Efficacy and Safety of Lomitapide in Japanese Patients with Homozygous Familial Hypercholesterolemia

J Atheroscler Thromb, 2017; 24: 402-411. doi: 10.5551/jat.38216 Original Article Efficacy and Safety of Lomitapide in Japanese Patients with Homozygous Familial Hypercholesterolemia Mariko Harada-Shiba1, Katsunori Ikewaki2, Atsushi Nohara3, Yoshihiko Otsubo4, Koji Yanagi5, Masayuki Yoshida6, Qing Chang7 and Pamela Foulds7 1National Cerebral and Cardiovascular Research Center, Osaka, Japan 2National Defense Medical College, Saitama, Japan 3Kanazawa University Graduate School of Medical Sciences, Ishikawa, Japan 4Shin-Koga Clinic, Medical Group Tenjin-kai, Fukuoka, Japan 5Kenporen Osaka Central Hospital, Osaka, Japan 6Tokyo Medical and Dental University, Tokyo, Japan 7Aegerion Pharmaceuticals, Inc., Cambridge, MA, USA Aim: There is an unmet need in Japan for more optimal lipid-lowering therapy (LLT) for patients with homozygous familial hypercholesterolemia (HoFH) who respond inadequately to available drug therapies and/or apheresis, to achieve goals of low-density lipoprotein cholesterol (LDL-C) reduction by 50% or to ＜100 mg/dL. Methods: In this study, Japanese patients with HoFH on stable LLT and diet were treated with lomitapide, initiated at 5 mg/day and escalated to maximum tolerated dose (up to 60 mg/day) over 14 weeks. The primary efficacy endpoint was mean percentage change from baseline to Week 26 in LDL-C. Secondary endpoints included changes in other lipid parameters and safety throughout the 56-week study (including follow-up). Results: Nine patients entered the efficacy phase of the study and, of these, eight completed 56 weeks. Mean LDL-C was reduced by 42% (p＜0.0001) at 26 weeks, from 199 mg/dL (95% CI: 149–250) at baseline to 118 mg/dL (95% CI: 70–166). A 50% reduction in LDL-C and LDL-C ＜ 100 mg/dL was achieved by five and six of nine patients, respectively, at 26 weeks. After 56 weeks, LDL-C was reduced by 38% (p=0.0032) from baseline. Significant reductions in non-HDL-C, VLDL-C, triglycerides, and apolipoprotein B were also reported at Week 26. There were no new safety signals and, similar to previous studies, gastrointestinal adverse events were the most common adverse events. Conclusion: Lomitapide, added to ongoing treatment with other LLTs, was effective in rapidly and significantly reducing the levels of LDL-C and other atherogenic apolipoprotein B-containing lipoproteins in adult Japanese patients with HoFH. See editorial vol. 24: 390-392 Key words: Homozygous familial hypercholesterolemia, Lomitapide, Hypercholesterolemia, LDL-C Copyright©2017 Japan Atherosclerosis Society This article is distributed under the terms of the latest version of CC BY-NC-SA defined by the Creative Commons Attribution License. (HoFH) is a rare, autosomal dominant genetic disor- Introduction der characterized by substantially elevated low-density Homozygous familial hypercholesterolemia lipoprotein cholesterol (LDL-C) levels. In untreated patients, total plasma cholesterol and LDL-C levels Address for correspondence: Mariko Harada-Shiba, are generally ≥ 500 mg/dL1) and markedly premature National Cerebral and Cardiovascular Research Center, atherosclerotic cardiovascular disease (ASCVD) 5-7-1 Fujishirodai, Suita, Osaka, 565-8565, Japan 2-4) Email: [email protected] occurs . If left untreated, most patients will develop Received: September 24, 2016 atherosclerosis before the age of 20 years and generally Accepted for publication: December 4, 2016 do not survive past the age of 30 years1). The primary 402 Lomitapide and LLT in Japanese HoFH Patients goal of therapy is the prevention of ASCVD including as an adjunctive therapy for adults with HoFH in a coronary artery disease by controlling hypercholester- number of countries, including the USA, Canada, olemia. The European Atherosclerotic Society has countries in the EU, Taiwan, and Korea21-23). defined the current LDL-C target for adults with HoFH as ＜100 mg/dL, or ＜70 mg/dL in the pres- Aim ence of clinical ASCVD1). The American Heart Asso- ciation recommends similar goals with the caveat that In Japan, there is an unmet need for more opti- these targets may be difficult to achieve, therefore mal lipid-lowering therapy (LLT) for patients with maximal LDL-C reduction that can be well tolerated HoFH who respond inadequately to available drug is a pragmatic target5). The Japan Atherosclerosis Soci- therapies and/or apheresis. The primary aim of this ety recommends that treatment for adults with HoFH study was to evaluate, in Japanese adult patients with should aim for LDL-C ＜100 mg/dL; however, HoFH, the efficacy of lomitapide in reducing LDL-C because this target may be challenging, they have sug- in combination with other LLTs. Secondary aims were gested a secondary target of a 50% reduction in pre- to evaluate the safety and tolerability of lomitapide treatment levels of LDL-C6). Individuals unable to and to evaluate changes in other lipid parameters, achieve these LDL-C target levels may remain at high hepatic fat, and xanthomas. risk for ASCVD1, 7). A recent review of familial hypercholesterolemia in Asia found that awareness of the Methods disease, and its diagnostic criteria, varied between countries; concluding that more resources are required Study Design to raise awareness, improve care, and increase research In this phase 3, single-arm, open-label study, in Asian populations8). Ongoing observational studies adult patients with HoFH added lomitapide to their will help elucidate geographic/epidemiological differ- maximally tolerated, stable, LLT. After initial screen- ences that may impact optimal management of ing, including informed consent (during Weeks -12 to HoFH, including screening, in different regions9, 10). -6), the study progressed in three phases (Fig.1): HoFH is commonly caused by loss of function -6–0 weeks, pre-treatment run-in during which both mutations in the gene encoding the LDL-receptor diet and other LLTs were stabilized; 0–26 weeks, dose- (LDLR)3), but can also be caused by mutations in sev- escalation and efficacy measures; and ＞26–56 weeks, eral other genes resulting in impairment of the LDLR safety measures. At the conclusion of this trial, pathway11-13). Consequently, treatments with statins patients had the option of continuing in a long-term and PCSK9 inhibitors, which rely on upregulating extension trial. hepatic LDLR, have reduced effects in most patients During the run-in phase, the diet stabilization with HoFH, whose LDLRs are absent or defective. target required patients to obtain ＜20% of food Since patients with HoFH usually do not achieve the energy as fat and to take daily supplements of vitamin E recommended LDL-C target by using these treat- (400 IU) and fatty acids (≥ 200 mg linoleic acid, 210 ments, adjunctive lipoprotein apheresis is also recom- mg alpha-linolenic acid, 110 mg eicosapentaenoic mended. Apheresis can transiently reduce LDL-C by acid, and 80 mg docosahexaenoic acid). Supplements more than 50%17, 18). However, the rapid re-accumula- of vitamin E, which is largely transported by LDL-C, tion of circulating LDL-C requires that apheresis be were given in anticipation of LDL-C reductions. The repeated frequently, every 1–2 weeks, and means that stabilization target for other LLTs (including lipopro- LDL-C targets are unlikely to be maintained. Even tein apheresis or plasmapheresis if applicable) was the with regular lipoprotein apheresis, many patients with maximum tolerated dose (MTD). The run-in phase HoFH still develop coronary artery disease and/or started with a screening visit between -12 weeks and aortic valve stenosis19). More effective treatments for -6 weeks. Adherence to the diet stabilization target HoFH are required to prevent atherosclerosis in these was assessed by reviewing patients’ self-completed patients. dietary records (supplied by the sponsor along with Lomitapide (Juxtapid [AEGR-733], Aegerion detailed instructions) at Week -2±1 and at all subse- Pharmaceuticals Inc., Cambridge, MA, USA; Lojuxta, quent study visits. Aegerion Pharmaceuticals Ltd, Uxbridge, UK) is an During the efficacy phase, oral lomitapide was inhibitor of the microsomal triglyceride transfer pro- initiated at 5 mg/day and escalated to each patient’s tein that transfers triglycerides within the liver onto MTD (up to a maximum of 60 mg/day). This dose is apolipoprotein B during the assembly of very-low- supported by previously reported pharmacokinetic density lipoproteins (VLDLs), which are the precur- results in Japanese patients24). MTD was defined as sors of circulating LDLs20, 21). Lomitapide is indicated the highest dose during Weeks 0–26 that did not 403 Harada-Shiba et al. Fig.1. Study design LLT, lipid-lowering therapy; MTD, maximum tolerated dose. result in unacceptable adverse events (AEs), including (TC) ＞250 mg/dL; or untreated TC ≥ 500 mg/dL elevated liver function tests (LFTs). Patients attended and triglycerides ＜300 mg/dL, and both parents hav- study visits at Weeks 0, 2, 6, 10, 14, 18, 22, and 26. ing documented untreated TC ＞250 mg/dL. The last permitted dose increase was at Week 22. Patients were excluded if they had uncontrolled In the safety phase, lomitapide was continued at hypertension, history of chronic renal insufficiency, or the patient’s MTD for an additional 30 weeks. Lomi- significant liver disease. Patients who required use of tapide dose could be decreased if dose modification potentially hepatotoxic medications, especially those rules were applied, and subsequent re-escalation was that could induce microvesicular or macrovesicular allowed up to the MTD that was determined during steatosis,

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