Vascular Access for Lipid Apheresis: A Challenge in Young Children With Homozygous Familial Hypercholesterolemia

Background Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder leading to extremely increased LDL-cholesterol (LDL-C), resulting in high cardiovascular risk in early childhood. Lipid apheresis (LA) is an effective treatment and should be started as early as possible to prevent premature cardiovascular events. As peripheral punctures in children can be challenging due to small vessels and anxiety, this study aimed to evaluate central venous catheters (CVCs) as vascular access for LA in young children with hoFH.MethodsRetrospective analysis (2016-2019) on four children with hoFH aged 3-5, performing weekly or biweekly LA with a CVC.ResultsLDL-C decreased by> 60%. In three children, the use of a permanent CVC for 698, 595, and 411 days, respectively, avoided difficult peripheral access, without the occurrence of occlusion or thrombosis. Unfortunately, one child had recurrent CVC-related infections and needed an arteriovenous fistula from the age of 5. Although the mean dwell time per catheter was 212 days, there were, as expected, severe side effects of early catheter infections with sepsis and accidental self-removal. Starting LA at an early age improved or stabilized carotid intima-media thickness (IMT) in all children. Finally, IMT did increase in one child caused by intolerance to peripheral punctures and LA interruption.ConclusionsPermanent CVCs are a viable temporary access choice for LA in young children with hoFH until peripheral venipuncture is practicable. The risk of CVC-related infections needs to be taken into account.

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].