PCSK9 inhibition-mediated reduction in Lp(a) with evolocumab: an analysis of 10 clinical trials and the LDL receptor's role

Lipoprotein (a) [Lp(a)] is independently associated with CVD risk. Evolocumab, a monoclonal antibody (mAb) to proprotein convertase subtilisin/kexin type 9 (PCSK9), decreases Lp(a). The potential mechanisms were assessed. A pooled analysis of Lp(a) and LDL cholesterol (LDL-C) in 3,278 patients from 10 clinical trials (eight phase 2/3; two extensions) was conducted. Within each parent study, biweekly and monthly doses of evolocumab statistically significantly reduced Lp(a) at week 12 versus control (P < 0.001 within each study); pooled median (quartile 1, quartile 3) percent reductions were 24.7% (40.0, 3.6) and 21.7% (39.9, 4.2), respectively. Reductions were maintained through week 52 of the open-label extension, and correlated with LDL-C reductions [with and without correction for Lp(a)-cholesterol] at both time points (P < 0.0001). The effect of LDL and LDL receptor (LDLR) availability on Lp(a) cell-association was measured in HepG2 cells: cell-associated LDL fluorescence was reversed by unlabeled LDL and Lp(a). Lp(a) cell-association was reduced by coincubation with LDL and PCSK9 and reversed by adding PCSK9 mAb. These studies support that reductions in Lp(a) with PCSK9 inhibition are partly due to increased LDLR-mediated uptake. In most situations, Lp(a) appears to compete poorly with LDL for LDLR binding and internalization, but when LDLR expression is increased with evolocumab, particularly in the setting of low circulating LDL, Lp(a) is reduced. Lipoprotein (a) [Lp(a)] is independently associated with CVD risk. Evolocumab, a monoclonal antibody (mAb) to proprotein convertase subtilisin/kexin type 9 (PCSK9), decreases Lp(a). The potential mechanisms were assessed. A pooled analysis of Lp(a) and LDL cholesterol (LDL-C) in 3,278 patients from 10 clinical trials (eight phase 2/3; two extensions) was conducted. Within each parent study, biweekly and monthly doses of evolocumab statistically significantly reduced Lp(a) at week 12 versus control (P < 0.001 within each study); pooled median (quartile 1, quartile 3) percent reductions were 24.7% (40.0, 3.6) and 21.7% (39.9, 4.2), respectively. Reductions were maintained through week 52 of the open-label extension, and correlated with LDL-C reductions [with and without correction for Lp(a)-cholesterol] at both time points (P < 0.0001). The effect of LDL and LDL receptor (LDLR) availability on Lp(a) cell-association was measured in HepG2 cells: cell-associated LDL fluorescence was reversed by unlabeled LDL and Lp(a). Lp(a) cell-association was reduced by coincubation with LDL and PCSK9 and reversed by adding PCSK9 mAb. These studies support that reductions in Lp(a) with PCSK9 inhibition are partly due to increased LDLR-mediated uptake. In most situations, Lp(a) appears to compete poorly with LDL for LDLR binding and internalization, but when LDLR expression is increased with evolocumab, particularly in the setting of low circulating LDL, Lp(a) is reduced. Lipoprotein (a) [Lp(a)] is an LDL-like particle consisting of hepatic synthesized apo(a), a plasminogen-like glycoprotein that is disulfide-linked to the apoB moiety of circulating LDL, most likely at the hepatocellular surface (1Utermann G. The mysteries of lipoprotein(a).Science. 1989; 246: 904-910Crossref PubMed Scopus (1098) Google Scholar). Lp(a) levels are highly variable, primarily genetically determined, and independently associated with CVD. Both epidemiological and genetic studies show that increased levels of Lp(a) are consistently and positively associated with CVD risk (2Erqou, S., S. Kaptoge, P. L. Perry, E. Di Angelantonio, A. Thompson, I. R. White, S. M. Marcovina, R. Collins, S. G. Thompson, and J. 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T. S. E. B. S. T. ; and of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in with a in patients with a phase Scholar). The by PCSK9 inhibition Lp(a) not determined, but potential apoB R. Scipione C.A. Boffa M.B. Marcovina S.M. Seidah N.G. Koschinsky M.L. Lipoprotein(a) catabolism is regulated by proprotein convertase subtilisin/kexin type 9 through the low density lipoprotein receptor.J. Biol. Chem. 2015; 290: 11649-11662Abstract Full Text Full Text PDF PubMed Scopus (150) Google Lp(a) reduced availability of for to Lp(a) and by the LDLR R. Scipione C.A. Boffa M.B. Marcovina S.M. Seidah N.G. Koschinsky M.L. Lipoprotein(a) catabolism is regulated by proprotein convertase subtilisin/kexin type 9 through the low density lipoprotein receptor.J. Biol. Chem. 2015; 290: 11649-11662Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar, H. A. N. M. convertase subtilisin/kexin type 9 with apolipoprotein and of the lipoprotein Biol. 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Danesh, ; Emerging Risk Factors Collaboration. 2009. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA. 302: 412–423.Google increased LDLR for of Lp(a) by potential effect in from randomized placebo-controlled phase and clinical trials M.J. R. J.B. B. T. L. M. S.M. and of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as in patients with a phase Full Text Full Text PDF PubMed Scopus Google M. P. M. J. M. M. L. J. J. B. R. S. M. and H. ; for the phase clinical of J. Cardiol. R. N. R. P. J. R. F. T. S. E. B. S. T. ; and of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in with a in patients with a phase G. B. S. J. J. J. M. D. R. J. C. P. R. ; Effect of evolocumab to on LDL-C lowering in patients with the randomized clinical JAMA. F. R. R. I. G. S.M. 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T. ; and of of evolocumab in patients with results from the of LDL-C randomized were in one of the phase clinical trials and to in the open-label studies were to of evolocumab 1, and was from patients to in the studies were by and and were in with and the of for analysis the percent from to parent week 12 and week 52 in Lp(a) and LDL-C and the potential Lp(a) was measured by the the In the phase LDL-C was by both and In the phase studies LDL-C was the but was measured by the LDL-C by was were LDL-C was measured by the in the control randomized to monthly as measured by and by cholesterol in the of for by Lp(a) by a of as of Lp(a) is cholesterol and of apolipoprotein (a) from lipoprotein Biol. PubMed Scopus Google Scholar). to the of evolocumab versus control for Lp(a) and LDL-C reductions were the in each was in the phase but not the phase Lp(a) and and for for were for patients with Lp(a) lower of at parent week were with and were of the and were as D. C. J. J. proprotein convertase subtilisin/kexin type 9 antibody cholesterol in and PubMed Scopus Google Scholar, B. M. J. J. J. R. L. antibody and in are and to Pharmacol. 2015; PubMed Scopus Google Scholar). The control for in studies was a antibody The in binding at and to in and of LDL-C lowering < < < B. M. J. J. J. R. L. antibody and in are and to Pharmacol. 2015; PubMed Scopus Google Scholar). were by with LDLR and and binding at the not were by the and at an for and of and to the for the and of were in studies in at of studies are in the The of and for the LDLR was of analysis are in the and PCSK9 were for the to expression of of HepG2 in a and with PCSK9 with without with were with to the receptor receptor and of PCSK9 inhibition to increase expression of the LDLR and increase hepatic of LDL in the PubMed Scopus Google studies to a potential the LDLR and Lp(a) were The of LDL is by the with potential in the PubMed Scopus Google LDL by HepG2 was as a of LDLR expression and LDL was with concentrations of unlabeled LDL Lp(a) and was with HepG2 in for at with cell-associated fluorescence were measured a with Lp(a) was by Lp(a) of HepG2 were with Lp(a) for at In the 10 of Lp(a) was with of LDL and with HepG2 for in at were with and was on for Lp(a) and for were to and with antibody antibody control The of LDLR in Lp(a) was by the level of LDLR on HepG2 LDLR expression was increased by HepG2 in maintained at levels by in LDLR levels were reduced by the with of PCSK9 in the of LDLR levels were the and at In each were with 10 Lp(a) for at were and with to and as A of 3,278 patients at one of and were in the The was most patients were were and most were with statins median and Lp(a) was LDL-C was when for LDL-C was In the pooled evolocumab and in percent reductions in LDL-C of and respectively. for reductions in LDL-C were of and reductions in LDL-C were and at week 12 for the and and the reductions and at week respectively. percent reductions in Lp(a) for and were 24.7% and 21.7% and reductions were and at week These reductions were maintained for an 52 of treatment and were not by In both the pooled parent and reductions in Lp(a) were significantly correlated with reductions in both and LDL-C at week 12 and < for and week 52 and < for a was within the evolocumab treatment for both the and LDL-C at week 12 (P < 0.0001). of LDL-C that patients with evolocumab with low LDL-C levels Lp(a) percent with patients with LDL-C results were in patients on treatment reductions in Lp(a) at parent week 12 by and LDL-C when LDL-C was and for in Lp(a) at 12 at at at at at at were patients to in the not a at for for were patients to in the not a at in a in Lp(a) statistically significantly correlated with in LDL-C at parent week 12 and open-label week 52 for Lp(a) in Lp(a) statistically significantly correlated with in LDL-C at parent week 12 and open-label week 52 for Lp(a) reductions in Lp(a) at parent week 12 by Lp(a) and LDL-C when and for at in Lp(a) at 12 at at for for in a In treatment in reductions from in a to the in LDL-C in Lp(a) was from was in Lp(a) was of that of the of effect was < < < A was for the percent in Lp(a) with the percent in LDL-C of unlabeled LDL in of cell-associated LDL fluorescence to effective for both the LDLR and concentrations of unlabeled Lp(a) reduced cell-associated LDL fluorescence to unlabeled LDL, effective levels of Lp(a) LDL a effect on reducing LDL by HepG2 the of Lp(a) with HepG2 were in the of Lp(a). In the of a at in the HepG2 with Lp(a) with the was by of the with and levels of LDL was not with LDLR expression was not by the the level of LDLR on HepG2 the of cell-associated Lp(a). cell-associated Lp(a) increased when LDLR expression was high and when LDLR expression was low The in LDLR expression was by PCSK9 with as the binding of PCSK9 to the LDLR D. C. J. J. proprotein convertase subtilisin/kexin type 9 antibody cholesterol in and PubMed Scopus Google Scholar). in LDLR expression the Lp(a) of LDLR expression by reduced Lp(a) the PCSK9 the the expression of the in HepG2 and do not expression of from HepG2 with PCSK9 with without were by and by with to The of Lp(a) is the for LDLR-mediated of Lp(a) was to V.W. B. H. M. Walli A.K. Seidel D. of lipoprotein and studies on the of two with the LDL receptor.J. 31: Full Text PDF PubMed Google a that was from both clinical and Statins, a to effect in reducing Lp(a). in studies that the of the LDL of Lp(a) for increased the of the and V.W. Walli A.K. Seidel D. and in of an lipoprotein on of Full Text PDF PubMed Google Scholar). pooled the reductions in Lp(a) and LDL-C in 12 week trials of evolocumab D. R. J.B. A. S.M. Stein E.A. Effect of a monoclonal antibody to PCSK9 on lipoprotein cholesterol levels in the randomized PubMed Scopus Google Scholar, M.J. R. J.B. B. T. L. M. S.M. and of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as in patients with a phase Full Text Full Text PDF PubMed Scopus Google Scholar, R. N. R. P. J. R. F. T. S. E. B. S. T. ; and of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in with a in patients with a phase Scholar, M. P. M. J. M. M. L. J. J. B. R. S. M. and H. ; for the phase clinical of J. Cardiol. Scholar, G. B. S. J. J. J. M. D. R. J. C. P. R. ; Effect of evolocumab to on LDL-C lowering in patients with the randomized clinical JAMA. Scholar, F. R. R. I. G. S.M. Stein E.A. lipoprotein of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in patients with the of LDL-C with PCSK9 in randomized PubMed Scopus Google Scholar, F. E. A. R. T. F. L. G. R. A. G. D. ; PCSK9 inhibition with evolocumab in a placebo-controlled Scholar, D. D. F. R. S. G. F. Watts, E. L. R. B. ; antibody lowers cholesterol in patients with the placebo-controlled phase clinical of J. Cardiol. Scholar, M. R. P. F. J. D. M. G. F. R. P. T. ; and of of evolocumab in patients with results from the of LDL-C randomized the of a for LDLR of Lp(a). These reductions were maintained to an 52 and significantly correlated with reductions in even when for in the reductions in LDL-C were not for the cholesterol in Lp(a) M.S. M.J. G. H. D. M. R. S.M. in lipoprotein(a) with PCSK9 monoclonal antibody evolocumab a pooled analysis of patients in phase Cardiol. 2014; PubMed Scopus Google Scholar). In for and a of reductions in Lp(a) and that are an was Lp(a) percent in patients lower levels of LDL-C treatment with evolocumab with patients with levels of LDL-C is with and of the that Lp(a) the particularly when for the receptor with LDL-C is reduced. of Lp(a) lowering appears to evolocumab treatment of support for the of the LDLR from in and In a of Lp(a) and LDL-C reductions the in The binding of to PCSK9 in in the of effect of was with the of each mAb. the of in LDL-C and Lp(a) that the in LDL-C by PCSK9 inhibition is to Lp(a) from in studies that of LDL by HepG2 was reduced by both LDL and but by that Lp(a) to the LDLR and with LDL uptake. by is and may to the of of lipoprotein The that concentrations of Lp(a) were to compete with LDL that binding of Lp(a) to the LDLR is that of LDL, and is with binding and of Lp(a) when levels of LDL are as in the clinical D. R. J.B. A. S.M. Stein E.A. Effect of a monoclonal antibody to PCSK9 on lipoprotein cholesterol levels in the randomized PubMed Scopus Google Scholar, M.J. R. J.B. B. T. L. M. S.M. and of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as in patients with a phase Full Text Full Text PDF PubMed Scopus Google Scholar, R. N. R. P. J. R. F. T. S. E. B. S. T. ; and of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in with a in patients with a phase Scholar, M. P. M. J. M. M. L. J. J. B. R. S. M. and H. ; for the phase clinical of J. Cardiol. Scholar, G. B. S. J. J. J. M. D. R. J. C. P. R. ; Effect of evolocumab to on LDL-C lowering in patients with the randomized clinical JAMA. Scholar, F. R. R. I. G. S.M. Stein E.A. lipoprotein of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in patients with the of LDL-C with PCSK9 in randomized PubMed Scopus Google Scholar, F. E. A. R. T. F. L. G. R. A. G. D. ; PCSK9 inhibition with evolocumab in a placebo-controlled Scholar, D. D. F. R. S. G. F. Watts, E. L. R. B. ; antibody lowers cholesterol in patients with the placebo-controlled phase clinical of J. Cardiol. Scholar, M. R. P. F. J. D. M. G. F. R. P. T. ; and of of evolocumab in patients with results from the of LDL-C randomized Scholar). that LDL with Lp(a) binding to the LDLR and Lp(a) LDL and Lp(a) for the LDLR may on the and and to with the binding of the The of Lp(a) with HepG2 was increased when LDLR expression was increased and when LDLR expression was reduced. PCSK9 to with and the expression of in to LDLR M. X. E. A. Seidah N.G. convertase subtilisin/kexin type 9 of the low density lipoprotein PubMed Scopus Google Scholar, C. M. M. M. J. H. O. P. A. PCSK9 Metab. 2014; Full Text Full Text PDF PubMed Scopus Google Scholar, M. G. J. M. G. A. is not in the of LDL and in the Full Text Full Text PDF PubMed Scopus Google Scholar, S. G. S. E. J. N. H. J. A. Seidah N.G. The proprotein convertase PCSK9 the of low density lipoprotein receptor (LDLR) and and Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, L. L. R. H. J.A. PCSK9 to and by an PubMed Scopus (150) Google Scholar). a for of in of in PCSK9 was not to expression of lipoprotein support for of Lp(a) LDLR The lipoprotein Lp(a) is and in a by the receptor.J. Clin. PubMed Scopus Google Scholar, M.J. B. is a receptor for Full Text Full Text PDF PubMed Scopus Google Scholar). the that receptor by PCSK9 that is in Lp(a) A of of in Lp(a) with may to the of PCSK9 both LDLR expression on and PCSK9 PCSK9 binding to the the of the Lp(a) binding to the LDLR the of the the of an effect on Lp(a) support that PCSK9 inhibition in Lp(a) both with without with percent reductions for patients not at levels of LDL is clinical for the of lowering Lp(a). is that lowers a at inhibition of is in S. M.J. J.L. Yang Marcovina S.M. a placebo-controlled phase 2015; Full Text Full Text PDF PubMed Scopus Google is epidemiological and genetic a of LDL (2Erqou, S., S. Kaptoge, P. L. Perry, E. Di Angelantonio, A. Thompson, I. R. White, S. M. Marcovina, R. Collins, S. G. Thompson, and J. Danesh, ; Emerging Risk Factors Collaboration. 2009. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA. 302: 412–423.Google Scholar, 3B. G. Nordestgaard, M. J. Chapman, K. Ray, J. Borén, F. Andreotti, G. F. Watts, H. Ginsberg, P. Amarenco, A. Catapano, O. S. Descamps, ; European Atherosclerosis Society Consensus Panel. 2010. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur. Heart J. 31: 2844–2853.Google Scholar, 4Clarke, R., J. F. Peden, J. C. Hopewell, T. Kyriakou, A. Goel, S. C. Heath, S. Parish, S. Barlera, M. G. Franzosi, S. Rust, ; PROCARDIS Consortium. 2009. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N. Engl. J. Med. 361: 2518–2528.Google Scholar). The clinical of the effect of on Lp(a) the and analysis of clinical The is the effect of PCSK9 inhibition with evolocumab on clinical cardiovascular and is due to results in M.S. A. N. H. T. S.M. R. and of the cardiovascular with PCSK9 in subjects with risk Heart J. PubMed Scopus Google Scholar). to the of the risk is to the LDL-C in with the of statins L. J. L. E. C. N. R. E. H. A. J. ; Collaboration. 2010. and of lowering of LDL a of from in Scholar). the risk is may due to effect on may to of reductions in Lp(a) from of reduced In evolocumab treatment both Lp(a) and both and for and reductions are The percent in Lp(a) in patients lower levels of and LDL-C with with levels is of the that Lp(a) with LDL-C for the In and in in analysis and R. Scipione C.A. Boffa M.B. Marcovina S.M. Seidah N.G. Koschinsky M.L. Lipoprotein(a) catabolism is regulated by proprotein convertase subtilisin/kexin type 9 through the low density lipoprotein receptor.J. Biol. Chem. 2015; 290: 11649-11662Abstract Full Text Full Text PDF PubMed Scopus (150) Google support the that the of LDLR by PCSK9 the of Lp(a). LDLR-mediated of due to a of of LDLR with reduced LDL likely a in the of Lp(a) by PCSK9 The and R. of for with the of LDL cholesterol LDL receptor lipoprotein (a) lipoprotein LDL monoclonal antibody proprotein convertase subtilisin/kexin type 9 quartile quartile monthly of receptor receptor

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