Real-world safety and efficacy of lomitapide in homozygous familial hypercholesterolemia: interim report of special-use survey in Japan

Figures & data

Table 1. Patient characteristics.

		Number of cases	%
Safety analysis population		39
Gender	Male	18	46.2
	Female	21	53.9
Age (years)	<15	3	7.7
	≥15 to <65	27	69.2
	≥65	9	23.1
BMI (kg/m^2)	<18.5	5	12.8
	≥18.5 to <25	24	61.5
	≥25 to <30	4	10.3
	≥30 to <35	1	2.6
	Unknown	5	12.8
Pregnancy (females)^†	No pregnancy or breastfeeding	21	100.0
Gene mutation^‡	Two alleles of the LDL receptor have the same mutation	12	40.0
	Two different mutations in two alleles of the LDL receptor	13	43.3
	Mutations in one of the two alleles of the LDL receptor and mutations in the PCSK9 or APOB genes	1	3.3
	ARH (autosomal recessive hypercholesterolemia)	1	3.3
	Unknown	3	10.0
LDL apheresis	Not implemented	13	33.3
	Implemented	26	66.7
Dietary therapy	Not implemented	3	7.7
	Implemented	36	92.3
Exercise therapy	Not implemented	27	69.2
	Implemented	11	28.2
	Unknown	1	2.6
Liver function	Normal	30	76.9
	Mild impairment (Child-Pugh classification A)	9	23.1
	Moderate impairment (Child-Pugh Classification B)	0	0
	Severe impairment (Child-Pugh Classification C)	0	0
Kidney function	Normal	36	92.3
	Mild renal impairment	3	7.7
	Moderate renal impairment	0	0
	Severe renal impairment and end-stage renal failure	0	0
Drugs for hypercholesterolemia (before starting lomitapide)	Not treated	1	2.6
	Treated	38	97.4
Concomitant medication: Statins	Not treated	2	5.1
	Treated	37	94.9
Concomitant medication: PCSK9 inhibitor	Not treated	26	66.7
	Treated	13	33.3
Previous experience with lomitapide treatment (at the time of initiation of administration)	Not treated	32	82.1
	Treated	7	18.0

† Pregnancy information is the percentage of the female population.

‡ Percentage of genetic mutations is based on the number of cases in whom genetic testing was performed.

LDL: Low-density lipoprotein.

Figure 1. Mean ± standard deviation lomitapide dosage.

Table 2. Average lomitapide dosage (mean ± standard deviation).

Observation period	Dose start date	1 week	2 weeks	1 month	2 months	3 months	6 months	9 months	12 months	15 months	18 months	21 months	24 months	27 months	30 months	33 months	36 months	39 months	42 months	45 months
Number of cases	39	39	39	39	39	38	38	38	26	20	18	16	10	10	9	8	7	6	5	5
Mean value	7.0	7.0	7.0	7.6	8.7	9.6	11.3	12.2	13.3	14.2	14.3	15.3	15.1	15.0	14.6	15.7	16.3	16.0	15.6	15.6
Standard deviation	7.0	6.9	6.9	6.8	6.6	6.5	6.6	6.7	7.7	8.5	9.2	9.4	10.1	10.1	10.6	10.6	10.8	11.9	13.3	13.3
Median	5	5	5	5.3	7.7	9.1	9.8	10.3	10.8	12.0	10.5	12.2	12.2	12.0	9.9	11.6	13.1	11.4	9.8	9.8
Minimum value	1.0	1.4	1.4	1.4	1.4	1.4	3.5	3.6	3.9	3.7	3.4	5.0	5.0	5.0	5.0	8.0	7.8	7.8	7.9	8.0
Maximum value	40.0	40.0	40.0	40.0	40.0	40.0	40.0	38.9	39.3	39.4	39.5	39.6	39.7	39.7	39.7	39.8	39.0	39.1	39.1	39.2

Table 3. Summary of drug-related adverse events during postmarketing surveillance.

Number of patients in safety analysis		39
Number of patients with drug-related AEs		24
Incidence rate of drug-related AEs		61.5%
Type of drug-related AE		Number of cases of drug-related AE by type (incidence rate)
Blood and lymphatic system disorders		1 (2.6%)
	Iron-deficiency anemia	1 (2.6%)
Gastrointestinal disorders		20 (51.3%)
	Abdominal discomfort	1 (2.6%)
	Abdominal pain	3 (7.7%)
	Constipation	1 (2.6%)
	Diarrhea	15 (38.5%)
	Increased frequency of bowel movements	1 (2.6%)
	Gastrointestinal disorder	1 (2.6%)
	Nausea	1 (2.6%)
	Vomiting	1 (2.6%)
	Loose or soft stool	1 (2.6%)
General disorders and administration site condition		1 (2.6%)
	Chest discomfort	1 (2.6%)
Hepatobiliary disorders		7 (18.0%)
	Liver dysfunction	5 (12.8%)
	Fatty liver^†	2 (5.1%)
	Liver impairment	1 (2.6%)
Investigations		9 (23.1%)
	Alanine aminotransferase increased	3 (7.7%)
	Aspartate aminotransferase increased	3 (7.7%)
	Increased blood creatine phosphokinase	1 (2.6%)
	Increased blood triglycerides	1 (2.6%)
	Computer tomography abnormality	1 (2.6%)
	Decreased ECG T wave amplitude	1 (2.6%)
	Increased PT-INR	1 (2.6%)
	Abnormal liver function tests	1 (2.6%)
	Abnormal liver ultrasound test	1 (2.6%)
	Elevated liver enzymes	1 (2.6%)
	Elevated liver fibrosis markers	1 (2.6%)
	Elevated liver function tests	2 (5.1%)
Metabolism and nutrition disorders		3 (7.7%)
	Decreased appetite	3 (7.7%)
Nervous system disorders		2 (5.1%)
	Cerebral infarction	1 (2.6%)
	Hypoesthesia	1 (2.6%)
Skin and subcutaneous tissue disorders		1 (2.6%)
	Pruritus	1 (2.6%)

† Liver fat content was measured by CT or ultrasound in 9/39 patients. It is assumed such imaging was not conducted in patients in whom liver abnormalities were not observed.

AEs were classified using MedDRA/J version (25.0).

AE: Adverse event; ECG: Electrocardiogram, PT-INR: Prothrombin time-international normalized ratio.

Table 4. Drug-related adverse events requiring special safety consideration per risk management plan in Japan.

Number of cases for safety analysis	39
Safety consideration	Total number^†		Serious^†		Non-serious^†
	Number of cases (%)		Number of cases (%)		Number of cases (%)
Important identified risks
Effects on the liver^‡	14	(35.9%)	5	(12.8%)	11	(28.2%)
Alanine aminotransferase increased	3	(7.7%)	0	(0.0%)	3	(7.7%)
Aspartate aminotransferase increased	3	(7.7%)	1	(2.6%)	2	(5.1%)
Liver dysfunction	5	(12.8%)	1	(2.6%)	4	(10.3%)
Fatty liver	2	(5.1%)	0	(0.0%)	2	(5.1%)
Increased PT-INR	1	(2.6%)	1	(2.6%)	0	(0.0%)
Liver impairment	1	(2.6%)	0	(0.0%)	1	(2.6%)
Abnormal liver function tests	1	(2.6%)	0	(0.0%)	1	(2.6%)
Abnormal liver ultrasound test	1	(2.6%)	1	(2.6%)	0	(0.0%)
Elevated liver enzymes	1	(2.6%)	0	(0.0%)	1	(2.6%)
Elevated liver fibrosis markers	1	(2.6%)	1	(2.6%)	0	(0.0%)
Elevated liver function tests	2	(5.1%)	0	(0.0%)	2	(5.1%)
Gastrointestinal disorder^§	19	(48.7%)	2	(5.1%)	19	(48.7%)
Abdominal discomfort	1	(2.6%)	0	(0.0%)	1	(2.6%)
Abdominal pain	3	(7.7%)	0	(0.0%)	3	(7.7%)
Constipation	1	(2.6%)	1	(2.6%)	0	(0.0%)
Diarrhea	15	(38.5%)	1	(2.6%)	15	(38.5%)
Increased frequency of bowel movements	1	(2.6%)	0	(0.0%)	1	(2.6%)
Nausea	1	(2.6%)	0	(0.0%)	1	(2.6%)
Vomiting	1	(2.6%)	0	(0.0%)	1	(2.6%)
Loose or soft stool	1	(2.6%)	0	(0.0%)	1	(2.6%)
Significant potential risks
Bleeding event^¶	1	(2.6%)	1	(2.6%)	0	(0.0%)
Increased PT-INR	1	(2.6%)	1	(2.6%)	0	(0.0%)
Malignant tumor^#	0	(0.0%)	0	(0.0%)	0	(0.0%)

† The total number of applicable PTs and the number of cases by serious and non-serious were counted. When patients had both serious and non-serious events, one serious case and one non-serious case were counted.

‡ Effects on the liver: PT encompassed by liver impairment (SMQ).

§ Gastrointestinal disorders: PT encompassed by non-specific inflammation and dysfunction of the gastrointestinal tract (SMQ).

¶ Hemorrhagic events: PT encompassed by bleeding (SMQ).

# Malignant tumor: PT encompassed by malignant tumor (SMQ).

AEs were classified using MedDRA/J version (25.0).

AE: Adverse event; PT: Preferred term; PT-INR: Prothrombin time-international normalized ratio; SMQ: Standardized MedDRA query.

Table 5. Drug-related adverse events in cases where the dose of lomitapide was reduced.

Number of cases for safety analysis		39
Number of cases with drug-related AEs		15
Incidence rate of drug-related AEs		38.5%
Type of drug-related AE		Number of cases of drug-related AEs by type (Incidence rate)
Metabolism and nutrition disorders		3	(7.7%)
	Decreased appetite	3	(7.7%)
Gastrointestinal disorder		11	(28.2%)
	Abdominal discomfort	1	(2.6%)
	Abdominal pain	2	(5.1%)
	Diarrhea	9	(23.1%)
	Nausea	1	(2.6%)
	Vomiting	1	(2.6%)
Hepatobiliary disorders		3	(7.7%)
	Liver dysfunction	2	(5.1%)
	Fatty liver	1	(2.6%)
Investigations		4	(10.3%)
	Increased blood creatine phosphokinase	1	(2.6%)
	Increased PT-INR	1	(2.6%)
	Abnormal liver function tests	1	(2.6%)
	Elevated liver enzymes	1	(2.6%)
	Elevated liver function tests	1	(2.6%)

AEs were classified using MedDRA/J version (25.0).

AE: Adverse event; PT-INR: Prothrombin time-international normalized ratio.

Table 6. Drug-related adverse events in cases where lomitapide was temporarily withdrawn.

Number of cases for safety analysis		39
Number of cases with drug-related AE		4
Incidence rate of drug-related AEs		10.3%
Type of drug-related AEs		Number of cases of drug-related AE by type (incidence rate)
Nervous system disorders		1	(2.6%)
	Cerebral infarction	1	(2.6%)
Gastrointestinal disorders		2	(5.1%)
	Diarrhea	2	(5.1%)
Skin and subcutaneous tissue disorders		1	(2.6%)
	Pruritus	1	(2.6%)
Investigations		1	(2.6%)
	Alanine aminotransferase increased	1	(2.6%)
	Aspartate aminotransferase increased	1	(2.6%)

AEs were classified using MedDRA/J version (25.0).

Some patients experienced more than one adverse event.

AE: Adverse event.

Table 7. Action with respect to lomitapide after the occurrence of drug-related adverse events.

Number of cases of drug-related AEs		24
Number of drug-related AEs^†		74
Action taken for lomitapide		Number of occurrences	%
	No change	32	43.2
	Increasing dose	3	4.1
	Decreasing dose	29	39.2
	Drug withdrawal	9	12.2
	Discontinued treatment	1	1.4
Treatment other than lomitapide		Number of occurrences	%
	No change	64	86.5
	Treatment for AEs	7	9.5
	Change in concomitant medications	2	2.7
	Other^‡	1	1.4

† Number of drug-related AEs is a duplicate count. For some AEs, lomitapide was withdrawn and restarted several times.

‡ The other breakdown is ’enhanced diet and exercise regimen’.

AE: Adverse event.

Table 8. Average blood low-density lipoprotein cholesterol concentrations (measured values; mean ± standard deviation).

Measurement period	Measured value (mg/dl) [mmol/l]
	Number of cases	Average	Standard deviation	Minimum value	Median	Maximal value	p-value^†
Baseline	39	225.9 [5.8]	172.0 [4.5]	77.0 [2.0]	188.6 [4.9]	927.0 [24.0]	–
3 months	36	183.4 [4.7]	151.9 [3.9]	22.4 [0.6]	154.0 [4.0]	888.0 [23.0]	p = 0.0106
6 months	37	175.4 [4.5]	145.6 [3.8]	46.0 [1.2]	140.0 [3.6]	872.0 [22.6]	p = 0.0008
12 months	21	159.4 [4.1]	93.0 [2.4]	44.0 [1.1]	161.0 [4.2]	360.0 [9.3]	p = 0.0245
24 months	12	139.6 [3.6]	80.9 [2.1]	56.0 [1.5]	96.5 [2.5]	315.0 [8.2]	p = 0.0716
36 months	9	151.0 [3.9]	91.9 [2.4]	27.0 [0.7]	118.0 [3.1]	322.0 [8.3]	p = 0.0909
42 months	8	122.1 [3.2]	66.7 [1.7]	56.0 [1.5]	85.0 [2.2]	213.0 [5.5]	p = 0.0128

† Correspondence t-test. Comparison of each measurement period with the time before the start of treatment (baseline).

Figure 2. Percentage change (mean ± standard deviation) in low-density lipoprotein cholesterol.

LDL-C: Low-density lipoprotein cholesterol.