Case of homozygous familial hypercholesterolaemia with premature coronary artery disease

Familial hypercholesterolaemia is a genetic disorder secondary to mutation of one or more of the genes critical for low-density lipoprotein cholesterol (LDL-C) metabolism; these mutation(s) cause highly elevated serum LDL-C, significantly increasing the risk of early cardiovascular events and mortality. Homozygous familial hypercholesterolaemia (HoFH) is rare and often leads to accelerated coronary atherosclerosis presenting within the first two decades of life. We report a case of a 14-year-old boy who presented after surviving a ventricular fibrillation cardiac arrest. His highly elevated LDL-C level prompted further workup and led to a diagnosis of HoFH. The treatment included medical therapy and coronary artery bypass grafting. The patient also required referral for lipid apheresis to meet goal LDL-C level, and an automated implantable cardioverter defibrillator for secondary prevention of sudden cardiac death. HoFH, if left untreated, can have devastating consequences Therefore, timely diagnosis initiating appropriate therapy is important.

Rare health conditions 43: phobias, homozygous familial hypercholesterolaemia and osteopetrosis

The purpose of this series is to highlight a range of rare health conditions. Rare health conditions are those that affect no more and usually fewer than one person in every 2000. Many healthcare assistants and nurses will encounter some of these conditions given the high number of these conditions. This 43rd article will briefly explore two of these conditions, homozygous familial hypercholesterolaemia and osteopetrosis, as well as a range of rare phobias.

P41 Pharmacokinetics-based estimation of evolocumab dosing for homozygous familial hypercholesterolemia (HoFH) in patients aged 6 to 12 years old

BackgroundHomozygous familial hypercholesterolaemia (HoFH) is a rare genetic disorder characterised by high plasma cholesterol levels and premature development of atherosclerotic cardiovascular disease.1Evolocumab is a high-cost monoclonal antibody to PCSK-9, an enzyme critical in cholesterol homeostasis. It is a subcutaneous injection commissioned for HoFH in children ≥12 years with persistently raised LDL-cholesterol (LDL-C) despite maximal tolerated lipid-lowering therapy.2 3 There is an unmet clinical need to allow patients ≥6 years meeting the same treatment threshold to access evolocumab and attenuate progression to invasive lipid apheresis or liver transplantation. However, as there are no published studies with PCSK-9 inhibitors in children <12 years, no established dosing regimen exists.Aims and objectivesPropose a safe, efficacious and cost-effective dose of evolocumab to be administered to eligible patients aged 6 to 12 years old with HoFH.Review all patients at 12 weeks to determine if 30% target LDL-C reduction is achieved thereby warranting treatment continuation in line with commissioning criteria.Review all patients at 12 months to establish if LDL-C reduction sustained.Assess all patients for incidence and nature of treatment-related adverse effects.MethodProposed evolocumab dosing determined using four criteria: potential dosing adjustments required based on population physiological and pharmacokinetic data, drug safety profile, practicalities of administration and cost implications.Clinic letters for all patients were reviewed 12 weeks and 12 months after treatment commenced.ResultsIn children <12 years dosing was proposed to start at 140 mg every 2 weeks, as this is the lowest administrable dose but is clinically equivalent to the 420 mg monthly dose (if information is extrapolated from heterozygous familial hypercholesterolemia studies4) and more cost-effective in terms of number of injections required. Furthermore, dose reduction in younger patients unlikely to be required as blood volume-dependent clearance of monoclonal antibodies and synthetic rates of PCSK-9 production do not significantly vary with age. Wide therapeutic index is implied as doses can be increased to 420 mg every 2 weeks and PCSK-9 has a limited physiological role with negligible ‘off target’ toxicity due to its inhibition.2 3 Therapeutic drug monitoring is not currently an option. Evolocumab was initiated using the proposed dose regimen in two eligible patients. Patient 1 had a 65% reduction in LDL-C (5.9 mmol/L to 1.9 mmol/L) at week 12, marginally subsiding at 12 months (2.7 mmol/L). No adverse effects reported and patient not yet progressed to lipid apheresis or liver transplantation. Patient 2 had only a 7% reduction in LDL-C (6.97 mmol/L to 6.48 mmol/L) at week 12 therefore evolocumab was stopped. No adverse effects were experienced. Lipid apheresis was continued throughout treatment.Conclusions and DiscussionExtrapolated dose of 140 mg every 2 weeks was safe and well-tolerated. Larger patient numbers are needed to further determine efficacy and safety, particularly due to promising significant and sustained LDL-C reduction in one patient. Licensed dose increases due to poor response in patients ≥12 years warrant investigation in younger population to allow potential treatment escalation for refractory patients. Therapeutic drug monitoring and antibody level testing are possible future research opportunities.ReferencesCuchel M, Bruckert E., Ginsberg HN, Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J, 2014;35:2146–57.Amgen Ltd., Summary of Product Characteristics for Repatha Sureclick. 2016. Available from www.medicines.org.uk [accessed: 24/05/2018]. Last updated 08/03/2018.NHS England, NHSE statement on evolocumab for the treatment of homozygous familial hypercholesterolaemia (circular). September 2016.National Institute for Health and Care Excellence, Evolocumab for treating primary hypercholesterolaemia and mixed dyslipidaemia [TA394]. 2016. Available from www.nice.org.uk [accessed:22/06/2018].

Lomitapide treatment in a female with homozygous familial hypercholesterolaemia: a case report

Background Homozygous familial hypercholesterolaemia (FH) is an autosomal-dominant inherited disease presenting with highly elevated low-density lipoprotein cholesterol (LDL-C) levels. Untreated, the patient can develop atherosclerosis and cardiovascular disease already in adolescence. Treatment with statins and ezetimibe is usually not sufficient and LDL apheresis is often required. Lomitapide, an inhibitor of the microsomal triglyceride transfer protein, reduces LDL-C and triglyceride levels and can be used alone or in combination with other therapies in homozygous FH. However, experience with this agent is still limited. Case summary We present a young female who was diagnosed with homozygous FH at 6 years of age. She shows a complete lack of normal LDL receptor activity and no cholesterol-lowering effect from statins. The patient was treated with LDL apheresis from 7 years of age. When LDL apheresis treatment extended to twice a week, she began to experience adverse effects, including catheter-related complications, infections, and hospital admissions. When lomitapide treatment was initiated, the frequency of apheresis reduced, the LDL-C levels improved and she has not had any further hospital admissions since. Initially, she suffered from gastrointestinal disturbances. However, after 3 years of treatment with lomitapide 20 mg/day, the patient has not experienced any adverse effects. Discussion In this female with homozygous FH adding lomitapide treatment to LDL apheresis has contributed to improved LDL-C levels, a reduction in LDL apheresis sessions and enhanced quality of life. No adverse effects have been reported. These findings suggest that lomitapide can be a drug of choice in patients with homozygous FH.