidelines Follow Long History Of Failed Outcomes Trials" - Pink Sheet, 2 December, 2013..

Approval of alirocumab would suggest that for the indicated population, the PCSK9 inhibitor's effect on LDL-C "can 'substitute' for an assessment of its effect on CV outcomes," Golden and Roberts said.

"The unexpected and disappointing results from CV outcomes trials for fenofibrate, cholesteryl ester transfer protein (CETP) inhibitors, and niacin, although most involved drugs with modest effects on LDL-C, should at least give us pause as we consider the use of lipid biomarkers in the assessment of benefit/risk for various patient populations, especially in light of the strong evidence of CV benefit and excellent safety profile established for the statins," the reviewers said.

The agency also points to the experience with ezetimibe, which was approved in 2002 on the basis of its LDL-C-lowering effects but became the source of controversy when two subsequent studies, ENHANCE and SEAS, failed to show a CV benefit with the drug when it was combined with simvastatin as Vytorin.

In November, Merck announced that results from the 18,000-patient IMPROVE-IT trial showed the ezetimibe/simvastatin combination was associated with significantly fewer CV events than simvastatin alone ([A#14141117002]).

FDA's briefing documents reference the publicly announced IMPROVE-IT results but note the agency has not yet reviewed the data and "it is possible that the division will reach different conclusions than the trial's investigators."

"It should be emphasized that the approval of ezetimibe – or any of the statins, for that matter – did not require the conduct of a post-approval CV outcomes trial," Smith said. "Given the agency’s historical acceptance of LDL-C as a validated surrogate endpoint for traditional approval, reductions in LDL-C have been accepted as a substitute for a demonstration of reducing CV risk."

"Sponsors who have chosen to conduct CV outcomes trials after approval, which we certainly have encouraged, have voluntarily done so to seek additional claims," Smith said. "With such a traditional approval, FDA does not have a regulatory mechanism to require any further efficacy trials."

An ALTERNATIVE For 'Statin Intolerance'?

Alirocumab's LDL-C-lowering effects have not been tested against high-intensity doses of statins, Smith noted.

"Even if it had been, however, the division has expressed concern regarding an indication for monotherapy before benefit has been demonstrated on clinical outcomes in some populations (e.g., patients already treated with statins)," Smith said.

Labeling alirocumab for use in "statin-intolerant patients" may encourage some patients to prematurely abandon drugs that have a proven clinical efficacy benefit, FDA's review division deputy director said.

The review division deputy director said one clinical scenario that may seem practical for monotherapy treatment is in patients who cannot tolerate statins.

"Although the division acknowledges that there are patients who will not take statins for any number of reasons … we have struggled with whether use of the description 'statin-intolerant' is warranted in labeling," Smith said. "Certainly, many patients who are not able to take statins are not truly intolerant of the pharmacological class."

For example, FDA reviewers point to Sanofi/Regeneron's ALTERNATIVE trial, which enrolled patients who purportedly could not tolerate statins due to muscle symptoms.

Patients who did not experience a musculoskeletal adverse event during a four-week placebo run-in period were randomized to alirocumab, ezetimibe or atorvastatin 20 mg (Pfizer Inc.'s Lipitor). Notably, approximately 70% of patients randomized to atorvastatin completed 24 weeks of the double-blinded treatment period.

"Thus, 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," Smith said.

"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," Smith said.

No Red Flags On Safety

FDA briefing documents do not raise any safety concerns that would appear to stand in the way of approval.

In draft questions for the meeting, the agency asks panelists to discuss alirocumab's safety in the clinical development program and to comment on adverse event data involving diabetes, liver effects and immunogenicity.

The agency seeks the committee's view on the adequacy of the current clinical database to characterize safety, including generalizability of the trial populations to the target population.

Discussion also is requested on the advisors' level of concern regarding the safety of achieving very low levels of LDL-C with alirocumab.

In a June 4 interview with "The Pink Sheet" DAILY, Sanofi and Regeneron officials said they recognize that practitioners have questions about the safety of bringing LDL-C levels too low ([A#14150315001]).

For that reason, the companies are highlighting alirocumab's two dosing options (75 mg or 150 mg every two weeks), which allows for flexible dosing and up- or down-titration as needed to reach target LDL-C goals.

Praluent Panel To Focus On Indication Breadth Absent CV Outcomes Data

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