Effects of PCSK9 inhibition with alirocumab on lipoprotein metabolism in healthy humans

Authors: REYES-SOFFER, GISSETTE - Columbia University; PAVLYHA, MARIANNA - Columbia University; NGAI, COLLEEN - Columbia University; THOMAS, TIFFANY - Columbia University; HOLLERAN, STEPHEN - Columbia University; RAMAKRISHNAN, RAJASEKHAR - Columbia University; KARMALLY, WAHIDA - Columbia University; NANDAKUMAR, RENU - Columbia University; FONTANEZ, NELSON - Columbia University; OBUNIKE, JOSEPH - City University Of New York; MARCOVINA - University Of Washington; LICHTENSTEIN, ALICE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; MATTHAN, NIRUPA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; MATTA, JAMES - Sanofi-Aventis Us, Inc; MAROCCIA, MAGALI - Umanis; BECUE, FREDERICK - Sanofi, Montpellier; POITIERS, FRANCK - Sanofi, Paris; SWANSON, BRIAN - Sanofi-Aventis Us, Inc; COWAN, LISA - Sanofi-Aventis Us, Inc; SASIELA, WILLIAM - Regeneron Pharmaceuticals, Inc; SURKS, HOWARD - Sanofi-Aventis Us, Inc; GINSBERG, HENRY - Columbia University

Submitted to: Circulation
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/7/2016
Publication Date: 12/16/2016
Citation: Reyes-Soffer, G., Pavlyha, M., Ngai, C., Thomas, T., Holleran, S., Ramakrishnan, R., Karmally, W., Nandakumar, R., Fontanez, N., Obunike, J., Marcovina, .M., Lichtenstein, A.H., Matthan, N.R., Matta, J., Maroccia, M., Becue, F., Poitiers, F., Swanson, B., Cowan, L., Sasiela, W.J., Surks, H.K., Ginsberg, H.N. 2016. Effects of PCSK9 inhibition with alirocumab on lipoprotein metabolism in healthy humans. Circulation. 135(4):352-362. https://doi.org/10.1161/CIRCULATIONAHA.116.025253.

Interpretive Summary: High levels of low density lipoprotein (LDL) cholesterol are associated with a higher risk of developing heart disease. LDL particles are removed from the blood by LDL receptors. PCSK9 is a protein that binds to LDL receptors and facilitates the breakdown, rather than recycling, of LDL, while limiting the number of functional LDL receptors. When there are fewer LDL receptors in tissue (especially the liver,) plasma LDL-cholesterol concentrations can rise. A synthetic antibody called alirocumab specifically binds to PCSK9 and prevents the LDL receptor degradation, and hence, substantially decreases LDL-cholesterol concentrations. Healthy subjects were first treated with a placebo and then alirocumab. At the end of each treatment period, lipoprotein production and LDL-breakdown rates were tracked. The results demonstrated that inhibition of PCSK9 activity increases the removal of LDL from circulation via the LDL receptors, which suggests that PCSK9 inhibitors may help prevent heart disease.

Technical Abstract: Background: Alirocumab, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), lowers plasma low density lipoprotein cholesterol (LDL-C) and apolipoprotein B100 (apoB). Although studies in mice and cells have identified increased hepatic LDL receptors as the basis for LDL lowering by PCSK9 inhibitors, there have been no human studies characterizing the effects of PCSK9 inhibitors on lipoprotein metabolism. In particular, it is not known if inhibition of PCSK9 has any effects on very low density lipoprotein (VLDL) or intermediate density lipoprotein (IDL) metabolism. Inhibition of PCSK9 also results in reductions of plasma Lp(a) levels. The regulation of plasma Lp(a) levels, including the role of LDL receptors (LDLRs) in the clearance of Lp(a), is poorly defined, and there have been no mechanistic studies of the Lp(a) lowering by alirocumab in humans. Methods: Eighteen (10F, 8M) participants completed a placebo-controlled, two-period study. They received 2 doses of placebo, 2 weeks apart, followed by 5 doses of 150 mg of alirocumab, 2 weeks apart. At the end of each period, fractional clearance rates (FCR) and production rates (PR) of apoB and apo(a) were determined. In 10 participants, postprandial triglycerides (TG) and apoB48 levels were measured. Results: Alirocumab reduced ultracentrifugally isolated LDL-C by 55.1%, LDL-apoB by 56.3%, and plasma Lp(a) by 18.7%. The fall in LDL-apoB was due to an 80.4% increase in LDL-apoB FCR and a 23.9% reduction in LDL-apoB PR. The latter was associated with a 46.1% increase in IDL-apoB FCR coupled with a 27.2% decrease in conversion of IDL to LDL. The FCR of apo(a) tended to increase (24.6%) without any change in apo(a) PR. Alirocumab had no effects on FCRs or PRs of VLDL-apoB and VLDL-TG, or on postprandial plasma TG or apoB48 concentrations. Conclusions: Alirocumab decreased LDL-C and LDL-apoB by increasing IDL- and LDL-apoB FCRs, and decreasing LDL-apoB PR. These results are consistent with increases in LDLRs available to clear IDL and LDL from blood during PCSK9 inhibition. The possible increase in apo(a) FCR during alirocumab treatment suggests that increased LDLRs may also play a role in the reduction of plasma Lp(a).