Effect of the Proprotein Convertase Subtilisin/Kexin 9 Monoclonal Antibody, AMG 145, in Homozygous Familial Hypercholesterolemia

Abstract

More than 95% of HoFH patients have a mutation in the LDL receptor, <4% in have a mutation in apolipoprotein B, and <0.5% have a mutation in proprotein convertase subtilisin/kexin 9 (PCSK9). 2,3 Although true genetic HoFH is not uncommon, the majority of patients are compound heterozygotes. 4 The residual LDL receptor activity, either negative (<2% function) or defective (2%-25% function), is associated with severity of LDL cholesterol elevation and the propensity for early cardiovascular disease. 1 Clinical Perspective on p 2120Conventional therapies such as statins 5,6 and ezetimibe 7 are the most commonly used drugs for HoFH and result in LDL cholesterol reductions of 15% to 25%. Patients usually also require LDL apheresis when available. 8 These improvements in LDL cholesterol, particularly with statins, appear to reduce cardiovascular disease morbidity and mortality.

Clinical experience of lomitapide therapy in patients with homozygous familial hypercholesterolaemia

“…Unsurprisingly, HoFH patients who are LDLreceptor negative are less likely to respond to such agents than patients with defective LDL-receptor function [4]. Similar results are also observed with newer lipid-lowering agents that are currently in development, such as monoclonal antibodies to proprotein convertase subtilisin/kexin 9 (PCSK9) that also act by increasing the number of LDL receptors [5].…”

Pcsk9

“…Although injections are not particularly attractive for lifelong treatment, such an approach would likely be embraced by patients having side effects from current lipid-lowering agents or by high-risk subjects striving to achieve lower LDL-C, as indicated by recent guidelines. 137,138 For example, homozygous patients with FH, for whom initial LDL-C levels starts ≈3 to 4× that of the general population, are usually unable to achieve a 50% reduction on available oral agents and thus require LDL-apheresis, a form of dialysis to eliminate the LDL-C from blood 139 Amazingly, administration of a blocking PCSK9 mAb to homozygote patients with FH with some residual LDLR activity resulted in ≈30% reduction in LDL-C, 140 giving some new hope for these patients that have to often undergo apheresis.…”

The Role of Genetic Counselors for Patients with Familial Hypercholesterolemia

“…For example, the effectiveness of certain therapies, such as the proprotein convertase subtilisin/kexin 9 monoclonal antibody, AMG 145, depended upon the HoFH patient's genotype in a recent study, with no LDL-C response seen in the two patients in this trial who were LDL receptor negative [38].…”