Lomitapide: a review of its clinical use, efficacy, and tolerability

Figures & data

Core evidence clinical impact summary for lomitapide

Outcome measure	Evidence	Implications
Disease-oriented evidence
LDL-C reduction in homozygous FH	Phase II and III, single-arm studies in HoFH >18 years old; real-world clinical experience (registries); clinical cases using lomitapide (dose up-titrated from 5 to 60 mg/day or to maximum tolerated every 4 weeks) in monotherapy (Phase II) or with statins with or without LDL-apheresis (Phase III and registries)	Dose-dependent LDL-C reductions between 25-51%; also, triglycerides were reduced by 35-65%. In Phase III trials, reduction was maintained after 26 weeks and in long-term extension studies. During the trial, 74% patients achieved an LDL-C level below 100 mg/dL at least once during the efficacy phase.In those adult patients on LDL- apheresis, it is probable that one in three will reduce the frequency of the apheresis or even discontinue it.
Patient-oriented evidence
Tolerability and safety	Phase II and III, single-arm studies in HoFH >18 years old; real-world clinical experience (registries); clinical cases using lomitapide (dose up-titratedfrom 5 to 60 mg/day or to maximum tolerated every 4 weeks) in monotherapy (Phase II) or with statins with or without LDL- apheresis (Phase III and registries)	All studies have demonstrated that gastrointestinal symptoms are the most frequent adverse events and are related to the dose, transient and related to a bad adherence to a low-fat diet.Due to its mechanism of action, variable liver fat accumulation and an increase in transaminases occurs with lomitapide and return to baseline levels after 4 weeks of discontinuation of the drug. In the extension trials, the frequency of adverse events diminished compared to pivotal trials.
Net Benefit		HoFH is a rare and severe disorder causing death and cardiovascular disease since childhood. These patients have few therapeutic options like LDL-apheresis (not available in all countries) or liver transplantation. Although there are some adverse events, few patients discontinued medication due to them, and LDL-C reduction is important depending of the dose. The up-titration every 4 weeks or more and a good adherence to a low-fat diet can improve the tolerability and maximize the efficacy.
Economicevidence		Lomitapide is an expensive medication, and there are no cost- effective studies.

Table 1 Main Phase II and Phase III trials with lomitapide in homozygous familial hypercholesterolemia patients

	Dose	Duration	Mean (mg/day)	Number of participants (completers)	Mean baseline LDL-C (mg/dL)	LDL-C reduction, % (SD)	Gastrointestinal adverse events (n)	Increase in transaminases (number of patients)	Hepatic fat
Phase II proof-of concept	0.03 mg/kg 0.3 mg/kg 0.1 mg/kg 1 mg/kg	4 weeks 4 weeks 4 weeks 4 weeks	All patients achieved max dose	6 (6)	614	3.7 (8.3) 7.1 (20.1) 24.7 (5.3) 50.9 (9.3)	Five of six, mild and transient	4	4/6 (<10% to >30%
Pivotal Phase III	5 mg/day, uptitrated every 4 weeks to MTD or 60 mg/day	Efficacy phase 26 weeks, then a safety phase for 52 weeks	40 mg	29 (23)	337	Efficacy phase: 40 ITT 50 completers Safety phase: 38 completers	27 of 29 in efficacy phase and 17 of 23 in safety phase; three patients discontinued medication in efficacy phase	Ten patients had ALT, AST, or both >3xULN; four with ALT >5xULN; one with AST >5xULN	Mean content increased from 1% to 8.6% at week 26 and 8.3% at week 78 (data available in 20 patients)
Extension trial	MTD from the pivotal trial	126 weeks up to 286 weeks from baseline	40 mg	19 (17) from pivotal trial	356	45.5 at week 126		Four with ALT or AST >5xULN	Mean content increased from 0.6% to 7.7% at week 126 and 10.2% at week 246 (data available in 17 patients)
Phase III, Japan	5 mg/day, uptitrated every 4 weeks to MTD or 60 mg/day	Efficacy phase 26 weeks, then a safety phase for 30 weeks	22 mg in efficacy phase and 18 mg in safety phase	9 (8)	199	Efficacy phase: 42% Safety phase: 38%	Eight of nine; no patient discontinued medication	Three patients had ALT and AST >3xULN; one had ALT >5xULN and discontinued treatment	Mean content increased from 3.2% to 15.6% at week 126 and 12.7% at week 56
Extension trial	MTD from the pivotal trial	119 weeks from baseline (60 weeks from end of previous trial)	22 mg	Five of eight from previous trial	Baseline value calculated as derived from end efficacy and safety phases	35.6% from derived baseline to week 60	Three of five; no discontinuation	Four of five with increase in ALT or AST <3xULN	Not measured

Table 2 Prescribing summary of lomitapide

Indications and cautions	• Adults (>18 years old) with homozygous familial hypercholesterolemia, if possible with molecular confirmation • Not indicated in heterozygous familial hypercholesterolemia patients or other hypercholesterolemic patients • Not indicated in children/adolescents <18 years old (lack of evidence) • Use with caution in patients >65 years old (limited evidence) • For patients with end-stage renal disease with dialysis, do not exceed 40 mg per day; not studied in end-stage renal disease not on dialysis • For patients with mild hepatic impairment, do not exceed 40 mg per day; contraindicated in more severe hepatic damage
Dosage	• Start with 5 mg once day and uptitrate gradually depending on safety and tolerability at least every 4 weeks. • Up to maximum tolerated dose or a maximum of 60 mg per day • Dose may be modified according to liver-function tests, tolerability, renal function, and concomitant medication
WhenŒ	• At least 2 hours after evening meal (empty stomach)
Dietary advice	• Low-fat diet, <20% of daily total energy from fat • Restriction of alcohol consumption (no more than 1 unit per day)
Supplementation	• Vitamin E (400 IU) + linoleic acid (200 mg), ALA (210 mg) + EPA (110 mg) + DHA (80 mg)
Monitoring liver function	• Before initiation of treatment • Prior to each increase of dose • Refer to hepatologist if liver-function testing persists >3*ULN, or data suggest liver steatohepatitis or fibrosis
Hepatic imaging	· Screen for liver steatosis, steatohepatitis, and fibrosis at the beginning
Concomitant medication	• Moderate and strong CYP3A4 medications and grapefruit juice are contraindicated with lomitapide • For patients taking a mild CYP3A4 inhibitor before use of lomitapide, uptitrate the dose according to safety and tolerance • If patient requires a mild CYP3A4 inhibitor while taking lomitapide, downtitrate the dose and then uptitrate according to LDL-C reduction, safety and tolerance