Target achievement and cardiovascular event rates with Lomitapide in homozygous Familial Hypercholesterolaemia

Dirk J Blom,Helen Phillips,Marina Cuchel,Marina Cuchel,Miranda Ager

doi:10.1186/s13023-018-0841-3

Abstract

BackgroundHomozygous familial hypercholesterolaemia (HoFH) is characterized by a markedly increased risk of premature cardiovascular (CV) events and cardiac death. Lomitapide reduces low-density lipoprotein cholesterol (LDL-C) levels; however, the probable impact on LDL-C goals and CV events is unknown.MethodsWe used data collected in the first 26 weeks of the lomitapide pivotal phase 3 study (NCT00730236) to evaluate achievement of European Atherosclerosis Society (EAS) LDL-C targets. We used publicly available data reporting major adverse CV events (MACE) rates from other cohorts of HoFH patients to compare event rates for an equivalent number of patient years of exposure (98) in the lomitapide extension trial (NCT00943306).ResultsTwenty-nine patients were included in the phase 3 study. During the first 26 weeks, 15 (51%) and eight (28%) reached LDL-C targets of 100 mg/dL and 70 mg/dL, respectively, at least once. Fourteen (74%) and 11 (58%) of the 19 patients who remained in the extension study after week 126 reached LDL-C targets of 100 mg/dL and 70 mg/dL at least once during the entire study period. Only two MACE were reported in the lomitapide trials (one cardiac death and one coronary artery bypass graft (CABG)) – equivalent to 1.7 events per 1000 patient months of treatment. MACE rates were 21.7, 9.5 and 1.8 per 1000 patient-months respectively in cohorts of HoFH patients pre- and post-mipomersen, and receiving evolocumab. On treatment LDL-C levels were 166, 331 and 286 mg/dL for lomitapide, mipomersen and evolocumab, respectively.ConclusionsApproximately three quarters and half of patients who took lomitapide for at least 2 years reached LDL-C goals of 100 mg/dL and 70 mg/dL, respectively. There were fewer major CV events per 1000 patient months of treatment in patients taking lomitapide, mipomersen or evolocumab than reported in the mipomersen cohort prior to starting mipomersen. These results support the hypothesis that novel lipid-lowering therapies may reduce CV events in HoFH patients by lowering LDL-C further.Trial registrationNCT00730236 (registered 8 Aug 2008) and NCT00943306 (registered 22 July 2009).

Highlights

Homozygous familial hypercholesterolaemia (HoFH) is characterized by a markedly increased risk of premature cardiovascular (CV) events and cardiac death
Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic condition characterised by markedly elevated low-density lipoprotein-cholesterol (LDL-C) levels, inadequate response to conventional drug therapy and premature-onset cardiovascular disease (CVD) [1]
The patients entering the pivotal study were receiving standard of care for HoFH with 93% of patients receiving statins, 76% of patients received ezetimibe while 62% of patients were treated with apheresis

Summary

Introduction

Homozygous familial hypercholesterolaemia (HoFH) is characterized by a markedly increased risk of premature cardiovascular (CV) events and cardiac death. Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic condition characterised by markedly elevated low-density lipoprotein-cholesterol (LDL-C) levels, inadequate response to conventional drug therapy and premature-onset cardiovascular disease (CVD) [1]. The European Atherosclerosis Society (EAS) has suggested that patients with HoFH should be treated to the same LDL-C targets set for other patients requiring lipid-lowering therapy, namely < 100 mg/dL (2.6 mmol/L) for primary prevention, and < 70 mg/dL (1.8 mmol/L) in the presence of clinical atherosclerotic CVD [1]. These targets are not achievable in the majority of HoFH patients with currently available standard therapies that require functioning LDL-receptors, such as statins, ezetimibe [3] and inhibitors of PCSK9 [4]

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