Praluent (Alirocumab) FDA Approval History

Original FDA Approval: July 24, 2015

The FDA approved alirocumab under BLA 125559 on July 24, 2015, making it one of the first two PCSK9 inhibitors to reach the U.S. market. The approval covered adults with HeFH or clinical ASCVD requiring additional LDL-C reduction beyond maximally tolerated statin therapy [1]. Regeneron and Sanofi co-developed the drug.

The approval relied on data from 10 Phase 3 trials in the ODYSSEY clinical program, which enrolled more than 5,000 patients across multiple hypercholesterolemia populations [2]. In the key ODYSSEY LONG TERM trial (N=2,341), alirocumab 150 mg every two weeks reduced LDL-C by 61% from baseline at week 24 compared with placebo, both on top of maximally tolerated statin therapy [3]. Mean absolute LDL-C reductions reached approximately 62 mg/dL. The effect was durable through 78 weeks of follow-up.

The FDA granted Praluent a priority review designation. This reflected the unmet need among patients with familial hypercholesterolemia who could not reach guideline LDL-C targets on statins alone. At the time of approval, an estimated 610,000 adults in the United States had HeFH, and a large subset remained above recommended thresholds despite maximum statin doses [4].

Initial approved dosing was 75 mg or 150 mg administered subcutaneously every two weeks via prefilled pen. The label recommended starting at 75 mg and titrating to 150 mg if LDL-C response was insufficient after 4 to 8 weeks.

ODYSSEY OUTCOMES and the 2019 Cardiovascular Label Expansion

In April 2019, the FDA approved a supplemental BLA adding a cardiovascular risk reduction indication to Praluent's label. This was a defining regulatory milestone for the PCSK9 inhibitor class.

The ODYSSEY OUTCOMES trial (N=18,924) randomized patients with recent acute coronary syndrome (ACS) within 1 to 12 months to alirocumab or placebo, both on top of high-intensity or maximally tolerated statin therapy [5]. The primary composite endpoint (coronary heart disease death, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization) occurred in 9.5% of alirocumab-treated patients versus 11.1% in the placebo group (hazard ratio 0.85; 95% CI 0.78 to 0.93; P=0.0003) over a median 2.8 years of follow-up.

That translates to a 15% relative risk reduction and a 1.6 percentage-point absolute risk reduction in MACE. The number needed to treat (NNT) was 63 over 2.8 years. A pre-specified exploratory analysis also showed a nominally significant reduction in all-cause mortality (3.5% vs. 4.1%; HR 0.85; 95% CI 0.73 to 0.98), although this was not adjusted for multiplicity [5].

The trial used a treat-to-target dosing strategy. Patients started on alirocumab 75 mg every two weeks, with blinded up-titration to 150 mg if LDL-C remained at or above 50 mg/dL. If LDL-C fell below 15 mg/dL on two consecutive measurements, patients were switched to placebo in a blinded fashion. This protocol is worth noting because it directly shaped how the FDA's approved label describes the treatment algorithm.

Dosing Updates and the 300 mg Monthly Option

Praluent's label was updated to include a 300 mg every-four-weeks dosing option, giving patients an alternative to biweekly injections. The 300 mg dose is delivered as two 150 mg injections at a single visit.

This change was supported by the ODYSSEY CHOICE I trial (N=803), which showed that alirocumab 300 mg every four weeks reduced LDL-C by approximately 58.8% at week 24 versus placebo in patients on maximally tolerated statin therapy [6]. The biweekly 75 mg regimen in the same study produced a 47.0% reduction. Both arms met their primary endpoints.

The monthly dosing option addressed a practical barrier. Patient surveys and real-world adherence data consistently showed that injection frequency was a primary concern for patients on injectable lipid-lowering therapies [7]. Reducing the dosing burden from 26 to 13 injections per year was designed to improve persistence.

Safety Profile Across the Regulatory Record

The Praluent prescribing information describes a safety database of over 3,500 patients treated for up to 78 weeks in the key trials. The most common adverse reactions (incidence of 1% or greater and more frequent than placebo) are nasopharyngeal reactions, injection site reactions, and influenza [1].

Injection site reactions occurred in 7.2% of alirocumab patients versus 5.1% on placebo across the Phase 3 program [2]. These were mostly mild (erythema, itching, swelling) and rarely led to discontinuation. Serious allergic reactions including hypersensitivity vasculitis and hypersensitivity requiring hospitalization have been reported in post-marketing surveillance, though the incidence is very low.

Neurocognitive safety received particular FDA scrutiny during the review process. The ODYSSEY OUTCOMES trial included a pre-specified neurocognitive sub-study, which found no significant difference in neurocognitive adverse event rates between alirocumab and placebo groups, even among patients whose LDL-C fell below 25 mg/dL [8]. The FDA's 2019 label update reflects this finding.

Hepatic effects: In pooled Phase 3 data, hepatic-related adverse events were similar between alirocumab (2.5%) and control (1.8%) groups. ALT elevations greater than 3 times the upper limit of normal were infrequent and occurred at comparable rates [2].

A long-term open-label extension study (ODYSSEY OLE) followed 985 patients on alirocumab for up to 4.5 years and reported no new safety signals [9]. The adverse event profile remained consistent with the controlled trial data, providing reassurance about the drug's long-term tolerability.

Immunogenicity and Anti-Drug Antibodies

As a biologic, alirocumab carries a theoretical risk of anti-drug antibody (ADA) formation. In the clinical trial program, treatment-emergent ADAs were detected in 5.1% of alirocumab-treated patients versus 0.8% in the placebo group [1]. Neutralizing antibodies developed in 1.3% of patients.

The clinical significance of these antibodies appears limited. Patients who developed ADAs did not show meaningfully reduced LDL-C lowering efficacy or increased adverse event rates in the Phase 3 data [2]. The prescribing information notes that immunogenicity assay results are highly dependent on test sensitivity and methodology, making cross-comparisons with other biologics unreliable.

Post-Market Regulatory Actions and Label Changes

Since the original 2015 approval, the Praluent label has undergone several revisions beyond the cardiovascular indication:

The prescribing information was updated to include data on very low LDL-C levels. In ODYSSEY OUTCOMES, 28.6% of alirocumab-treated patients achieved LDL-C levels below 25 mg/dL at some point during follow-up [5]. The label notes that while no adverse consequences of very low LDL-C were identified, long-term effects are not fully established.

The FDA also required updates regarding concomitant use with other lipid-lowering agents. The label was revised to include interaction data with statins, ezetimibe, and fenofibrate. No clinically significant pharmacokinetic interactions were identified [1].

In 2019, Sanofi and Regeneron implemented a net price reduction of approximately 60% for Praluent, bringing the list price from around $14,000 per year to approximately $5,850 per year [10]. While not a regulatory action per se, this pricing change was closely linked to payer access restrictions that had limited utilization following the initial approval. The FDA had noted during the advisory committee process that cost-effectiveness considerations would influence real-world access.

Regulatory Comparison: Alirocumab vs. Evolocumab

Both PCSK9 inhibitors received FDA approval in 2015 within weeks of each other. Evolocumab (Repatha) was approved on August 27, 2015, roughly one month after alirocumab [11]. Both drugs target the same biological pathway but differ in their antibody engineering, approved indications, and trial evidence base.

A notable regulatory distinction: evolocumab holds an FDA-approved indication for homozygous familial hypercholesterolemia (HoFH), while alirocumab does not. The Praluent label is limited to HeFH and clinical ASCVD. This reflects differences in the clinical development programs rather than any fundamental pharmacologic limitation.

Both drugs demonstrated cardiovascular event reduction in large outcomes trials. The FOURIER trial (evolocumab, N=27,564) showed a 15% relative risk reduction in the primary MACE composite [12], numerically similar to the 15% reduction seen with alirocumab in ODYSSEY OUTCOMES. Direct comparisons between the two trials are complicated by differences in patient populations, event definitions, and follow-up duration.

"The cardiovascular outcomes data for both PCSK9 inhibitors provide clinicians with evidence-based options for high-risk patients who cannot reach LDL-C goals on statin therapy alone," according to the 2018 AHA/ACC cholesterol guideline writing committee [13].

International Regulatory Status

The European Medicines Agency (EMA) authorized alirocumab on September 23, 2015, two months after the FDA approval [14]. The EMA indication was broadly similar, covering adults with primary hypercholesterolemia (HeFH and non-familial) or mixed dyslipidemia as adjunct to diet.

Praluent has also received regulatory authorization in Japan (2016), Canada (2016), and Australia (2016). Each regulatory body imposed slightly different conditions regarding prior statin therapy requirements and reimbursement criteria.

In 2024, Regeneron and Sanofi announced plans to discontinue marketing of Praluent in certain European markets, citing commercial considerations related to biosimilar competition for evolocumab and ongoing payer restrictions [10]. The U.S. market access picture remained stable, with Praluent continuing on the FDA's approved drug list without interruption.

"We recommend PCSK9 inhibitors for patients with ASCVD at very high risk whose LDL-C remains at or above 70 mg/dL on maximally tolerated statin plus ezetimibe therapy," the Endocrine Society clinical practice guideline states [15].

Current Prescribing Information Highlights

The current Praluent label recommends the following dosing in adults:

Starting dose: 75 mg subcutaneously every 2 weeks or 300 mg every 4 weeks. If the LDL-C response is inadequate, the dose may be increased to 150 mg every 2 weeks (maximum approved dose). LDL-C levels should be measured 4 to 8 weeks after initiation or titration to assess response [1].

Contraindications are limited to a history of serious hypersensitivity reaction to alirocumab or any excipient. There is no boxed warning. The label carries no specific dose adjustment for renal or hepatic impairment, as population pharmacokinetic analyses showed no clinically meaningful effects of mild to moderate organ dysfunction on alirocumab exposure [1].

Storage requires refrigeration at 2°C to 8°C. The prefilled pen may be kept at room temperature (below 25°C) for up to 30 days in the original carton to protect from light.