Treatment Of Homozygous Familial Hypercholesterolemia Research Articles

Lomitapide for the treatment of homozygous familial hypercholesterolaemia in children

Lomitapide for the treatment of homozygous familial hypercholesterolaemia in children

Is Liver Transplantation Alone an Effective Treatment for Homozygotic Familial Hypercholesterolemia in Children?

To examine the long-term results and treatment effectiveness of liver transplantation (LT) in the treatment of homozygous familial hypercholesterolemia (HoFH) in children and adolescents. Patients who underwent LT due to HoFH between 2007 and 2023 were included in the study. The patients' demographic data, clinical findings, preoperative and postoperative laboratory examinations, transplantation complications, and postoperative disease courses were evaluated. There were five boys with an average age of 6.2 (median: 6, range 4-10) years in the study. The average total cholesterol level of the patients before transplantation was 923 (median: 950, range: 780-1002) mg/dL and the average LDL-cholesterol level was 864 (median: 852, range: 770-957) mg/dL. No patients died of transplant-related complications. After an average follow-up of 9.2 (median: 9, range: 1.5-16) years, the average total cholesterol level of the patients was 197 (median: 164, range: 137-359) mg/dL, and the average LDL-cholesterol level was 138 (median: 92, range: 85-313) mg/dL. Four (80%) patients developed atherosclerotic cardiovascular disease during follow-up, and two (40%) died of this cause. LT in the treatment of HoFH did not help our patients reach the target LDL-cholesterol level after transplantation and did not prevent the development of cardiovascular disease. Therefore, LT alone is not curative in the treatment of HoFH.

Compassionate use of evinacumab for the treatment of homozygous familial hypercholesterolaemia (HoFH) in children under 5 years of age: Clinical experience

Compassionate use of evinacumab for the treatment of homozygous familial hypercholesterolaemia (HoFH) in children under 5 years of age: Clinical experience

An investigational in vivo base editing medicine targeting ANGPTL3, VERVE-201, achieves potent and LDLR-independent liver editing in mouse models

Abstract Background VERVE-201 is an investigational medicine composed of a messenger RNA for an adenine base editor and a guide RNA that targets the ANGPTL3 gene packaged in a GalNAc lipid nanoparticle (LNP). Delivered via a one-time intravenous infusion, VERVE-201 is designed to inactivate ANGPTL3 in the liver and thereby lower low-density lipoprotein cholesterol (LDL-C) concentrations to treat atherosclerotic cardiovascular disease (ASCVD). VERVE-201 is initially being developed for the treatment of homozygous familial hypercholesterolemia—a rare genetic disorder in which severe or complete low-density lipoprotein receptor (LDLR)-deficiency leads to marked elevations in LDL-C and premature ASCVD. Purpose We first evaluated the potential of VERVE-201 to achieve on-target ANGPTL3 editing in human liver cells in vitro and humanized ANGPTL3 mice in vivo. Second, while standard LNPs are taken up into hepatocytes primarily by the LDLR, the GalNAc targeting ligand included in the VERVE-201 LNP is expected to enable LDLR-independent delivery via an alternate receptor (ASGPR). We test the hypothesis that VERVE-201mu (mouse surrogate of VERVE-201) can achieve comparable degree of Angptl3 editing in wild-type mice and those with partial (Ldlr+/-) or complete (Ldlr-/-) LDLR-deficiency. Methods VERVE-201 was first assessed in primary human hepatocytes at a range of doses in vitro. To assess whether VERVE-201 edits the human ANGPTL3 gene in vivo, a human ANGPTL3 mouse model was generated and VERVE-201 was evaluated at 7 dose levels ranging from 0.1 to 3.0 mg/kg (n=4 in each group). Next, one of four doses of VERVE-201mu ranging from 0.25 to 2.0 mg/kg or a vehicle control was administered to wild type, Ldlr+/−, and Ldlr−/− mice (n=5 in each genotype treatment group). In mouse experiments, tissue and blood samples were collected 7 days following dosing for evaluation. Results In primary human hepatocytes, VERVE-201 achieved potent and dose-responsive ANGPTL3 editing in cells from each of three donors. In human ANGPTL3 mice, VERVE-201 treatment resulted in dose-responsive liver ANGPTL3 editing. In mice treated with the highest dose of 3 mg/kg, mean liver editing of 64% and reduction in blood ANGPTL3 protein of 98% were observed. In wild type, Ldlr+/−, and Ldlr−/− mice, VERVE-201mu was similarly well-tolerated and achieved highly consistent potency across the doses studied (Figure). In mice treated with the highest dose of 2.0 mg/kg, mean liver Angptl3 editing of 60% and reductions in blood ANGPTL3 protein of 99% were observed, with no detectable differences across wild-type, Ldlr+/−, and Ldlr−/− mice. Conclusions These nonclinical data support the potential of VERVE-201 to enable precise and potent ‘once-and-done’ ANGPTL3 inactivation in the context of the severe or complete LDLR deficiency that occurs in homozygous familial hypercholesterolemia, a patient population that struggles to achieve adequate LDL-C reduction even on multiple lipid-lowering therapies.

OR24-02 Case Series Of Canadian Patients With Homozygous Familial Hypercholesterolemia Treated With ANGPTL3 Inhibitor Evinacumab

Abstract Disclosure: I. Shamsudeen: None. B.W. McCrindle: Consulting Fee; Self; Jansen Pharmaceuticals, Amryt, Ultragenyx, Chiesi, Esperion. R.A. Hegele: Advisory Board Member; Self; Amgen Inc, HLS Pharmaceuticals, Novartis Pharmaceuticals. Consulting Fee; Self; Akcea Therapeutics, Ultragenyx, Medison, Acasti, Amgen Inc, Novartis Pharmaceuticals, Amryt, Amgen Inc, Pfizer, Inc., Arrowhead, Sanofi, HLS Pharmaceuticals, Regeneron Pharmaceuticals. Background: Homozygous familial hypercholesterolemia (HoFH) is an ultrarare, life-threatening condition characterized by markedly elevated levels of low-density lipoprotein cholesterol (LDL-C) due to biallelic LDL receptor variants. Patients have an increased risk of premature atherosclerotic cardiovascular disease (ASCVD). Traditional lipid-lowering agents are minimally effective and the gold standard treatment is serial apheresis. Recently, an angiopoietin-like protein 3 (ANGPTL3) inhibitor, evinacumab, was introduced as a promising new treatment for HoFH. It was FDA-approved in 2021, but is currently available in Canada only through clinical trials or special access programs. Case Presentations: The first five Canadian HoFH patients to receive evinacumab via special access are presented. Their mean age is 24.6 years (SD = 13.9). As of December 2022, they have received evinacumab 15 mg/kg intravenously every four weeks for a mean of 12.2 months (SD = 11.3). Their mean incremental LDL-C reduction is 49.4% (SD = 8.9) on evinacumab along with reduced apheresis frequency for those on serial apheresis. Safety labs for all patients are normal. Brief case summaries are as follows: (a) Patient A is a 36-year-old man with severe ASCVD who has been on evinacumab for 30 months, in addition to a statin, ezetimibe, evolocumab and LDL-apheresis. His time-averaged LDL-C has decreased by 46.2%, from 4.76 to 2.56 mmol/L (184 to 99 mg/dL), on evinacumab. (b) Patient B is a 17-year-old male with elevated LDL-C levels despite being on a statin, ezetimibe and LDL-apheresis. After 14 months on evinacumab, his time-averaged LDL-C reduced by 40.3%, from 8.75 to 5.22 mmol/L (338 to 202 mg/dL). (c) Patient C is a 30-year-old woman with ASCVD and xanthomas on a statin and ezetimibe, but not apheresis. She has been on evinacumab for 12 months with a 57.7% reduction in LDL-C, from 11.43 to 4.83 mmol/L (442 to 187 mg/dL). (d) Patient D is a 36-year-old man with ASCVD on a statin, ezetimibe, evolocumab and lomitapide in addition to plasmapheresis. He started evinacumab 2 months ago and has already had a 42.6% decrease in time-averaged LDL-C, from 4.34 to 2.49 mmol/L (168 to 96 mg/dL). (e) Patient E is a 4-year-old boy with HoFH and xanthomas on a statin, ezetimibe and plasmapheresis. After 3 months of treatment with evinacumab, his time-averaged LDL-C decreased by 59.9%, from 9.45 to 3.79 mmol/L (365 to 147 mg/dL). Concurrently, he has developed unexplained intermittent abdominal pain, with temporary suspension of evinacumab pending further assessment. Discussion: Five HoFH patients with distinctive histories, baseline treatments and ASCVD have all shown marked improvement in LDL-C levels with a mean reduction of 49.4% on evinacumab on top of existing therapy. Overall, observations from our case series suggest that evinacumab is an effective new treatment for HoFH, a life-threatening condition with few therapeutic options. Presentation: Saturday, June 17, 2023

Efficacy and safety of lomitapide in familial chylomicronaemia syndrome

Background and aimsFamilial chylomicronaemia syndrome (FCS) is a rare autosomal recessive disorder, resulting in elevated triglycerides (TGs), abdominal pain and pancreatitis. Treatment options are limited. Lomitapide, a microsomal triglyceride transfer protein inhibitor, is approved for the treatment of homozygous familial hypercholesterolaemia. Whether its therapeutic use may be extended to FCS remains unknown. The aim of this study was to evaluate the efficacy and safety of lomitapide in adult patients with FCS. MethodsThe open-label, single-arm ‘LOCHNES’ study of lomitapide in FCS enrolled patients >18 years with genetically confirmed FCS, elevated fasting TG ≥ 750 mg/dL and history of pancreatitis. Patients were administered lomitapide to the maximum tolerated dose for 26 weeks. The primary endpoint was the percent change in TGs from baseline to Week 26. ResultsEighteen patients were enrolled with median baseline TG levels 1803.5 mg/dL (97.5% CI, 1452–2391 mg/dL). At Week 26, median fasting TGs were reduced to 305 mg/dL (97.5% CI 219–801 mg/dL; 70.5% reduction); median lomitapide dose was 35 mg/day; 13 patients achieved TGs ≤750 mg/dL. Adverse events were mild to moderate and mainly related to gastrointestinal tolerability. Liver imaging at baseline and Week 26 revealed hepatic fat increases from median 12.0%–32.5%, while median hepatic stiffness remained normal. No patient experienced acute pancreatitis or severe abdominal pain during lomitapide treatment. ConclusionsLomitapide is effective and well tolerated in reducing TGs in FCS patients with a history of pancreatitis. Larger studies are warranted to determine lomitapide effectiveness in FCS.

Evinacumab: a new option in the treatment of homozygous familial hypercholesterolemia

ABSTRACT Introduction Familial hypercholesterolemia is a genetic disorder characterized by elevated levels of low-density lipoprotein cholesterol (LDL-C) since birth and an exceedingly high risk of premature cardiovascular disease, especially in the homozygous form (HoFH). Despite the availability of effective cholesterol-lowering drugs, substantial LDL-C and cardiovascular risk reductions in these patients are still problematic, especially in those carrying mutations in the low-density lipoprotein receptor (LDLR) gene. Areas covered Loss-of-function mutations in angiopoietin-like 3 (ANGPTL3) encoding gene are associated with lower levels of LDL-C and reduced cardiovascular risk; the pharmacological inhibition of ANGPTL3 reduces LDL-C levels independently of LDLR. This approach can thus improve the treatment of HoFH using a monoclonal antibody targeting ANGPTL3 (evinacumab). Expert opinion Most lipid-lowering agents available so far are insufficient to achieve an appropriate response in HoFH patients. The inhibition of ANGPTL3 with evinacumab halves LDL-C levels in HoFH patients by an LDLR-independent mechanism. The results obtained so far have clearly indicated a promising improvement in the management of these patients. As the reduction of CV risk is proportional to the absolute reduction in LDL-C levels, we can expect that treatment with evinacumab, added to the maximally tolerated lipid-lowering therapy, will turn into a significant clinical benefit.

Lessons learned from the evinacumab trials in the treatment of homozygous familial hypercholesterolemia.

Homozygous familial hypercholesterolemia (HoFH) is a life-threatening disease characterized by extremely elevated LDL cholesterol (LDL-C) levels which result in premature atherosclerotic cardiovascular disease. As conventional lipid-lowering therapies, which mainly depend on LDL receptors for LDL particle clearance, remain insufficient for reaching the recommended LDL-C levels in HoFH, agents acting independently of LDL receptors, such as ANGPTL3 inhibitors, constitute a promising target. Evinacumab, a monoclonal antibody directed against ANGPTL3, was approved in the USA in 2021 for treating patients with HoFH. Evinacumab has shown an adequate safety profile with strong LDL-lowering efficacy. This review highlights the development path of evinacumab and provides insight on the lessons learned from trials as well as the hurdles facing accessibility.

Evinacumab for the treatment of homozygous familial hypercholesterolemia

ABSTRACT Introduction Hypercholesterolemia is mainly caused by abnormal lipoprotein metabolism and can increase the risk of cardiovascular disease. Angiopoietin-like protein 3 (ANGPTL3) can increase low-density lipoprotein cholesterol (LDL-C) and other lipids by inhibiting lipoprotein lipase activity. Evinacumab is a monoclonal antibody against ANGPTL3, it can decrease levels of LDL-C and has shown potential benefit in patients with homozygous familial hypercholesterolemia (HoFH). Areas covered A comprehensive literature search was conducted in PubMed (January 2000 to August 2021). Key search terms included ANGPTL3, evinacumab and HoFH. Other sources were derived from product labeling and ClinicalTrials.gov. All English-language articles identified from the data sources were reviewed and evaluated. Phase 1, 2 and 3 clinical trials were included. The pharmacological characteristics, clinical evidence, and safety of evinacumab were reviewed. Expert opinion Evinacumab is an ANGPTL3 inhibitor. Phase 3 clinical trials found that in patients with HoFH, evinacumab reduced LDL-C by 47%, but placebo increased by 2%. Evinacumab was well-tolerated. Common adverse events included nasopharyngitis, influenza-like illness, dizziness, rhinorrhea, and nausea. It has the potential to become a valuable treatment option for patients with HoFH.

Evolocumab in patients with homozygous familial hypercholesterolemia in India

Evolocumab is a fully human monoclonal antibody inhibitor of proprotein convertase subtilisin/kexin type 9 approved in India for treatment of homozygous familial hypercholesterolemia (HoFH) in patients aged ≥12 years. RAMAN (NCT03403374) was a single-country, open-label, phase 4 study evaluating the safety and tolerability of evolocumab in patients with HoFH in India. Patients ≥12 to ≤80 years of age on stable lipid-lowering therapy with fasting low-density lipoprotein cholesterol (LDL-C) >3.4mmol/L (>130mg/dL) received evolocumab 420mg subcutaneously monthly (every 2 weeks if on apheresis). The primary endpoint was patient incidence of treatment-emergent adverse events. Secondary endpoints included percent changes at week 12 in LDL-C and other lipids. Of 30 enrolled patients, 13 were <18 years of age. Mean±SD baseline levels of LDL-C, apolipoprotein B, and lipoprotein(a) were 12.3±3.5mmol/L (473.5±135.2mg/dL), 2.8±0.7g/L (275.3±69.1mg/dL), and 201.3±177.6nmol/L, respectively. Ten patients (33%) reported treatment-emergent adverse events, with 2 (7%) serious adverse events and none leading to discontinuation; no deaths occurred during evolocumab treatment. At week 12, mean (SE) percent changes from baseline in LDL-C, apolipoprotein B, and lipoprotein(a) were -6.4% (4.2), -6.0% (3.7), and -0.2% (4.9), respectively. Reductions in LDL-C among individual patients were variable and greatest in patients ≥18 years of age and with baseline LDL-C <13mmol/L (<500mg/dL). Evolocumab was safe and well tolerated in patients with HoFH in India with smaller reductions in LDL-C and other lipids than those observed in previous studies with HoFH and different populations.

Lipid-Lowering Drug Therapy: Critical Approach for Implementation in Clinical Practice.

Increased levels of low-density lipoprotein cholesterol (LDL-C) are recognized as a primary risk factor for atherosclerotic cardiovascular disease, which remains the leading cause of death worldwide. Lowering LDL-C levels clearly reduces the risk of cardiovascular events, with benefits related to both absolute reduction and duration of treatment; however, a threshold below which low LDL-C levels can be dangerous has never been established. Since the discovery of statins, cardiovascular research has focused on developing new lipid-lowering agents. Ezetimibe and proprotein convertase subtilisin–kexin type 9 inhibitors have been found to further reduce LDL-C values and subsequent cardiovascular risk. Novel recently approved inclisiran and bempedoic acid, currently being tested in cardiovascular outcomes studies, are further expanding our pharmacological armamentarium, enabling the clinician to diminish residual risk related to LDL-C. Moreover, new agents are paving the way to successful treatment of homozygous familial hypercholesterolemia. This review summarizes the main characteristics of current and emerging lipid-lowering therapies to assist with comprehensive evidence-based decision making.

Long-term efficacy of lipoprotein apheresis and lomitapide in the treatment of homozygous familial hypercholesterolemia (HoFH): a cross-national retrospective survey

BackgroundHomozygous familial hypercholesterolemia (HoFH) is a rare life-threatening condition that represents a therapeutic challenge. The vast majority of HoFH patients fail to achieve LDL-C targets when treated with the standard protocol, which associates maximally tolerated dose of lipid-lowering medications with lipoprotein apheresis (LA). Lomitapide is an emerging therapy in HoFH, but its place in the treatment algorithm is disputed because a comparison of its long-term efficacy versus LA in reducing LDL-C burden is not available. We assessed changes in long-term LDL-C burden and goals achievement in two independent HoFH patients’ cohorts, one treated with lomitapide in Italy (n = 30) and the other with LA in France (n = 29).ResultsThe two cohorts differed significantly for genotype (p = 0.004), baseline lipid profile (p < 0.001), age of treatment initiation (p < 0.001), occurrence of cardiovascular disease (p = 0.003) as well as follow-up duration (p < 0.001). The adjunct of lomitapide to conventional lipid-lowering therapies determined an additional 58.0% reduction of last visit LDL-C levels, compared to 37.1% when LA was added (padj = 0.004). Yearly on-treatment LDL-C < 70 mg/dl and < 55 mg/dl goals were only achieved in 45.5% and 13.5% of HoFH patients treated with lomitapide. The long-term exposure to LDL-C burden was found to be higher in LA than in Lomitapide cohort (13,236.1 ± 5492.1 vs. 11,656.6 ± 4730.9 mg/dL-year respectively, padj = 0.002). A trend towards fewer total cardiovascular events was observed in the Lomitapide than in the LA cohort.ConclusionsIn comparison with LA, lomitapide appears to provide a better control of LDL-C in HoFH. Further studies are needed to confirm this data and establish whether this translates into a reduction of cardiovascular risk.

Monoclonal Antibodies: New Drugs, New Indications.

The newest indications for monoclonal antibodies are as treatment for homozygous familial hypercholesterolemia, advanced triple-negative breast cancer, advanced urothelial cancer, relapsed or refractory large B-cell lymphoma, and non-small cell lung cancer with epidermal growth factor receptor exon 20 insertion mutations.

Evinacumab: First Approval.

The recombinant human monoclonal antibody evinacumab (evinacumab-dgnb, EVKEEZA™) is an angiopoietin-like protein three (ANGPTL3) inhibitor that has been developed by Regeneron Pharmaceuticals for the treatment of homozygous familial hypercholesterolaemia (HoFH), refractory hypercholesterolemia (both familial and non-familial) and severe hypertriglyceridaemia. Based on the results of the phase III ELIPSE HoFH trial, evinacumab was recently approved in the USA as an adjunct to other LDL-C lowering therapies for the treatment of adult and paediatric patients aged 12 years and older with HoFH, and has received a positive opinion in the EU. This article summarizes the milestones in the development of evinacumab leading to this first approval for HoFH.

Developing a second-generation clinical candidate AAV vector for gene therapy of familial hypercholesterolemia

Gene therapy for hypercholesterolemia offers the potential to sustainably ameliorate disease for life with a single dose. In this study, we demonstrate the combinatorial effects of codon and vector optimization, which significantly improve the efficacy of an adeno-associated virus (AAV) vector in the low-density lipoprotein receptor (LDLR)-deficient mouse model (Ldlr−/−, Apobec1−/− double knockout [DKO]). This study investigated vector efficacy following the combination of intervening sequence 2 (IVS2) of the human beta-globin gene and codon optimization with the previously developed gain-of-function, human LDLR triple-mutant variant (hLDLR-L318D/K809R/C818A) in the treatment of homozygous familial hypercholesterolemia (HoFH). Vector doses as low as 3 × 1011 genome copies (GC)/kg achieved a robust reduction of serum low-density lipoprotein cholesterol (LDL-C) by 98% in male LDLR-deficient mice. Less efficient LDL-C reduction was observed in female mice, which was attributable to lower gene transfer efficiency in liver. We also observed persistent and stable transgene expression for 120 days, with LDL-C levels being undetectable in male DKO mice treated with the second-generation vector. In conclusion, codon and vector optimization enhanced transgene expression and reduced serum LDL-C levels effectively at a lower dose in LDLR-deficient mice. The second-generation clinical candidate vector we have developed has the potential to achieve therapeutic effects in HoFH patients.

Evinacumab — an ANGPTL3 inhibitor; a new drug in the treatment of lipid disorders. Review on the literature and clinical studies

Angiopoietin-like proteins (ANGPTL) are a family of several proteins, of which ANGPTL3, 4 and 8 are involved in lipid metabolism. These proteins, discovered relatively recently, regulate the availability of triglycerides for the heart, skeletal muscles and white and brown adipose tissue depending on the nutritional status of the body, thus contributing to the maintenance of energy homeostasis. ANGPTL3, 4 and 8 gene mutations are associated with a significant reduction in plasma lipid levels, which translates to a reduction in the risk of ischaemic heart disease and diabetes type 2. It was shown that blood levels of ANGPTL3, 4, 5 and 8 may change in various disease states, such as obesity or diabetes type 2, and thus may constitute biomarkers of the cardiovascular risk. Evinacumab, being a fully humanized anti-ANGPTL3 antibody, February, 11 th , 2021, as Evkeeza® preparation, has been registered by the US Food and Drug Administration for the treatment of homozygous familial hypercholesterolaemia. In clinical trials, evinacumab was characterized by a high lipid-lowering efficacy in patients with homozygous and heterozygous familial hypercholesterolaemia, as well as treatment-resistant hypercholesterolaemia and hypertriglyceridaemia. Another drug that reduces ANGPTL3 activity are antisense oligonucleotides targeting Angptl3 mRNA (ANGPTL3 ASO) which were also characterized by lipid lowering properties in clinical trials.

Evinacumab - a new drug in the treatment of homozygous familial hypercholesterolaemia

Evinacumab - a new drug in the treatment of homozygous familial hypercholesterolaemia

Will evinacumab become the standard treatment for homozygous familial hypercholesterolemia?

ABSTRACT Introduction: Homozygous Familial Hypercholesterolemia (HoFH) is a very severe genetic form of hypercholesterolemia. Lacking LDL receptors in the liver, subjects with HoFH have raised plasma levels of LDL cholesterol, and up to 100 times higher risk of premature atherosclerotic cardiovascular disease than the general population. Areas covered: This evaluation is of a phase 3 trial of evinacumab; Evinacumab Lipid Studies in Patients with Homozygous Familial Hypercholesterolemia (ELIPSE HoFH). Evinacumab is a human monoclonal antibody inhibitor of angiopoietin-like protein 3 (ANGPTL3). In ELIPSE HoFH, evinacumab reduced LDL cholesterol by 47.1 ± 4.6%, HDL cholesterol by 30.4%, and triglycerides by 50.4 ± 7.7%. Expert opinion: Evinacumab is not the ideal treatment for HoFH as it does not reduce LDL cholesterol levels to treatment targets while increasing HDL cholesterol. Although the incidence of adverse effects with evinacumab was low in ELIPSE HoFH, further studies are necessary to clarify its effects on liver enzymes and clinical cardiovascular outcomes. Evinacumab is a candidate to become the standard treatment for HoFH, as it may be better tolerated and/or more efficacious than the presently available specific treatment (lomitapide). However, the widespread use of evinacumab to treat high triglycerides or LDL cholesterol is unlikely due to evinacumab decreasing HDL cholesterol.

Acute hepatic encephalopathy in a patient treated with lomitapide

Background and Aims: Lomitapide, a MTP inhibitor, is a new treatment for Homozygous familial hypercholesterolemia (HoFH). Little experience is available in patients with history of portocaval shunt.

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 &lt;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 &lt;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].