Investigational PCSK9 inhibitor lowers LDL-C, may reduce cardiovascular events

PCSK9 inhibitor alirocumab (Praluent) reduced low-density lipoprotein (LDL) cholesterol levels in patients receiving statin therapy, according to a study published online in the New England Journal of Medicine.

The phase 3 ODYSSEY Long Term study evaluated alirocumab 150 mg (n=1,553) every 2 weeks compared to placebo (n=788) in patients who were at high cardiovascular (CV) risk and who were receiving maximally tolerated statin therapy with or without other lipid-lowering treatment. The trial included patients with heterozygous familial hypercholesterolemia (HeFH) (n=276 alirocumab, n=139 placebo). Patients received 78 weeks of treatment followed by an 8-week safety assessment. Patients self-administered a subcutaneous injection every 2 weeks via a pre-filled syringe.

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The study showed that alirocumab reduced low-density lipoprotein cholesterol (LDL-C or “bad” cholesterol) by an additional 62% when added to maximally tolerated statins with or without maximal lipid-lowering therapy compared to placebo (P<.001). That efficacy remained consistent throughout treatment; at week 78, there was a 56% reduction from baseline in LDL-C for alirocumab compared to placebo (P<.001). Alirocumab was generally well-tolerated.

Other key results include:

• At week 24, 81% of patients in the alirocumab group achieved their pre-specified LDL-C goal (either 70 mg/deciliter [mg/dL] or 100 mg/dL depending on baseline CV risk) compared to 8.5% for placebo (P<.0001).

• Adverse events (AEs) occurred in 81% of alirocumab and 83% of placebo patients, leading to discontinuation in 7.2% and 5.8% of patients, respectively. AEs were similar between groups, apart from differences in injection-site reactions, myalgia, neurocognitive events, and ophthalmological events. In a 3,759-patient, pooled safety analysis of 9 placebo-controlled alirocumab studies, rates of skeletal muscle-related and neurocognitive events were generally balanced between alirocumab and placebo.

• At week 78, positively adjudicated pre-specified CV AEs (including additional CV AEs beyond those in the pre-specified ODYSSEY Outcomes end point of ‘major adverse cardiac events’ described below) occurred in 4.6% and 5.1% of alirocumab and placebo patients, respectively.

• In a post-hoc analysis using a pre-specified end point that included coronary heart disease death, myocardial infarction, stroke, or unstable angina requiring hospitalization, a lower rate of adjudicated major cardiac events was observed in the alirocumab group (27 of 1,550 patients, 1.7%) compared with the placebo group (26 of 788 patients, 3.3%; hazard ratio 0.52; 95% CI, 0.31 to 0.90; nominal P=.02). The cumulative incidence curve diverged progressively over time.

Dr Robinson“Patients with genetic hypercholesterolemia and high-risk patients unable to tolerate maximal statin therapy need additional LDL-C lowering options,” said the study’s lead author Jennifer Robinson, MD, MPH, director of the Prevention Intervention Center, and professor, departments of epidemiology & medicine, College of Public Health at the University of Iowa, Iowa City.

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“In other research presented, we saw that despite treatment with the current standard of care, data suggest cardiovascular event rates continue to remain high among high-risk managed care patients in the United States. Thus, new treatment options that are shown to reduce cardiovascular events are needed,” Dr Robinson said.

“The results of the [study] demonstrate durable efficacy for alirocumab when added to maximally tolerated statin therapy and further reinforce its generally consistent safety profile,” Dr Robinson added. “Additionally, the post-hoc analysis of major cardiovascular events represents an important finding for alirocumab.

"We look forward to results from the ongoing ODYSSEY Outcomes trial is prospectively evaluating the potential of alirocumab reduce cardiovascular events and long-term safety profile."

The study was sponsored by Sanofi and Regeneron.

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