Real-World Outcomes with Lomitapide Use in Paediatric Patients with Homozygous Familial Hypercholesterolaemia

This report is the first available of a case series in paediatric patients with HoFH receiving lomitapide, and it shows that, as in adult patients, marked reductions in LDL-C are possible in these patients. In all cases, the LDL-C values at diagnosis were very high—some as high as 1000 mg/dL. Even with the use of statins, ezetimibe and in some cases LA, LDL-C levels remained highly elevated in most cases. Notably, some patients received the PCSK9 inhibitor evolocumab, with little effect. The failure of evolocumab to lower LDL-C levels in some patients with HoFH is likely to be due to its mechanism of action. PCSK9 inhibitors prevent the binding of PCSK9 to the LDL-C/LDL receptor complex and thereby prevent the degradation of the LDL receptors, ultimately increasing their recycling to the cell surface [22]. This means that PCSK9 inhibitors require a functional LDL-R to exert their effect. Since LDL-R activity is impaired or absent in HoFH, PCSK9 inhibitors have reduced effectiveness in comparison to that seen in heterozygous familial hypercholesterolaemia or other dyslipidaemia patients in whom LDL receptor functionality is maintained. In the TAUSSIG study of evolocumab in FH patients, LDL-C was reduced on average by 25%, but with no effect in patients with null mutations (i.e. LDL-R functionality < 2%) [23]. This is borne out by data from patients 1, 2 and 6 where LDL-C levels remained very high (263–430 mg/dL), despite use of a PCSK9 inhibitor; patients 2 and 6 had null mutations.

Exposure to high levels of LDL-C for an extended period presents a high risk of ASCVD. In patients with HoFH, the LDL-C levels are so high that the threshold exposure level whereby cardiovascular disease can occur is reached by the age of 12 years, in contrast to 55 years for individuals without FH [2]. All of the patients in the present report were 16 years of age or younger at the start of treatment (range 4–16 years), and all but case 10 had evidence of cardiovascular disease. The youngest patient was case 7, and even she had evidence of thickened aortic cusps and a possible mobile atheroma at the age of 3 years old. Case 9 was diagnosed at the age of 2 years, when there was already subclinical aortic insufficiency.

The early-onset cardiovascular and valvular heart diseases in HoFH demand early lipid-lowering intervention such as statins, ezetimibe, PCSK9 inhibitors and LA that are nevertheless often not sufficient to achieve proposed target LDL-C levels in HoFH patients. Early access to lomitapide, either through an expanded access programme or on a named patient basis, has provided unique opportunities for early-life access to this MTP inhibitor. Introduction and dose escalation of lomitapide was associated with marked decreases in LDL-C levels. For cases 1–8, percentage reductions (nadir) were in the range 44–91%. Six of the patients (cases 1–3, 6, 8 and 9) were able to achieve EAS targets for LDL-C levels in children with HoFH (nadir < 135 mg/dL) [1]. For case 9, baseline LDL-C values were already at target but the patient needed to undergo LA twice weekly which was very burdensome on the patient and became problematic with increasing demands of schooling (Table 1). This patient was able to reduce his LA frequency from an unmanageable twice weekly to a more satisfactory biweekly (75% reduction in apheresis) and still maintain target levels.

Case 9 was not the only patient able to maintain control of LDL-C levels with extended LA intervals. Case 1 has stopped LA, and continues to do well. Case 2 has extended intervals from Q2W to Q4W with LDL-C levels at about 150 mg/dL. Case 3 extended intervals from QW to Q2W. No LA was used in cases 4 and 5; and case 6 has stopped LA for a year, and has LDL-C levels of 34.8 mg/dL (87% reduction from baseline). Case 8 had multiple changes to LA frequency prior to lomitapide, but was able to stop the therapy between April 2017 and July 2018 with the availability of lomitapide. Alterations to LA frequency have been observed in the phase 3 clinical trial of lomitapide and in real-world, adult case series of lomitapide use in HoFH [15, 24]. In the phase 3 study, six of the 13 patients on LA from weeks 26 to 78 underwent permanent changes to their LA regimens [25], some of whom were able to stop LA entirely [26]. Similarly, in a real-word cohort of HoFH adult patients undergoing lomitapide therapy, eight of the 10 patients (80%) on LA were able to stop the treatment, and a further patient was able to reduce LA frequency by 50% [15]. LA presents a huge burden of time, discomfort and expense on patients with HoFH [12], and is also a psychological burden for the patients and their families. This would particularly affect children who need to increase their involvement in education and other activities as they get older. Development of additional effective pharmacotherapies has the potential to reduce or eliminate the constraints of regular LA on patients [27]. The data from this case series suggest that lomitapide may be useful to reduce LA frequency in this particularly difficult-to-treat patient population.

Blunted LDL-C responses in cases 10 and 11 underscore the need for patients to remain compliant with all aspects of their therapy, including low-fat diet, lifestyle modifications and lomitapide dosing.

In the phase 3 clinical trial of lomitapide, there was a dose escalation protocol that increased lomitapide doses until the maximum tolerated dose up to 60 mg/day was reached. This resulted in a median dose of 40 mg/day (mean 44.0 ± 3.8 mg/day) and a mean reduction in LDL-C of 50% versus baseline (baseline 336.4 ± 112.1 mg/dL; 26 weeks 116.3 ± 96.7 mg/dL) [25]. In the present case series, there was no such driver to increase lomitapide dose. Five of the patients described here are maintained on 20 mg/day, two on 15 mg/day, one on 10 mg/day, one on 30 mg/day, one on 40 mg/day and one on 60 mg/day. The mean dose was 24.5 mg/day (median 20 mg/day) resulting in a mean 58.4% reduction in LDL-C at nadir. In a real-world study where the treatment strategy was similar—i.e. to titrate the dose of lomitapide to LDL-C levels as opposed to a maximum tolerated dose—the mean LDL-C levels in a cohort of 15 Italian patients was 19 mg/day with a mean LDL-C reduction at nadir versus baseline of 76.5% (baseline 426.0 ± 204.0 mg/dL; nadir 81.9 ± 56.0 mg/dL) [15]. In the present paediatric case series, the LDL-C lowering is similar to the Italian cohort at a similar mean dose.

Through its mechanism of action, lomitapide results in a reduced absorption of fats in the intestine, resulting in the possibility of GI adverse effects. A corresponding block on the release of VLDL from the liver can result in increases in hepatic fat [16]. In the present case series, adverse events were consistent with those seen in the phase 3 study in adults and in real-world use. Those that did occur were nearly all GI complaints, presented early in the treatment course, and resolved with minimal active management. There were some increases in LFTs with patients 3, 6 and 8 experiencing transient elevations in LFTs above three times the ULN. In patient 3, the LFT increases were managed with a brief dose reduction to 30 mg/day, followed by gradual restoration to 40 mg/day, and later to 60 mg/day. In patient 6, LFT excursions resolved without intervention. Patient 8 had one episode controlled by a lomitapide dose reduction, and the second episode was due to a peritoneal infection.

This paediatric case series—the first of its kind for lomitapide in HoFH—demonstrates that lomitapide has been effective in reducing LDL-C in paediatric patients with HoFH, and suggests that the drug has a similar adverse event and usage profile to that observed in adult patients. Consistent with real-world data from adult patients [15, 28], this paediatric case series shows a greater reduction in LDL-C at a lower mean dose of lomitapide than in the phase 3 study. This is a curious finding but is replicated across data sets and may be explained by the titration of the dose of lomitapide to desired LDL-C reduction as opposed to the ‘forced’ escalation protocol based on tolerability as used in the phase 3 study. Irrespective of rationale, these data show a reduced level of adverse effects related to the lower mean dose and an improved benefit-to-risk profile compared with data from formal clinical trials.

A further benefit of lomitapide in HoFH is the ability for patients to reduce or stop LA, which is an important and positive outcome for many of the children in this case series. The efficacy and safety of lomitapide will be explored in a formal phase 3 study (registration pending) in patients from at least 5 to at most 18 years old, and will provide further evidence to explore the efficacy, tolerability and safety of lomitapide in this cohort. Mean exposure in this case series was 19.9 months (range 12–48 months). The phase 3 study will employ an efficacy period of 24 weeks and a safety phase of an additional 80 weeks, total study duration of 2 years and will assess growth, bone development and reproductive maturation which are all important safety aspects to consider in treating children from the ages of 5 to 18 years. One patient in this series underwent treatment during puberty and had a normal menarche, but further safety data are warranted.

In this paediatric case series, all the patients except cases 10 and 11 already had atherosclerosis on screening and patients 3 and 9 already had revascularisation procedures at the ages of 12 and 8.5 years respectively. Modelling data in adult patients have shown that early intervention with lomitapide has the potential to increase life expectancy and delay the time to first major adverse cardiovascular event (MACE) [29]. Treatment of HoFH patients from very early life may have the potential to realise further outcome benefits through the prevention of atherosclerosis development and progression, thereby underscoring that effective treatments that can significantly lower LDL-C are valuable tools in the management of this severe, progressive and life-threatening condition.

This study, however, has several limitations: (1) the wide variations in underlying standard of care among the different centres, (2) the variability in time of exposure to lomitapide treatment, (3) issues with access and compliance to lomitapide therapy and (4) a non-randomized open design. However, despite these factors, this case series highlights the effectiveness of lomitapide in children with HoFH, and suggests that robust LDL-C reduction can be achieved with lower doses than used in the phase 3 clinical trial in adults and with generally good tolerability. With the exception of one case report [21], there are currently no data on the use of lomitapide in children with HoFH. Given that these patients have an urgent need for effective medical intervention, the information provided here is valuable to guide physicians considering lomitapide for paediatric patients. Further data are necessary to more fully determine the long-term efficacy tolerability and safety of lomitapide in this rare, life-threatening condition. A phase 3 study is planned for lomitapide in paediatric HoFH and this may result in a change to the licensed indication for the drug.