Evinacumab as an adjunct to lipid apheresis in an infant with homozygous familial hypercholesterolemia

Introduction

Isolated hypercholesterolemia, characterized by elevated levels of LDL cholesterol (LDL-C) in children and adolescents, is found in the context of familial hypercholesterolemia (FH), in polygenic forms influenced by lifestyle, or in secondary diseases [1], 2].

FH is a monogenic autosomal dominantly inherited disease caused by pathogenic variants in the gene encoding the LDL receptor (LDL-R) or genes that directly influence the function of the receptor. The prevalence of heterozygous FH (HeFH) is about 1:200–300. It usually leads to LDL cholesterol (LDL-C) levels>190 mg/dL, but does not show any early clinical symptoms. It can therefore only be detected by laboratory and/or genetic screening. Children and adolescents with HeFH have up to a 20-fold increased risk of atherosclerotic changes, which can lead to cardiovascular events from the fourth to fifth decade of life [3].

In contrast, homozygous FH (HoFH) is a very rare disease (2000–3000 patients in Europe) associated with LDL-C >400 mg/dL [4]. Patients, especially with variants that are associated with a complete loss of LDL receptor function, often show xanthomas on the tendons at an early age and cardiovascular events can occur as early as the first years of life [5]. The average life expectancy of untreated patients with HoFH is less than 20 years. This makes HoFH a metabolic emergency [4].

Most drug treatment options for hypercholesterolemia aim to improve cholesterol clearance by LDL-R and are therefore dependent on receptor function [6], 7]. In patients with no receptor function in HoFH, these drugs therefore show no or only a very reduced effect. According to international recommendations, the early onset of lipid apheresis with extracorporeal filtering of LDL cholesterol is considered the method of choice in severely affected patients without a significant reduction in LDL-C despite optimal lipid-lowering therapy with statins, PCSK9 inhibitors and/or ezetimibe [8].

Recently, angiopoietin-like protein 3 (ANGPTL3) was identified as a protein whose inactivation by genetic variants leads to significantly reduced LDL-C. The pathophysiological mechanism has not yet been clearly clarified [9]. Pathogenic variants in the ANGPTL3 gene lead to lower LDL-C and reduce the risk of atherosclerotic events [10]. Clinical studies with the antibody evinacumab, which is directed against ANGPTL3, showed an approximately 50 % reduction in LDL-C in patients with HoFH when given evinacumab in adults [11] as well as in children older than 5 years old [12]. Therefore, in 2021, the European Medical Agency approved evinacumab (Evkeeza^®) as an adjuvant therapy in patients with HoFH from the age of 12 years, which was extended to 5 years of age and older in March 2023 and now to children above 6 months of age since January 2025.

We report on a boy who was diagnosed with xanthomas of the Achilles tendon at the age of two years and who was subsequently diagnosed with HoFH with complete loss of LDL-R function. Despite twice weekly lipid apheresis from the age of 3 years, no sufficient enough reduction of LDL-C could be achieved, so that therapy with evinacumab was initiated at the age of four years as an individual clinical trial.

Case presentation

In the case of a 2-year-old boy, the parents noticed xanthomas on both Achilles’ heels (Figure 1A). A blood test by the pediatrician showed massively elevated cholesterol levels (total cholesterol 1021 mg/dL, LDL-C 892 mg/dL). Both parents were known to have hypercholesterolemia; they are not consanguineous.

Figure 1:

Xanthoma at the Achilles tendon before any treatment, age 2 years (A), disappearance of the xanthoma after therapy with lipidapheresis and evinacumab, age 4.5 years (B).

The patient was presented to our outpatient clinic. The examinations confirmed the pronounced hypercholesterolemia (total cholesterol 1052 mg/dL, LDL-C 890 mg/dL). A molecular genetic examination of the LDLR gene identified the known pathogenic variant c.1646G>A p.(Gly549Asp) in a homozygous state. This variant has been previously described to lead to a residual function of the receptor of less than 2 %. A therapy with rosuvastatin was started, which resulted in only a slight reduction in cholesterol levels (<10 %) despite escalation of the dose to a maximum of 20 mg. Orienting echocardiography and ultrasound examination of the intima thickness of the carotid artery were unremarkable at this time.

Figure 2:

Levels of cholesterol and LDL-C before apheresis and mean LDL-C given in mg/dL. Column a (blue): pre-apheresis values or mean LDL-C with regular lipidapheresis twice/week. Column B (orange): pre-apheresis values or mean LDL-C with evinacumab and lipid apheresis once/week. Column C (gray): Pre-apheresis values or mean LDL-C with evinacumab, lipidapheresis once/week and rosuvastatin/ezetimib-combination. Mean LDL-C was calculated with the modified Kroon formula [7].

At the age of 3 years, the patient underwent lipid apheresis via an implanted atrial dialysis catheter. During the individual sessions, a reduction in total cholesterol of 67 % and LDL cholesterol of 72 % was achieved on average.

Lipid apheresis was scheduled twice a week, but initially had to be interrupted repeatedly due to technical problems. From the age of 3.5 years, it could be carried out regularly twice a week. This resulted in a constant reduction in cholesterol levels, but the average LDL-C of 313 mg/dL (−64 % to values before apheresis) remained well above the recommended level of 115 mg/dL [4] (Figure 2).

At the age of 4 3/12 years, therapy with evinacumab was started as an individual clinical trial after approval by the health insurance company. At that time, therapy with evinacumab was approved for the treatment of HoHF from the age of 12 years. In the first weeks after the start of therapy, the frequency of lipid apheresis was maintained at twice a week. This resulted in reduction of cholesterol before apheresis from 319 to 146 mg/dL (−54 %) and LDL-C from 313 to 104 mg/dL (−67 %) with evinacumab (Figure 3).

Figure 3:

Levels for cholesterol and LDL-C before and after starting evinacumab. Given are pre-apheresis values with regular apheresis twice/week.

Following the significant reduction in cholesterol levels, the frequency of lipid apheresis could be reduced to once a week by continuing treatment with evinacumab. However, even after halving the frequency of lipid apheresis, there was a further reduction in LDL-C to 209 mg/dL (−33 %) compared to twice-weekly apheresis without evinacumab (Figure 2).

After a catheter infection at the age of 4.5 years, apheresis therapy could be continued via regular punctures of a cimino-fistula. At this time, the xanthomas had completely regressed (Figure 1B).

After a detailed discussion about medication compliance with the parents, drug therapy was intensified with rosuvastatin 10 mg and ezetimibe 10 mg in a combination tablet. Thereafter, there was a further reduction of cholesterol and an average LDL cholesterol in the required range below 115 mg/dL (Figure 2).

The exact methods of treatment and the course of mean LDL-C over time (Figure 4) are shown in the Supplementary Material.

Discussion

Our patient was found to have a severe form of HoHF with almost complete absence of LDL-R function. Clinical symptoms in the form of xanthomas of the Archilles’ heel appeared at the age of 2 years. Accordingly, laboratory tests revealed an extremely elevated LDL-C.

In the treatment of FH, non-pharmacological therapies such as dietary changes and weight loss usually lead to only a small reduction in LDL-C. The focus is on medication. Statins are the drugs of first choice for hypercholesterolemia, even in childhood; they increase hepatic LDL-C clearance by upregulating LDLR on the surface of hepatocytes. They therefore require functional LDLR. This was not the case in our patient carrying a homozygous pathogenic LDLR variant. Accordingly, a therapy trial with rosuvastatin resulted in only very small LDL-C reduction.

According to the guidelines, lipid apheresis was started at the age of 3 years at a weight of 14 kg. Due to the limited extracorporeal volume possible, only cascade filtration after plasma separation with a small plasma filter was possible. More details of the lipid apheresis procedure were given in the Supplemental Material. The therapy was well tolerated and a reduction in LDL-C of more than 70 % per apheresis session was achieved. However, due to dislocations and infections of the catheter, the therapy had to be interrupted several times in the first months.

After the initial difficulties, apheresis therapy was then established twice weekly with a significant reduction in mean LDL-C, which was still well above the recommended values.

In the absence of further therapeutic options, therapy with evinacumab was started as part of an individual clinical trial, as this therapy was only approved in patients older than 12 years at that time. We started with a dosage of 15 mg/kg body weight as in the studies in adults and older children [12] which we increased up to 18 mg/kg as the levels of LDL-C were a little higher just at the time of the evinacumab infusion compared to the values short after the infusion.

In the first four weeks after administration of evinacumab, apheresis continued to be carried out twice/week, resulting in a 67 % reduction of LDL-C before apheresis. This is higher than the 50 % reduction in LDL-C achieved by evinacumab in Wiegman’s study in paediatric patients between 5 and 17 years of age [11], however there was also a LDL-C reduction of 62.8 % in their study if two non-complaint subject were excluded. It should be noted that the reduction of LDL-C with evinacumab was higher in adolescents (−55.4 %) as in adult patients (−41.7 %) in a recent study of long-term safety and efficiency [13]. In a primary report of children younger than 5 years receiving evinacumab in a compassionate use program, there was a reduction of LDL-C of about 70 % by infusion of evinacumab in two children without lipid apheresis and of about 30 % in one child with also halving the frequency of apheresis which corresponds to our results [14].

The infusion of evinacumab was well tolerated, allergic reactions did not occur during our observation of now 20 months. There were also no other side-effects with the patient which could be attributed to the therapy with evinacumab. In a large real-time observational study of evinacumab in adult and adolescent patients, serious side effects of the therapy were rare and only few related to the therapy [13]. This is in accordance to very promising safety profile in the three children younger than 5 years in the compassionate use program [14]. However, the use of evinacumab in such young patients should be done with increased caution, as long-term data are lacking for these patients.

The reduction of LDL-C with evinacumab enabled our patient’s apheresis frequency to be reduced to 1x/week, resulting in a significant improvement in quality of life for the patient and his family. Despite halving the frequency of apheresis, there was a further reduction in mean LDL-C of 37 %.

A further improvement of the mean LDL-C could then be achieved by the now regular intake of a combination preparation with rosuvastatin and ezetimibe. This was the first time that an average LDL-C in the desired range of <115 mg/dL was achieved.

Clinically, the complete regression of the xanthomas of the Achilles tendon demonstrated the convincing success in lowering LDL-C.

The clinical course reported in our patient shows that lipid apheresis is possible and indicated at an early stage in HoFH. However, a significant improvement in the metabolic situation in our patient was only achieved after the start of treatment with evinacumab and drug therapy with a statin preparation and ezetimibe. In addition, the reduction in the frequency of apheresis significantly improved the quality of life of the patient and his family. Despite the young age of our patient, evinacumab was well tolerated without any side effects.

In patients with HoFH, a primary therapy trial with evinacumab is indicated, even in very young patients [6] as it is now approved after the age of 6 months. Further experience in pediatric patients must show whether apheresis therapy can be prevented by this therapy and consistent further drug therapy, especially in patients with still partially preserved LDL-R function. However, a significant reduction in apheresis frequency is probably possible in all patients.

Learning points

1. Homozygous familial hypercholesterolemia is a metabolic emergency that, if left untreated, can lead to early cardiovascular events and death.

2. In addition to drug therapy, the current therapy consists of starting lipid apheresis at an early stage.

3. Therapy with the angiopoietin-like protein 3 antibody evinacumab significantly lowers LDL cholesterol, even in very young children with HoFH, reducing or eliminating the need for lipid apheresis.

What is new?

Treatment with evinacumab is effective and safe even in young children and should be considered as a forward-looking therapy in all children with homozygous familial hypercholesteolemia.