Metabolic

Clinically Meaningful Reductions in LDL-C With Monthly Alirocumab Treatment

Heather R. Johnson
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2015 saw a great leap forward in the development and use of PCSK9 (proprotein convertase subtilisin/kexin) inhibitors. This past July, the FDA approved alirocumab (Praluent, Regeneron), followed 1 month later by the approval of a second PCSK9 inhibitor evolocumab (Repatha, Amgen). The drugs were approved for use in addition to diet and maximally tolerated statin therapy in adult patients with heterozygous familial hypercholesterolemia or those with clinical atherosclerotic cardiovascular disease requiring additional LDL-C lowering. A third drug, bococizumab (Pfizer), is currently in development. Data from large, long-term randomized controlled outcomes trials—ODYSSEY Outcomes (alirocumab), FOURIER (evolocumab), and SPIRE (bococizumab)—are anticipated to provide clear answers as to the drugs' impact on cardiovascular events and safety profiles. –from "The Promise of PSCK9 Inhibitors by Brian Ellis,” published 11/9/15.
2015 saw a great leap forward in the development and use of PCSK9 (proprotein convertase subtilisin/kexin) inhibitors.

This past July, the FDA approved alirocumab (Praluent, Regeneron), followed 1 month later by the approval of a second PCSK9 inhibitor evolocumab (Repatha, Amgen). The drugs were approved for use in addition to diet and maximally tolerated statin therapy in adult patients with heterozygous familial hypercholesterolemia or those with clinical atherosclerotic cardiovascular disease requiring additional LDL-C lowering. A third drug, bococizumab (Pfizer), is currently in development.

Data from large, long-term randomized controlled outcomes trials—ODYSSEY Outcomes (alirocumab), FOURIER (evolocumab), and SPIRE (bococizumab)—are anticipated to provide clear answers as to the drugs’ impact on cardiovascular events and safety profiles.

–from “The Promise of PSCK9 Inhibitors by Brian Ellis,” published 11/9/15.

Monthly treatment with 300 mg alirocumab was found to be associated with clinically meaningful reductions in LDL-C.

Monthly treatment with 300 mg alirocumab was found to be associated with clinically meaningful reductions in low-density lipoprotein-cholesterol (LDL-C), according to the results of a clinical trial published in the Journal of Clinical Lipidology.

In this ODYSSEY CHOICE I study (ClinicalTrials.gov Identifier: NCT01926782), the efficacy of alirocumab (300 mg every four weeks) for the lowering of LDL-C was examined in 803 patients with hypercholesterolemia treated with statins (n=547) or not (n=256). The 300 mg alirocumab dose has been approved for the reduction of LDL-C in adults with heterozygous familial hypercholesterolemia and for the management of adults with cardiovascular disease who require cholesterol-lowering therapy in addition to dietary changes and statin therapy. With this study, researchers sought to investigate the relationship between Proprotein convertase subtilisin/kexin type 9 (PCSK9), alirocumab, a monoclonal antibody, which, by binding to PCSK9, prevents the  downregulation of LDL receptors mediated by this enzyme, thereby lowering the level of circulating LDL particles, and LDL-C concentrations.

Participants were randomly assigned to receive 300 mg alirocumab every four weeks, 75 mg alirocumab every two weeks, or placebo, for a period of 24 weeks. For participants whose LDL-C levels were >70 (or >100 mg/dL based on cardiovascular risk) or who had a reduction in LDL-C <30% from baseline at week 8, doses were adjusted to 150 mg every two weeks at week 12. Blood samples were collected weekly between weeks 20 and 24 to allow for a detailed assessment of the time course of alirocumab effects.

Reductions in LDL-C levels ranged from 60.5% to 71.9% during the week 20 to 24 after treatment initiation in patients receiving 300mg alirocumab every 4 weeks, and from 57.2% to 63.0% in patients for whom the dose of alirocumab was adjusted from 300 mg every 4 weeks to 150 mg every 2 weeks.

Patients who were vs were not on a statin regimen had higher levels of free PCSK9 and lower alirocumab concentrations.

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Most patients (82.1%) remained on the 300 mg alirocumab 4-week regimen for the study’s duration.

“Monoclonal antibodies are subject to target-mediated clearance, where clearance of the antibody (in this case alirocumab) and therefore duration of the pharmacodynamic effect (LDL-C reduction) is dictated by concentrations of the target (PCSK9) and influenced by factors that affect target production (which may include use of statins and other lipid-lowering therapies such as ezetimibe and fenofibrate, as well as disease states including familial hypercholesterolemia, chronic kidney disease, and diabetes),” noted the study authors. “In this analysis, we demonstrated that patients receiving a statin had higher free PCSK9 concentrations at baseline and during treatment. Alirocumab concentrations were also lower in patients receiving a statin, suggesting increased target-mediated clearance.”

Disclosure: The study was sponsored by Sanofi and Regeneron Pharmaceuticals.

Reference

Roth EM, Kastelein JJP, Cannon CP, Farnier M, McKenney JM, DiCioccio AT, et al. Pharmacodynamic relationship between PCSK9, alirocumab, and LDL-C lowering in the ODYSSEY CHOICE I trial. Journal of Clinical Lipidology. doi:https://doi.org/10.1016/j.jacl.2020.07.009

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