This is 13-year-old girl with a homozygous LDLR c.313+5G>A mutation and evidence of an aortic root plaque. Her parents are first-degree cousins, both with heterozygous FH (HeFH).
This patient was initially treated with statins, ezetimibe and biweekly LA but the patient remained with increased LDL-C and evidence of atherosclerotic disease in the form of an aortic root plaque. Evolocumab was tried, but only for 3 months because of lack of response. With a background therapeutic regimen of atorvastatin 40 mg/day, ezetimibe 10 mg/day and biweekly (Q2W) LA, mean interval LDL-C levels were 263 mg/dL. The patient was commenced on lomitapide 5 mg/day. The patient initially suffered from nausea, occasional vomiting, reduced appetite and increased stool frequency; however, these symptoms became tolerable and no other adverse events were observed. Liver enzymes remained within normal limits. The patient was gradually escalated to lomitapide 20 mg/day and atorvastatin 40 mg/day with cessation of LA. Mean interval LDL-C levels are now maintained at 72 mg/dL (76% decrease) without the need for LA (Fig. 1). The patient has been treated for over 18 months with no alteration in liver enzymes (Fig. 1).
This is a 12-year-old boy with a homozygous LDLR c.682G>T mutation. Both parents have HeFH. The patient has left ventricle dilatation, mild aortic regurgitation and atherosclerotic plaques (1.5–2.1 mm thick) in both carotid bulbs, and in the common and internal carotid arteries. Imaging revealed diffuse atherosclerotic involvement of all coronary arteries, but this was not clinically significant.
The patient was treated with rosuvastatin 20 mg/day, ezetimibe 10 mg/day, LA Q2W, but mean interval LDL-C levels remained increased at approximately 300 mg/dL. The patient was commenced on lomitapide 5 mg/day following a normal FibroScan test. Rosuvastatin 20 mg/day, ezetimibe 10 mg/day and LA Q2W were maintained.
Mean interval LDL-C levels decreased modestly over 2 months (Fig. 2). The patient then took a vacation with no LA, and experienced an increase in LDL-C levels that was gradually brought under control with escalating doses of lomitapide. Overall, LDL-C levels decreased by 50–70%. There has been no evidence of adverse events to lomitapide, and liver function tests (LFTs) remain normal (Fig. 2). Gastrointestinal (GI) complaints were only present when dietary advice was not followed. The patient achieved an LDL-C nadir of 98 mg/dL (70% reduction). LA intervals have been gradually extended to Q4W with a modest increase in LDL-C levels to 184 mg/dL (44% reduction from baseline).
This is a 16-year-old boy diagnosed with HoFH at the age of 10 months on the basis of development of xanthomas, LDL-C levels 981 mg/dL, and LDLR genotyping with the finding of homozygosity for the LDLR mutation c.119_1207del. Both parents have HeFH, and the patient has a right coronary lesion evident on computed tomography, which has been treated with percutaneous revascularisation (at the age of 14 years). The patient was commenced on statins at the age of 2 years, which was gradually escalated to rosuvastatin 20 mg/day, ezetimibe 10 mg/day and colesevelam 3250 mg/day. At the age of 5 years, weekly LA was commenced, which resulted in regression of xanthomas by the age of 10 years, but without complete control of LDL-C levels (mean interval LDL-C 168 mg/dL).
In 2016, at age 14 years, the patient was commenced on evolocumab 420 mg QW with no effect on LDL-C levels. The following year, lomitapide was commenced at 5 mg/day, and gradually escalated to 40 mg/day. Mean interval LDL-C levels were reduced to 75–83 mg/dL, which represents a greater than 60% reduction in LDL-C (Fig. 3).
The patient began to have some recurrent issues with elevated liver enzymes, possibly related to rosuvastatin, which had caused this in the past. Lomitapide dose was reduced to 30 mg/day, and rosuvastatin briefly stopped while the LFTs resolved. Eventually, LA intervals were extended to every 2–3 weeks and rosuvastatin was permanently stopped. The patient remained on lomitapide 40 mg/day. Increasing lomitapide dose to 45 mg/day was associated with an increase in LFTs that was brought under control with dose reduction and gradual re-escalation. The patient is now doing well on lomitapide 60 mg/day with an LDL-C level of just 90.8 mg/dL and LA Q2W. There has been no evidence of GI adverse events apart from mild flatulence.
This patient is a 7-year-old boy with compound heterozygote mutations in LDLR c.666C>A and c.1646C>A. The patient has a sister with HoFH who is on LA and not part of this patient series. Both parents have HeFH. The patient has a large aortic plaque extending the length of the thorax with 25–50% narrowing of the lumen.
Before lomitapide, the patient was treated with rosuvastatin 40 mg/day, ezetimibe 10 mg/day and colesevelam 625 mg/day. No LA was used as a result of venous access issues. LDL-C levels were increased at 866 mg/dL. The patient underwent dose reduction of rosuvastatin (20 mg) and was commenced on lomitapide 2.5 mg/day, which was gradually escalated to 30 mg/day in 5-mg increments. LDL-C levels reduced by 78% to 360 mg/dL (Fig. 4). Notably, this patient has been treated for over 18 months and has not experienced any side effects of lomitapide.
This patient is an 11-year-old girl with a homozygous duplication spanning the promoter region to exon 6 of LDLR (c.-187-? 940+? Dup) . Family history includes sudden death in an older brother aged 17. Another brother has HoFH with aortic stenosis and a non-critical obstruction of the right coronary artery. The patient presented with non-critical aortic stenosis/supra aortic stenosis, and non-obstructive plaques in the carotid arteries. Her computed tomography angiography showed no signs of coronary artery disease.
The patient commenced LLT at the age of 2 years when LDL-C levels were 1009 mg/dL. Up until the age of 7, she was treated with atorvastatin 40 mg/day and ezetimibe 10 mg/day and her LDL-C level was 453 mg/dL. LA is not available in the patient’s home country.
At age 7, atorvastatin dose was decreased to 10 mg/day, and lomitapide was commenced at a dose of 5 mg/day. Over the next year, lomitapide was escalated to 30 mg/dL but this dose was reduced back to 20 mg/day as a result of diarrhoea. LDL-C levels were effectively reduced with treatment (nadir 231 mg/dL; 40.7% reduction) with no elevations in LFTs (Fig. 5). A trip to a remote region of Brazil led to brief discontinuation of lomitapide with a consequent increase in LDL-C levels. Following resolution of the issues, reintroduction of lomitapide resulted in the expected decrease in LDL-C levels.
The patient is now maintained on atorvastatin 60 mg/day, ezetimibe 10 mg/day and lomitapide 20 mg/day and has been treated with lomitapide for 4.5 years. She continues to develop normally and had her menarche at the age of 11 years. LDL-C levels are 266 mg/dL (38% reduction from pre-lomitapide values). A routine check-up revealed no calcification in the coronary arteries; however, there were signs of aortic stenosis and supra aortic stenosis, and some non-obstructive plaques in the carotid arteries, but these are not considered to be life-threatening. There were no elevations of liver enzymes during treatment. A detailed history of this patient has been published by Chacra et al. .
This is a 16-year-old boy with compound heterozygote mutations LDLR c.131G>A and c.2043C>A and a history of HeFH in both parents (LDL-C levels at 271 mg/dL and 387 mg/dL). The patient has carotid plaques occluding 25–30% of the carotid lumina, but with no impairment of perfusion. The patient was diagnosed with HoFH at the age of 9 years with Achilles’ xanthomata and LDL-C levels at 900 mg/dL. LLT with rosuvastatin 20 mg/day, ezetimibe 10 mg/day and weekly apheresis was started, with dietary modifications to reduce fat intake to 15% of total energy. On this regimen, mean interval LDL-C levels reduced to 206 mg/dL.
As the patient got older, issues with schooling meant that there was a desire to extend the LA interval to biweekly. This change was made, and evolocumab 420 mg Q2W was added to the background LLT. However, as a result of the mutation profile of the patient, evolocumab did not work (mean interval LDL-C 329 mg/dL), and the decision was taken to prescribe lomitapide. The patient was commenced on lomitapide at 5 mg/day with escalation to 15 mg/day over 3 months (Fig. 6). Apheresis was stopped, lomitapide was increased to 20 mg, rosuvastatin was increased to 40 mg and ezetimibe doses were maintained. LDL-C levels remained at approximately 190 mg/dL for more than 6 months and therefore lomitapide was increased to 30 mg/day and rosuvastatin reduced to 35 mg/day. Figure 6 shows that LDL-C levels continued to rise after commencement of lomitapide, followed by a subsequent marked decrease. There is no direct explanation for this other than the cessation of apheresis.
Mean interval LDL-C levels are now at 34.8 mg/dL (a remarkable 85.7% decrease), with no LA currently ongoing. Early GI issues resolved. There were no other adverse events, other than slightly depressed alkaline phosphatase levels. Alanine aminotransferase briefly increased by more than three times the upper limit of normal (ULN) on two occasions, and reduced to less than three times the ULN without intervention. All other laboratory parameters remain normal and there is no evidence of hepatic steatosis.
This is a 4-year-old girl with a homozygous c.2043C>A mutation who presented at the age of 3 with an LDL-C level of 739 mg/dL. Her father has a severe form of HeFH. At diagnosis, the patient had normal echocardiography; but, by 2016, she had mild aortic thickening and some mild aortic valve regurgitation. There was evidence of a pedunculated atheroma at the aortic arch that had potentially embolised as it was no longer apparent on a later scan. For this reason, the treating physician decided that the patient was a candidate for aggressive LLT, but low body weight meant that LA was not suitable. LDL-C levels were reduced very slightly to 685 mg/dL with atorvastatin 10 mg/day and ezetimibe 10 mg/day, and the decision was taken to intensify LLT with lomitapide. Doses were escalated gradually from 2.5 mg/day in 2.5-mg increments given the young age of the patient and low body weight, and LDL-C levels became reduced. By the time the dose was escalated to 15 mg/day in August 2018 (patient now 5 years old), LDL-C had reached a nadir of 235 mg/dL (Fig. 7). There have been no side effects in this patient apart from one episode of a loose stools when pancakes were eaten. No liver pathology is evident on ultrasound. The patient has recently had a significant reduction in triglycerides to 21 mg/dL, and so the levels of fat-soluble vitamins are being checked prior to any further dose increase given the young age of the child.
This is a 14-year-old boy with an extensive family history of HeFH and a brother with HoFH. The boy has a compound heterozygous for the LDLR mutations c.1846-? 2311+?del and c.1895A>T (variant of unknown significance). The boy presented with xanthomas and hypercholesterolemia at 4.8 years of age. High dose (for age) statins and ezetimibe were started (atorvastatin 20–30 mg/day; ezetimibe 10 mg/day). At the age of 8 years, mild aortic regurgitation was evident. Treatment with plasma exchange (PE) was commenced every 15–20 days. Three years later, the patient required composite graft replacement of the aortic valve, aortic root and ascending aorta, with re-implantation of the coronary arteries (Bentall procedure).
At this point, lomitapide was initiated as add-on to the previous treatment regimen, escalating from 5 to 10 mg/day. LDL-C levels decreased to almost 100 mg/dL (Fig. 8). Lomitapide dose was increased to 15 mg/day and then briefly escalated to 20 mg, but the patient experienced elevated transaminases, so the dose was reverted with consequent normalization of LFTs. The LA frequency was altered a number of times in this patient (Q2W–Q6W), and was eventually stopped once the patient was on the 15 mg dose of lomitapide. The response to lomitapide was a 66.4% reduction, and apheresis has been discontinued, apart from two emergency sessions when an insurance issue interrupted the lomitapide dosing (Fig. 8).
This is a 15-year-old boy with compound heterozygous LDLR c.313+1G>A and a deletion spanning exon 1–6. Both parents have HeFH with no evidence of cardiovascular disease (CVD). The patient was diagnosed at the age of 2 years old as a result of the presence of xanthomas. LDL-C levels were found to be elevated to 982 mg/dL, and diagnosis was confirmed via genetic testing. Asymptomatic aortic insufficiency was evident. Medication was commenced with atorvastatin 40 mg/day plus ezetimibe 10 mg/day. The patient received once-weekly lipoprotein apheresis, but LDL-C levels remained elevated (mean interval LDL-C 197 mg/dL). At the age of 8.5 years, chest pain led to a diagnosis of angina and a coronary bypass operation. LA was intensified to two times per week.
At 13.5 years of age, prior to the initiation of lomitapide, mean interval LDL-C levels were at 85 mg/dL with LA twice weekly, and therefore well below current treatment target. Unlike the other patients in this case series, the treatment plan for this patient was to attempt to maintain the LDL-C levels at target but to reduce the apheresis burden. Lomitapide was commenced at a dose of 5 mg/day and apheresis was decreased to once weekly. After 6 months, the lomitapide dose was intensified to 10 mg/day followed by 15 mg/day and after an additional 5 months, apheresis was reduced to Q2W. Through these modifications, LDL-C levels remained under control (nadir 62 mg/dL) (Fig. 9).
No adverse events have been reported for lomitapide, liver enzymes and imaging are normal, and the patient has reported improved quality of life due to less disruption from apheresis sessions resulting in less time away from school, sports and other leisure activities. As a result, the LDL-C target levels have been maintained despite reducing apheresis burden by 75%.
Cases 10 and 11
These two patients (both homozygous for the LDLR c.1731G>T mutation) are siblings born to consanguineous parents with HeFH. They have one other sibling with HeFH, and without the disease. The girl presented at age 2 with high LDL-C and xanthomas, but with normal cardiac status. Her brother with HoFH was referred at age 9 on the basis of the family history, and has mild, stable aortic insufficiency and focal thickening of the right common carotid artery. Development was normal in both patients. The patients were managed with atorvastatin 40 mg/day, ezetimibe 10 mg/day, a low-fat diet, cholestyramine 4 g/day and aspirin 75 mg QD.
In September 2017 (girl aged 11 with LDL-C 684 mg/dL, boy aged 9 with LDL-C 705 mg/dL) the children commenced lomitapide with rapid escalation from 5 to 20 mg/day. Initial LDL-C decreases were modest (Figs. 10 and 11), and investigations revealed that the parents were not administering the medication regularly to the children. After counselling the parents on the burden of HoFH and the need to adhere to therapy, LDL-C levels have decreased but remained above 440 mg/dL in November 2018. Lomitapide has not been associated with side effects in either patient. In the female patient, an echocardiogram conducted in March 2018 revealed a supra aortic stenosis with a peak of gradient of 50 mmHg, mild tricuspid regurgitation with normal right ventricular systolic pressure and normal biventricular function. Ultrasound Doppler of carotid arteries was normal at the same date. For the male patient, there was aortic insufficiency evident in 2011 that progressed slightly to 2013 but remained stable and mild. An ultra-sounded Doppler of carotid arteries in 2013 showed focal intimal thickening of the right common carotid artery. An echocardiogram conducted in March 2018 showed thickened tricuspid aortic valve leaflets. Development has been normal in the girl. The boy is in second grade school with below average performance.
Summary of the Case Series
A summary of baseline, nadir and current LDL-C values is presented in Table 1. Patients 1–8 show substantial reductions in LDL-C levels. Patient 9 was at target LDL-C levels, and the aim of treatment with lomitapide was to reduce LA frequency from twice per week, so the LDL-C decrease is more modest than for other patients. In patients 10 and 11 compliance with lomitapide therapy was suboptimal, and they have yet to reach stable LDL-C levels.
Table 2 provides summary descriptive statistics for all 11 patients. Baseline LDL-C was 419.9 ± 74.6 mg/dL. The mean at nadir was 176.7 ± 46.3 mg/dL, representing a 58.4 ± 6.8% reduction in LDL-C. Note that patients 9–11 had modest decreases in LDL-C levels (patient 9 was treated to reduce LA frequency, and patients 10 and 11 had compliance issues). These LDL-C reductions were achieved with a mean dose of lomitapide 24.5 ± 4.3 mg/day over a mean period of 20.0 ± 2.9 months. Most adverse events (Table 2) resolved without intervention.