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

Homozygous familial hypercholesterolemia (HoFH) is an inherited disorder caused by mutations of two alleles in the low-density lipoprotein (LDL) receptor gene or mutations in the LDL receptor gene and related genes [1]. It is characterized by high levels of LDL cholesterol (LDL-C) from birth, leading to skin and tendon xanthomas, and to the development of juvenile atherosclerosis, resulting in coronary artery stenosis, aortic valve stenosis and supravalvular aortic stenosis [2]. In many cases, conventional drug therapy is ineffective at lowering LDL-C levels, and consequently national and international academic societies recommend periodic lipoprotein apheresis [2–4]. Combination lipid-lowering pharmacotherapy is needed, which may include statins, ezetimibe and PCSK9-directed therapy initially, followed by newer agents such as lomitapide and evinacumab, where available [4].

Lomitapide was the first oral drug for HoFH and is approved in 38 countries worldwide including the USA as of February 2021. Lomitapide mesylate is a MTP inhibitor that directly binds to MTP in the lumen of the endoplasmic reticulum in hepatocytes and small intestinal epithelial cells, and inhibits the transfer of lipoproteins including triglycerides and apoprotein B (apo B) [5]. It has a different mechanism of action from conventional lipid-lowering drugs and reduces LDL-C independently of LDL receptor activity [1].

The first study evaluating the efficacy and safety of lomitapide in patients with HoFH was a phase II dose-escalation study conducted in 2003, which required patients to follow a low-fat diet [6]. Since it was well tolerated in the dose-escalation study, a phase III study in patients with HoFH was initiated in 2007, which confirmed its efficacy and acceptable tolerability [7], and in December 2012 lomitapide was approved by the US FDA for the treatment of HoFH [5]. A long-term extension of this trial showed that efficacy was maintained during a median of 5 years of treatment and that the tolerability profile remained acceptable, with the most common adverse events reported being gastrointestinal events [8]. Observational studies in a real-world setting in Europe confirmed the effectiveness of lomitapide in reducing LDL-C levels in patients with HoFH, and also that gastrointestinal adverse events were most common [9–14].

For the development of lomitapide in Japan, a phase I study in Japanese and Caucasian subjects performed in 2012 found no differences between ethnicities [15], and a phase III study initiated in 2013 confirmed the efficacy of lomitapide and found no new safety signals [16]. Lomitapide was approved in Japan for the indication of HoFH in September 2016 and was launched in December 2016. More recently, data from an extension of the phase III study has supported the long-term efficacy and safety of lomitapide in patients with HoFH in Japan [17].

However, since the number of patients enrolled in clinical trials for this disease is extremely limited due to the rarity of the disorder, a specific drug use-results survey was initiated in Japan in July 2017 to evaluate the safety and efficacy of lomitapide in real-world clinical practice. We report here an interim analysis of 39 patients enrolled in the all-case surveillance study up to September 2022.

Patients & methods

Survey method

The survey involved an all-case surveillance of patients with HoFH treated with lomitapide, managed via a central registration method. Investigators were asked to enroll all patients to whom lomitapide was administered as soon as possible after obtaining patient consent. In addition, because this was an all-case surveillance study, retrospective case enrollment was accepted for cases where lomitapide was prescribed and enrollment occurred prior to the end of the survey contract with the facility.

The overall planned number of enrolled patients was 166, with an observation period of at least 2 years and up to a maximum 8 years. Patients who were observed for less than 1 year were included in the safety evaluation where possible. The study was conducted in compliance with the ‘Ordinance of the Ministry of Health, Labor and Welfare on Standards for Conducting Post-Marketing Surveillance and Testing of Pharmaceuticals (Ordinance of the Ministry of Health, Labor and Welfare No. 171, December 20, 2004)’ (GPSP Ordinance) for Japan.

Survey items

The following items were included in the survey: patient background (height, weight, BMI, abdominal circumference, pregnancy, allergy history, etc.); reason for use (diagnosis, year and month of diagnosis, presence or absence of genetic testing); treatment prior to the start of lomitapide (hypercholesterolemia medications, lipoprotein apheresis, dietary therapy, exercise therapy); parameters related to HoFH (untreated LDL-C level, family history of familial hypercholesterolemia [FH] or premature coronary atherosclerosis in second-degree relatives, presence of cutaneous nodular xanthomas, tendon xanthomas, corneal arcus, coronary artery disease); hepatic or renal dysfunction before starting lomitapide; medical history and complications; status of nondrug therapy (compliance with low-fat diet, fat-soluble nutrients intake, exercise therapy); lipoprotein apheresis therapy; lomitapide administration status (starting date, dosage and administration, duration of administration, etc.); lomitapide continuation status at the time of filling out the questionnaire; other hypercholesterolemia medications; lipid parameters (total cholesterol, HDL-C, LDL-C, triglycerides, etc.); other laboratory values, especially hyaluronic acid and type IV collagen; adverse events; ECG (if measured), echocardiography (if measured) and liver fat content; and plasma biochemical markers of hepatotoxicity including aspartate aminotransferase, alanine aminotransferase and bilirubin.

Safety evaluation

Safety was evaluated by the presence or absence of adverse events (AEs), type of AEs, dates of occurrence, severity, lomitapide treatment status, non-lomitapide treatments, outcome, date of outcome, causal relationship to lomitapide and factors other than lomitapide.

Special safety considerations for lomitapide were specified in the drug risk management plan (RMP). The RMP defined ‘important identified risks’ as liver effects and gastrointestinal disorders, ‘important potential risks’ as bleeding events and malignant tumors, and ‘important missing information’ as safety issues during long-term administration. If any of these events occurred, they were evaluated in detail.

All events that occurred from the start of lomitapide administration to the time of completing the survey response form were included in the study and were treated as AEs, regardless of whether there was or was not a causal relationship with lomitapide. For events that occurred on or after the last date of lomitapide administration, only those events for which the physician judged that a causal relationship with lomitapide could not be ruled out were included. AEs for which either the physician or sponsor judged that a causal relationship could not be ruled out (including ‘unknown’) were classified as drug-related adverse events.

The following were defined as serious AEs: (1) death, (2) disability, (3) possible death (life-threatening), (4) possible disability (potential for disability, but did not result in disability), (5) hospitalization for treatment or prolonged hospitalization, (6) events not completely consistent with criteria 1–5 but nonetheless considered serious and (7) congenital diseases or birth defects. AEs could be judged to be serious by either the physician or the sponsor.

AEs were classified by system organ class (SOC) and preferred terms (PT) using the Japanese version of the International Council for Pharmaceuticals for Human Use Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Medical Dictionary for Regulatory Activities (MedDRA/J) version 25.0.

Efficacy

Efficacy was evaluated as the change in LDL-C level over time and the change ratio from baseline after the start of treatment with lomitapide.

Statistical analysis

The corresponding t-test was used to compare LDL-C level before start of lomitapide and at each measurement time point. The significance level was set at 5% two-sided. Analyses were performed using SAS Ver. 9.4.

Results

Patient disposition

This study was initiated in July 2017 and is ongoing. 58 patients were enrolled during the period July 2017 to July 2022 and 53 survey response forms were collected. Of these, 39 cases were included in the safety and efficacy analyses, after excluding 14 cases that are undergoing reinvestigation.

Patient characteristics

Patients' characteristics are summarized in Table 1. Of the 39 patients included in the safety analysis, 18 (46.2%) were male and 21 (53.9%) were female, and most patients (27/39; 69.2%) were aged 15–<65 years. Most patients (29/39; 74.4%) weighed 40–<70 kg and most (24/39; 61.5%) had a BMI of 18.5–<25. Nine patients (23.1%) had mild hepatic dysfunction (Child-Pugh classification A) and 3 patients (7.7%) had mild renal dysfunction.

Genetic testing was performed in 30 patients (76.9%). Twelve of these patients (40.0%) had the same mutation in the two alleles of the LDL receptor (true homozygote) and 13 (43.3%) had two different mutations in the two alleles of the LDL receptor (compound heterozygote). One patient (3.3%) had a single mutation in one of the alleles of the LDL receptor and also had a mutation in the PCSK9 or APOB gene (double heterozygote); the survey asked whether patients had a PCSK9 or APOB mutation but did not require the specific type to be stated, and so it was not possible to identify which mutation the patient had. One case (3.3%) had the same mutation in the two alleles of the autosomal recessive hypercholesterolemia (ARH) gene. Thus, 27 patients had a genetic diagnosis consistent with HoFH. The other 12 patients were diagnosed clinically as HoFH for which existing lipid-lowering drugs were not sufficiently effective.

38 patients (97.4%) were treated with drugs for hypercholesterolemia prior to receiving lomitapide. The situation was similar after the start of lomitapide administration as most patients received drugs for hypercholesterolemia as concomitant medication (statins 94.9%; PCSK9 inhibitor 33.3%). Among patients who had been receiving treatment other than pharmacotherapy prior to the start of lomitapide, lipoprotein apheresis was performed in 26 cases (66.7%), diet therapy in 36 (92.3%) and exercise therapy in 11 (28.2%). At the start of lomitapide treatment, 25 patients were undergoing lipoprotein apheresis. Thereafter, the apheresis interval remained unchanged in 21 patients, 1 patient withdrew from apheresis, 1 patient had a longer interval and 2 patients had a shorter interval. In addition, 1 patient started lipoprotein apheresis after lomitapide administration, but the interval was subsequently prolonged compared with the time of initiation.

Daily dosage

Among the 39 patients included in the safety analysis, the most common daily dose of lomitapide used continuously was 10 mg (17 patients; 43.6%), followed by 20 mg (8 patients; 20.5%) and 5 mg (6 patients; 15.4%).

The overall mean daily dose was 7.0 mg on the first day of treatment, and also after 1 and 2 weeks. Thereafter, the mean dose gradually increased to 7.6 mg at 1 month, 9.6 mg at 3 months, 11.3 mg at 6 months, 13.3 mg at 12 months, 14.3 mg at 18 months, 15.1 mg at 24 months after which it remained between 14 mg and 16 mg, although there was only a small number of cases at these later timepoints (Figure 1 & Table 2). The median dose of lomitapide over 42 months was 9.8 mg/day.

Safety

Incidence of drug-related adverse events

A total of 74 drug-related AEs were reported in 24 (61.5%) of the 39 patients included in the safety analysis. The most common drug-related AEs were diarrhea (15 patients; 38.5%), liver dysfunction (5 patients; 12.8%), abdominal pain, increased alanine aminotransferase, increased aspartate aminotransferase, decreased appetite (each in 3 patients; 7.7%), and fatty liver, increased liver function test values (each in 2 patients; 5.1%) (Table 3). Serious drug-related AEs included constipation, diarrhea, liver dysfunction, increased aspartate aminotransferase, abnormal computed tomography [assessment of fat in liver; abnormal result determined by physician], increased prothrombin time-international normalized ratio (PT-INR), abnormal liver ultrasound test [assessment of fat in liver; abnormal result determined by physician], increased liver fibrosis markers and cerebral infarction (one patient each). Among the serious AEs, diarrhea and increase in PT-INR occurred in the same patient (who was taking warfarin) and both resolved after the dosage of lomitapide was reduced; constipation recovered without any change in lomitapide dosage and symptoms of cerebral infarction recovered after lomitapide was withdrawn.

Special safety considerations

With respect to drug-related AEs specified in the RMP as being particular safety considerations, 14 patients experienced liver effects (designated as an important identified risk), 19 patients had gastrointestinal disorders (an important identified risk) and 1 patient had a bleeding disorder (important potential risk) (Table 4). There were no cases of malignancy (important potential risk).

Among the 14 patients with drug-related AEs affecting the liver, the most common were liver dysfunction (5 cases), increased alanine aminotransferase, increased aspartate aminotransferase (3 cases each), fatty liver and increased liver function test values (2 cases each). Five events were considered serious drug-related AEs (increased aspartate aminotransferase, liver dysfunction, increased PT-INR, abnormal liver ultrasound test and increased hepatic fibrosis markers). The case of liver dysfunction resolved after lomitapide was discontinued, the case of increased aspartate aminotransferase resolved after temporary withdrawal of lomitapide, the case of increased PT-INR recovered after dose reduction, and the patients with abnormal liver ultrasound test and increased liver fibrosis markers were maintained on the same dose and the AEs had not resolved at the time of reporting.

Among the 19 patients with drug-related AEs affecting the gastrointestinal tract, the most common was diarrhea (15 cases), followed by abdominal pain (3 cases). Two of the events were serious drug-related AEs (1 case each of constipation and diarrhea). The patient with severe constipation recovered after 3 days of treatment with a laxative (sennoside) without a change in lomitapide dosage. The patient with severe diarrhea recovered 7 days later, after the dosage of lomitapide was reduced; 14 months later, this patient developed non-serious diarrhea and the lomitapide dosage was reduced again followed by recovery 4 days later.

The patient with an adverse reaction related to a bleeding event was taking concomitant warfarin and experienced an increase in PT-INR, which recovered after administration of vitamin K and reduction of the dose of lomitapide.

AE-related discontinuation, dose reduction or withdrawal of lomitapide

Lomitapide treatment was discontinued in one patient with a serious drug-related AE of liver dysfunction. This occurred 8 days after the start of lomitapide (5 mg/day) administration, and it resolved after discontinuation of lomitapide and concomitant medications (rosuvastatin and probucol) that had also been used prior to lomitapide.

A dose reduction due to drug-related AEs occurred in 15 patients (38.5%). The most common of these AEs was diarrhea (9 cases), followed by decreased appetite (3 cases), abdominal pain and liver dysfunction (2 cases each) (Table 5).

Four patients (10.3%) had lomitapide temporarily withdrawn because of drug-related AEs, among whom there were two reports of diarrhea, and one report each of cerebral infarction, pruritus, increased alanine aminotransferase and increased aspartate aminotransferase (Table 6). Two of these events were considered serious drug-related AEs – cerebral infarction and increased aspartate aminotransferase. In the case of cerebral infarction, symptoms resolved after the addition of clopidogrel 75 mg/day and temporary withdrawal of lomitapide. The case of increased aspartate aminotransferase resolved after temporary withdrawal of lomitapide.

Among the 24 patients with drug-related AEs (74 events), the most common action with respect to lomitapide was dose reduction (29 events), followed by drug withdrawal (9 events) (Table 7). Seven AEs required treatment with other medications.

Efficacy

The mean ± SD blood LDL-C level before lomitapide treatment was 225.9 ± 172.0 mg/dl (5.8 ± 4.5 mmol/l). Mean LDL-C level decreased significantly to 183.4 ± 151.9 mg/dl (4.7 ± 3.9 mmol/l) at 3 months, 175.4 ± 145.6 mg/dl (4.5 ± 3.8 mmol/l) at 6 months and 159.4 ± 93.0 mg/dl (4.1 ± 2.4 mmol/l) at 12 months (Table 8). At later timepoints there was a continued (almost non-significant) trend toward a decrease, with mean LDL-C levels of 139.6 ± 80.9 mg/dl (3.6 ± 2.1 mmol/l) at 24 months, 151.0 ± 91.9 mg/dl (3.9 ± 2.4 mmol/l) at 36 months and 122.1 ± 66.7 mg/dl (3.2 ± 1.7 mmol/l) at 42 months.

The percent change in LDL-C level from pre-dose to timepoints for which information was available for more than half of the efficacy-analysis patients was -12.3% at 3 months, -16.3% at 6 months, -22.4% at 12 months, -22.9% at 24 months, -35.8% at 36 months and -41.2% at 42 months (Figure 2).

Discussion

Lomitapide is effective in the treatment of patients with HoFH [5,18], and is recommended by current guidelines for inclusion in combination LDL-C lowering therapy for this patient population [4]. Efficacy and tolerability data from clinical trials [6–8,15–17] has been followed by evidence of its effectiveness and tolerability in the real-world setting, most of which has come from Europe [9–14].

An all-case surveillance study of patients with HoFH treated with lomitapide in real-world clinical practice in Japan is ongoing. We have reported an interim analysis that included 39 patients.

The overall profile of the patients was generally consistent with the characteristics reported by a Japanese national HoFH registry, although a larger proportion of patients in our study had undergone LDL apheresis (66.7 vs 21%) [19]. In our study, 9/39 patients were more than 65 years old, and in the national registry the mean age was 54 ± 15 years, indicating that a considerable number of HoFH patients in Japan are aged above 65 years. This may be due to the fact that lipoprotein apheresis has been actively performed on HoFH patients in Japan for a long time, and the government has established a medical expense subsidy system.

Overall, 61.5% of the patients in our study experienced drug-related AEs. However, only one AE resulted in discontinuation of lomitapide. Other AEs could be managed with temporary withdrawal of lomitapide, with a dose reduction, or with no change in lomitapide. A few patients required other drugs to treat AEs.

The incidence of drug-related AEs in the current study was lower than the incidence reported in the Japanese phase III pre-registration study, which included only 9 patients, all of whom experienced drug-related AEs [16]. Consistent findings were seen in overseas studies. In the overseas phase III clinical trial (n = 29), more than 90% of patients experienced AEs [7], while in an overseas registry study in real-world clinical practice (LOWER 5; n = 187), AEs occurred in 75.7% of patients [20]. In the LOWER 5 study, 23.2% of patients discontinued treatment due to AEs.

Among drug-related AEs that were designated as special safety considerations, liver effects occurred in 14 of 39 (35.9%) patients, gastrointestinal disorders in 48.7% and bleeding disorders in 1 (2.6%) patient in the current study. In the Japanese phase III study, liver effects were reported in 3 of 9 patients (33.3%) and gastrointestinal disorders in 9 of 9 patients (100.0%) [16]. The findings suggest that gastrointestinal disorders were less frequent in the current study than in the phase III study, although the evaluation is limited by the small number of patients in the latter study.

A similar observation was found in a comparison between the overseas phase III study [7] and the LOWER 5 real-world treatment study [20]. In the overseas phase III study, drug-related AEs affecting the liver (increased aspartate aminotransferase and alanine aminotransferase) were observed in 10 of 29 cases (34.5%) and gastrointestinal disorders in 27 of 29 cases (93.1%) [7], while in the overseas report of real-world treatment, drug-related AEs affecting the liver were observed in 34 of 185 cases (18.4%) and gastrointestinal disorders were reported in 86 of 185 cases (46.5%) [20].

The dose of lomitapide was 9.8 mg/day (median dose during 42 months) in the current study, 20 mg/day (median during 26 weeks) in the Japanese phase III study [8], 40 mg/day (median during 76 weeks) in the overseas phase III study [7], and 10 mg/day (median during 23.8 months) in the LOWER 5 study [20], suggesting that the dose in real-world clinical practice is lower than in phase III clinical trials. This may have led to the lower frequency of gastrointestinal disturbances in studies in real-world clinical practice. In addition, it has been reported that side effects can be reduced by increasing the dose gradually by 5 mg/day [21], and it is possible that the frequency of gastrointestinal disturbances could have been reduced by physicians following this dosage increase method. The median dose in Japanese phase III trials was 20 mg/day compared with 40 mg/day in overseas phase III trials, suggesting that the effective dose in Japanese patients may be lower than in overseas studies.

In the current study, an increase in PT-INR was observed in one patient who was being treated with warfarin, and therefore it is unclear whether this was due to lomitapide or to a stronger effect of warfarin; however, it suggests the PT-INR should be measured regularly and monitored carefully in such patients. In the 5-year analysis of the LOWER registry, events of special interest (regardless of severity) associated with lomitapide or the underlying homozygous familial hypercholesterolemia were collected [20]. Four patients developed neoplasms (benign, malignant or unspecified, including cysts and polyps), but causality was not confirmed. Importantly, no cases of malignancy occurred in our study. We will continue to collect information on the matters described in the drug RMP and review details of the collected events.

In the current study, efficacy was evaluated by analyzing the change in average LDL-C level and the rate of change from baseline in 39 patients. In the Japanese phase III study, the addition of lomitapide led to further reductions in LDL-C in patients receiving other lipid-lowering therapy such as statins, ezetimibe or lipoprotein apheresis [16]. In the current study blood LDL-C levels also decreased from baseline, confirming the efficacy of lomitapide in patients with HoFH treated in real-world clinical practice. The reduction in LDL-C at 12 months was modest, probably because physicians continued to prescribe the drug at low doses due to concerns about adverse events. However, a greater reduction in LDL-C was seen at later timepoints.

Patients with HoFH are at extremely high risk of atherosclerotic cardiovascular disease, and Japanese and other guidelines recommend using multiple drugs to lower LDL-C to management targets [2–4]. When the target is not achieved with initial treatment, other drugs should be added. This strategy may include new agents, as they become available. One such drug is the angiopoietin-like 3 inhibitor evinacumab [22]. In January 2024, evinacumab was approved in Japan, and it is expected that this drug will be added to lomitapide treatment in the near future, further improving LDL-C control in patients with HoFH.

Limitations of this observational study include the absence of a control group, the fact that laboratory data were not measured at a central laboratory, efficacy data were not available for all patients at all timepoints, and adherence to treatment could not be measured. Nonetheless, the study provides important information about treatment of this rare condition with lomitapide in Japan and expands on information obtained from clinical trials. This all-case surveillance study is ongoing, and we will continue to investigate the usefulness of lomitapide, including factors that may affect its safety and efficacy.

Conclusion

We conducted an interim analysis of an ongoing specific drug use-results study that is evaluating the safety and efficacy of lomitapide in real-world clinical practice. The interim analysis involved 39 patients, and we were able to confirm the safety and efficacy of lomitapide in real-world treatment in Japan. The safety and efficacy data obtained were consistent with the results of the overseas phase III and real-world studies and no new safety concerns were identified. However, at this point, the number of cases accumulated is still small. Further studies are needed to investigate factors that may affect both safety and efficacy.