In-Depth Analysis of Sanofi and Regeneron's Cholesterol Drug Favored by FDA Panel

By lowering LDL-C levels, alirocumab may reduce cardiovascular risk.

At a June 9, 2015 meeting an FDA panel recommended approval of Sanofi and Regeneron Pharmaceuticals' hypercholesterolemia drug alirocumab (Praluent) in a 13-3 vote.

Proposed indications for the biweekly subcutaneous injection include:

• Long-term treatment of adult patients with primary hypercholesterolemia, or mixed dyslipidemia, and dyslipidemia associated with type 2 diabetes mellitus to reduce low-density lipoprotein cholesterol (LDL-C) levels, total cholesterol levels, and other unfavorable cardiovascular markers, as well as to increase levels of the favorable high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-1
• As monotherapy, or as add-on to a nonstatin lipid-modifying treatment, including in patients who cannot tolerate statins

In an important limitation of this indication, the medication’s efficacy in terms of cardiovascular morbidity and mortality reduction remains undetermined.

Mechanism of action

Alirocumab works by inhibiting the activity of a protein in the blood called protein proprotein convertase subtilisin/kexin type 9 (PCSK9). Normally, PCSK9 inhibits the function of a LDL receptors (LDLRs) on the surface of liver cells, limiting the ability of LDLRs to capture and sequester LDL-C from the blood. As alirocumab inhibits PCSK9 activity, more LDLRs remain on the surface of liver cells, and with more LDLRs present, more LDL-C is captured from the blood and sequestered in the liver.

By lowering LDL-C levels, alirocumab may reduce cardiovascular risk, particularly in statin-intolerant patients, or in patients who have not achieved a 50% or greater reduction in LDL-C with existing therapies alone.

Dosage and administration

Alirocumab will be supplied in prefilled pens and syringes. Proposed dosing of alirocumab would be 75 mg administered via subcutaneous injection every 2 weeks, with a possible increase to 150 mg every 2 weeks in patients requiring LDL-C reductions exceeding 60% of initial levels.

Patient initiating treatment may receive a dosage adjustment pursuant to LDL-C levels measured as few as 4 weeks after starting therapy, as steady-state LDL-C levels are generally achieved within 4 weeks of treatment initiation or dosage adjustment.

Pharmacokinetics

Pharmacokinetic studies of alirocumab indicate a half-life of 17 to 20 days at steady-state levels. However, when alirocumab is used with statins the half-life of alirocumab is shortened to approximately 12 days. This shortened elimination half-life may occur because statins increase PCSK9 production, resulting in increased alirocumab clearance as alirocumab binds with circulating PCSK9 proteins.

There are no data on the disposition of alirocumab in patients with severe renal impairment or severe hepatic impairment due to exclusion of these patients from clinical studies. However, pharmacokinetic parameters were not affected by race, sex, or mild to moderate hepatic impairment or renal impairment.

Clinical studies

Alirocumab has been studied in 3188 patients with hypercholesterolemia in 10 double-bind phase 3 studies of 6 to 24 months' duration. Of these 10 studies, 5 compared alirocumab with a placebo, and 5 compared alirocumab with ezetimibe. Three studies included patients with heterozygous familial hypercholesterolemia (a genetic condition that predisposes patients to high cholesterol levels), and 1 study was limited to statin-intolerant patients. Nearly one-third (30%) of patients receiving alirocumab had diabetes mellitus.

Across studies, use of alirocumab resulted in:

• 45.6% to 48.9% reduction in LDL-C levels over the first 24 weeks of therapy
• LDL-C level reductions averaging 60.4% in patients receiving intensified dosing of alirocumab (150 mg every 2 weeks)
• A 50% or greater reduction in LDL-C levels over 24 weeks of therapy in 54.6% to 75.7% of users, depending on the clinical trial population

Warnings and precautions

Common adverse events with alirocumab that occurred more frequently than in patients taking placebo included injection site reactions and pruritus. In patients receiving alirocumab and ezetimibe, common adverse events included myalgia (6.7%), upper respiratory tract infection (5.9%), and nasopharyngitis (5.4%). Most adverse events were transient, of mild intensity, and did not result in treatment discontinuation.

Local injection site reactions were the most common adverse event resulting in treatment discontinuation, with 0.2% of patients receiving alirocumab discontinuing due to local reactions versus 0.3% of patients in control groups.

Hypersensitivity, hypersensitivity vasculitis, and nummular eczema have all been observed in association with alirocumab exposure. Although many of these hypersensitivity events led to discontinuation of therapy, all recorded cases resolved after alirocumab discontinuation and/or a short course of corticosteroid therapy.

Researchers did not identify any increase in the risk of neurocognitive events, with the exception of an imbalance between the treatment and control groups in a 78-week study. Neurocognitive events occurred in a total of 29 patients taking alirocumab across all clinical trials.

Anti-drug antibodies appeared in 4.8% of patients receiving alirocumab versus 0.6% of patients receiving control medications or placebo, whereas drug-neutralizing antibodies appeared in 1.2% of patients receiving alirocumab. Importantly, drug-neutralizing antibodies usually appeared on a single test, and not on subsequent tests. Patients with 2 or more blood samples containing drug-neutralizing antibodies comprised just 0.3% of patients.

In patients with diabetes mellitus, treatment with alirocumab did not result in clinically meaningful changes in glycemic control.

Reproductive concerns with alirocumab were not addressed in an FDA briefing document regarding the drug.

Conclusions

Although alirocumab has not yet been approved, Sanofi and Regeneron are optimistic about the drug’s outlook considering the FDA committee’s positive opinion of the new medication.

In a press release, Elias Zerhouni, MD, President of Global Research and Development at Sanofi stated, “We are pleased with the Committee's recommendation to approve Praluent.” Regeneron president and chief scientific officer George D. Yancopoulos, MD, PhD, noted, “Today's outcome brings us one step closer to translating this genetics-based discovery into a treatment that may help the many patients in need of additional cholesterol lowering.”

A final FDA decision on the drug is expected July 24, 2015.

References

• Vermes K. FDA Panel Advises Praluent PCKS9 Inhibitor Approval. http://www.pharmacytimes.com/product-news/fda-panel-advises-praluent-pcks9-inhibitor-approval. Accessed June 2015.
• FDA. FDA Advisory Committee Briefing Document Praluent (alirocumab). http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM449867.pdf. Accessed June 2015.
• Regeneron. FDA Advisory Committee Recommends Approval of Regeneron and Sanofi's Praluent® (alirocumab) Injection for Patients with Hypercholesterolemia [press release]. http://files.shareholder.com/downloads/REGN/291494936x0x834686/F63401CF-4E49-4B8B-9783-7187EAF25CC1/REGN_News_2015_6_9_General_Releases.pdf. Accessed June 2015.