Effect of Alirocumab, a Monoclonal Proprotein Convertase Subtilisin/Kexin 9 Antibody, on Lipoprotein(a) Concentrations (a Pooled Analysis of 150 mg Every Two Weeks Dosing from Phase 2 Trials)

Abstract

Lipoprotein(a) [Lp(a)] is an independent risk factor for cardiovascular disease, with limited treatment options. This analysis evaluated the effect of a monoclonal antibody to proprotein convertase subtilisin/kexin 9, alirocumab 150 mg every 2 weeks (Q2W), on Lp(a) levels in pooled data from 3 double-blind, randomized, placebo-controlled, phase 2 studies of 8 or 12 weeks' duration conducted in patients with hypercholesterolemia on background lipid-lowering therapy (NCT01266876, NCT01288469, and NCT01288443). Data were available for 102 of 108 patients who received alirocumab 150 mg Q2W and 74 of 77 patients who received placebo. Alirocumab resulted in a significant reduction in Lp(a) from baseline compared with placebo (-30.3% vs -0.3%, p <0.0001). Median percentage Lp(a) reductions in the alirocumab group were of a similar magnitude across a range of baseline Lp(a) levels, resulting in greater absolute reductions in Lp(a) in patients with higher baseline levels. Regression analysis indicated that <5% of the variance in the reduction of Lp(a) was explained by the effect of alirocumab on low-density lipoprotein cholesterol. In conclusion, pooled data from 3 phase 2 trials demonstrate substantive reduction in Lp(a) with alirocumab 150 mg Q2W, including patients with baseline Lp(a) >50 mg/dl. Reductions in Lp(a) only weakly correlated with the magnitude of low-density lipoprotein cholesterol lowering.

Efficacy and Safety of Alirocumab in Japanese Patients With Heterozygous Familial Hypercholesterolemia or at High Cardiovascular Risk With Hypercholesterolemia Not Adequately Controlled With Statins – ODYSSEY JAPAN Randomized Controlled Trial –

“…In a pooled analysis of three double-blind phase 2 trials, alirocumab 150 mg Q2W produced a 30% reduction vs. placebo (P<0.0001) in lipoprotein(a). 22 An even greater reduction (-43.3%) was observed in a Japanese phase 2 study in hypercholesterolemic patients on alirocumab 150 mg Q2W. 14 The mechanism by which alirocumab reduces lipoprotein(a) is as yet unclear, but Gaudet et al postulated that upregulation of LDL receptors by statins and alirocumab, combined with very low concentrations of LDL-C and apolipoprotein B, resulted in the uptake of lipoprotein(a) by LDL receptors.…”

“…14 The mechanism by which alirocumab reduces lipoprotein(a) is as yet unclear, but Gaudet et al postulated that upregulation of LDL receptors by statins and alirocumab, combined with very low concentrations of LDL-C and apolipoprotein B, resulted in the uptake of lipoprotein(a) by LDL receptors. 22 Unlike other ODYSSEY studies, in which the medication was selfadministered from the outset, 11,13 in this Japanese study all patients were injected by the study personnel up to week 24, at which point they could choose to self-inject the medication. The overall rate of subsequent TEAEs was lower among patients who chose to self-inject, and no differences were apparent in the rates of injection site reactions between patients who self-administered the medication and patients in whom the injections were given by site personnel.…”

Population and assay thresholds for the predictive value of lipoprotein (a) for coronary artery disease: the EPIC-Norfolk Prospective Population Study

“…LPA4 is a murine monoclonal IgG antibody to apo(a) that was generated by immunizing mice with the apo(a) sequence TRNYCRNPDAE-IRP. This sequence is present as one copy on KIV 5 , KIV 7 , and KIV 8 of apo(a) and does not cross-react with plasminogen. This assay is also a true "Lp(a)" assay as it uses a capture antibody to apoB-100 and detects apo(a) with biotinylated LPA4.…”

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

“…Other lipid-lowering drug therapies that do not primarily lower LDL-C by upregulating LDL receptor (LDLR) activity (e.g., bile acid sequestrants, ezetimibe) have no reported effect on Lp(a), while moderate reductions are seen with drugs that inhibit the production of LDL-C or its precursor [e.g., niacin (13), mipomersen, lomitapide]. Yet Lp(a) is robustly and consistently reduced by treatment with proprotein convertase subtilisin/kexin type 9 (PCSK9) antibodies, which reduce LDL-C via upregulation of LDLR activity (15)(16)(17)(18)(19)(20)(21). The mechanism(s) by which PCSK9 inhibition reduces Lp(a) has not yet been determined, but potential explanations include decreased apoB synthesis (11), decreased Lp(a) synthesis, reduced availability of apoB-containing lipoproteins (LDL) for linkage to Lp(a), enhanced Lp(a) uptake and clearance by the LDLR (11,22), or other hepatic receptors in the setting of low LDL-C levels (22).…”