This is a single arm, open label, multi centre phase III study to evaluate the efficacy and long term safety of lomitapide in paediatric patients with HoFH receiving stable lipid lowering therapy (LLT) (including lipoprotein apheresis (LA), when applicable) comprising of the following phases:

• Screening Period (starting at Week 12, i.e. ≤12 weeks prior to Baseline for up to 6 weeks)
• Stratified Enrolment and Start of Run in Period (starting at minimum at Week 6, i.e., 6 weeks prior to Baseline for a minimum of 6 weeks):
• Efficacy Phase (starting at Baseline, i.e. Day [D] 0 for 24 weeks±3 days
• Safety Phase (starting at Week 24±3 days for 80±1 weeks)

Lomitapide has been approved for use in adult patients with HoFH in the European Union (EU) and European Economic Area (EEA), United States of America (USA), Israel, Argentina, Canada, Colombia, and Japan. This study is designed to determine if lomitapide is effective and can be safely administered to paediatric patients with HoFH. If the efficacy and safety so far observed in adults is confirmed in paediatric patients, the potential exists to significantly lower low-density lipoprotein cholesterol (LDL-C) levels in paediatric patients with HoFH. Furthermore, the lower LDL-C levels may reduce atherosclerosis progression and would be expected to benefit these paediatric patients with HoFH.

A single arm, non comparator design has been selected due to the rarity of the disease and because the evaluation of safety variables such as growth and sexual maturation requires longer term observation than would be feasible in the context of a placebo controlled study.

To mitigate the disadvantages of a single arm design, the study includes a Run in Period of at least 6 weeks during which current lipid lowering therapy (LLT) (including lipoprotein apheresis (LA), when applicable) will be stabilised to establish baseline levels allowing each patient to serve as his/her own control. Patients will also remain on stable LLT (including LA, when applicable) during the Efficacy Phase of the study through Week 24±3 days.

Inclusion criteria

• Male and female patients aged 5 to ≤17 years with HoFH as defined by any of the following criteria recommended by the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society (EAS) (Cuchel, Bruckert et al. 2014):

  1. Genetic confirmation of 2 mutant alleles at the LDL receptor (LDLR), apo B, Proprotein convertase subtilisin/kexin type 9 (PCSK9), or LDL receptor adapter protein 1 (LDLRAP1) gene locus OR
  2. An untreated LDL C >500 mg/dL (13 mmol/L) or treated LDL C ≥300 mg/dL (8 mmol/L ) together with either Cutaneous or tendon xanthoma before age 10 years or Untreated LDL C levels consistent with heterozygous FH in both parents

• Baseline LDL C on LLT (maximum concentration [Cmax] immediately prior to LA, if applicable)

  1. >160 mg/dL (4.1 mmol/L, no documented cardiovascular disease [CVD]) or
  2. >130 mg/dL (3.4 mmol/L, established CVD defined as aortic valve disease and/or coronary atherosclerosis)

• Body weight ≥15 kg or body mass index (BMI) and height both >10th percentile according to World Health Organization (WHO) Growth Charts for Boys and Girls 5 to 19 Years of Age

• Patient and/or his/her legal representative has/have been informed, has/have read and understood the patient information/informed consent form, and has/have given written informed assent/consent

• Patient and/or his/her legal representative must be able and willing to follow study procedures and instructions, particularly that

  1. LLT (including LA, when applicable) must be stable for at least 6 weeks prior to Baseline (Run in Period) and remain stable through Week 24±3 days (end of Efficacy Phase)
  2. The patient must be compliant with both the low fat diet supplying <20% of energy (calories) from fat or <30 g fat, whichever is the lesser amount starting at the beginning of the Run in Period and the dietary supplement regimen starting at Week 2 of the Run in Period, both continuing until completion of the study

• Postmenarchal female adolescents must be willing to use an effective form of birth control with failure rates <1% per year (e.g., implant, injectable, combined oral contraceptive, intrauterine contraceptive device, sexual abstinence, vasectomy or vasectomised partner) during participation in the study (and at least 4 weeks thereafter). Patients taking oestrogen based oral contraceptives should be advised about possible loss of effectiveness due to diarrhea and/or vomiting. Additional contraceptive measures should be used for 7 days after resolution of symptoms.

• Patient must be in stable physical and mental health at screening

Exclusion criteria

• Other forms of primary hyperlipoproteinaemia and secondary causes of hypercholesterolaemia (e.g., nephrotic syndrome, hypothyroidism)
• Contraindications for the use of lomitapide according to section 4.3 of the European Medicines Agency (EMA) Summary of Product Characteristics (SmPC), such as hypersensitivity to the active substance or to any of the excipients listed in Section 6.1 of the SmPC, known significant or chronic inflammatory bowel disease or malabsorption
• Moderate (Child Pugh B) or severe hepatic impairment (Child Pugh C), active liver disease and/or abnormal liver function tests at screening (AST or ALT >1.5 x upper limit of normal (ULN) and/or total bilirubin >1.5 x ULN in the absence of Gilbert's syndrome or AP >1.5 x ULN [based on appropriate age and gender normal values])
• Serum CK >2 x ULN
• Chronic renal insufficiency with glomerular filtration rate (GFR) <70 mL/min/1.73 m2 calculated using the Schwartz formula
• Uncontrolled hypertension (defined as mean systolic and/or diastolic blood pressure ≥95% of normal for age and sex) despite medical therapy
• New York Heart Association (NYHA) Class III or IV congestive heart failure
• Precocious/delayed puberty or endocrine disorder affecting growth (e.g., hypothyroidism, premature adrenarche)
• History of drug abuse within the last 3 years or habitual alcohol consumption (defined as >1 ounce [28 g] of liquor or 4 ounce glass [113 g] of wine, or the equivalent, ≥3 times per week)
• Life expectancy predicted to be <5 years
• History of a non skin malignancy (with the exception of cervical cancer in situ) within 3 years prior to enrolment
• Treatment with any Investigational Medicinal Product (IMP) within 6 months or 5 times the terminal half life of the corresponding IMP, whichever is longer, before the screening visit
• Patient is a dependent of the sponsor, of the investigational team or his/her immediate family
• Pregnant or nursing women

The investigators may use the study data only after prior written consent of Amryt Pharmaceuticals DAC. Amryt will review the proposed publication/disclosure prior to submission for publication, presenting, using for instructional purposes or otherwise disclosing the study results. If Amryt supposes the publication/disclosure to risk its ability to patent any invention related to the study, the publication/disclosure will be modified or delayed to allow Amryt to file a patent application.