Phase I Study of the Safety, Tolerability, PK & PD of Lomitapide in Japanese and Caucasian Subjects With Elevated LDL-C

Study Overview
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Brief Summary
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This is a randomized, double-blind, placebo-controlled, single ascending dose (SAD) and multiple ascending dose (MAD) study of orally administered lomitapide in healthy male Japanese and Caucasian subjects with elevated LDL-C. The purpose for this study is to evaluate the PK and PD of lomitapide in Japanese subjects as compared to Caucasian subjects.

Official Title
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A Randomized, Double-blind, Placebo-controlled, Single Ascending and Multiple Ascending Dose Study of the Safety, Tolerability, Pharmacokinetics(PK) and Pharmacodynamics(PD) of Lomitapide in Japanese and Caucasian Volunteers With Elevated Low-density-lipoprotein(LDL-C)

Conditions
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Healthy Volunteer

Intervention / Treatment
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* Drug: lomitapide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Subject is a healthy male or female, Caucasian or Japanese, aged 20 - 45 years, inclusive, at screening. 2. Subject has a BMI of 18.5 - 30 kg/m2 inclusive at screening. 3. Subjects must have a screening LDL-C measurement and the mean of Day 5 and Day 6 measurements greater than or equal to 110mg/dL. 4. Subjects must agree to use acceptable methods of contraception (details provided in the protocol) 5. Subjects must be capable of understanding and complying with the requirements of the protocol and must have signed the informed consent form prior to undergoing any study-related procedures. Exclusion Criteria: Subject has a clinically significant disease or any condition or disease that might affect drug absorption, distribution or excretion. Any clinically significant abnormal laboratory, vital signs or other safety findings as determined by medical history, physical examination or other evaluations conducted at screening or on admission. Electrocardiogram (ECG) abnormalities in the standard 12-lead ECG (at screening) which in the opinion of the Investigator is clinically relevant or will interfere with the ECG analysis. History or current evidence of any clinically relevant cardiovascular, pulmonary, hepatic, renal, gastrointestinal, haematological, endocrinological, metabolic, neurological, psychiatric or other disease. Positive results in any of the serology tests for Hepatitis B Surface Antigen (HbsAg), anti-Hepatitis core antibody (anti-HBc Ig G [and anti-HBc IgM if IgG is positive], Hepatitis C antibodies (anti-HCV), and HIV 1 and 2 antibodies, (anti-HIV 1/2) at screening. Confirmed positive results from urine drug screen or from the alcohol breath test at screening and on admission (Day -1). History or clinical evidence of alcohol or drug abuse. Mentally handicapped. Participation in a drug trial within 90 days prior to first drug administration. Use of any medication (including over-the-counter (OTC) medication) within 2 weeks prior to admission (Day -1) or within less than 10 times the elimination half-life of the respective drug, or anticipated concomitant medication during the treatment periods. Use of any substance inhibiting CYP3A4 enzymes within 2 weeks prior to admission (Day -1). Donation of more than 500 mL of blood within 90 days prior to drug administration. Subjects who smoke more than 10 cigarettes or equivalent amount of tobacco per day and/or who cannot stop smoking for the duration of the study whilst in the CPU. Treatment with herbal supplements during the 7 days prior to dosing, or use of vitamins during 48 hours prior to admission (Day -1). Any circumstances or conditions, which, in the opinion of the PI, may affect full participation in the trial or compliance with the protocol. Legal incapacity or limited legal capacity at screening. Subjects who are vegetarians, vegans or have any dietary restrictions conflicting with the study standardised menus. If female, subject was pregnant or lactating (females of child bearing potential must have negative pregnancy tests at screening and admission).

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>12 Japanese and 12 Caucasian subjects. 10 out of 12 will receive 10 mg lomitapide and 2 will receive placebo. | Drug: lomitapide<br> <br> |
| Experimental: Cohort 2<br>8 Japanese and 8 Caucasian subjects. 6 out of 8 subjects will receive 20 mg lomitapide and 2 will receive placebo. | Drug: lomitapide<br> <br> |
| Experimental: Cohort 3<br>8 Japanese and 8 Caucasian subjects. 6 out of 8 subjects will receive 40 mg lomitapide and 2 will receive placebo. | Drug: lomitapide<br> <br> |
| Experimental: Cohort 4<br>8 Japanese and 8 Caucasian subjects. 6 out of 8 subjects will receive 60 mg lomitapide and 2 will receive placebo. | Drug: lomitapide<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax for Lomitapide | Maximum observed plasma concentration for lomitapide | 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose on Day 7 | 
| Tmax for Lomitapide | Time to maximum observed concentration for lomitapide | 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose on Day 7 | 
| AUC0-t for Lomitapide | Area under the plasma concentration versus time curve from hour 0 to the last measurable concentration for lomitapide | 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose on Day 7 | 
| AUC0-∞ for Lomitapide | Area under the plasma concentration versus time curve from zero to infinity for lomitapide | 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose on Day 7 | 
| t1/2 for Lomitapide | Apparent terminal elimination half-life for lomitapide | 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose on Day 7 | 
| Cmax for Lomitapide | Maximum observed plasma concentration for lomitapide | 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose on Day 27 | 
| Tmax for Lomitapide | Time to maximum observed concentration for lomitapide | 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose on Day 27 | 
| AUC0-t for Lomitapide | Area under the plasma concentration versus time curve from hour 0 to the last measurable concentration for lomitapide | 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose on Day 27 | 
| t1/2 for Lomitapide | Apparent terminal elimination half-life for lomitapide | 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose on Day 27 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax for M1 | Maximum observed plasma concentration for M1 metabolite of lomitapide | 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose on Day 7 | 
| Tmax for M1 | Time to maximum observed concentration for M1 metabolite of lomitapide | 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose on Day 7 | 
| AUC0-t for M1 | Area under the plasma concentration versus time curve from hour 0 to the last measurable concentration for M1 metabolite of lomitapide | 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose on Day 7 | 
| AUC0-∞ for M1 | Area under the plasma concentration versus time curve from zero to infinity for M1 metabolite of lomitapide | 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose on Day 7 | 
| t1/2 for M1 | Apparent terminal elimination half-life for M1 metabolite of lomitapide | 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose on Day 7 | 
| Cmax for M3 | Maximum observed plasma concentration for M3 metabolite of lomitapide | 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose on Day 7 | 
| Tmax for M3 | Time to maximum observed concentration for M3 metabolite of lomitapide | 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose on Day 7 | 
| AUC0-t for M3 | Area under the plasma concentration versus time curve from hour 0 to the last measurable concentration for M3 metabolite of lomitapide | 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose on Day 7 | 
| AUC0-∞ for M3 | Area under the plasma concentration versus time curve from zero to infinity for M3 metabolite of lomitapide | 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose on Day 7 | 
| t1/2 for M3 | Apparent terminal elimination half-life for M3 metabolite of lomitapide | 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose on Day 7 | 
| Cmax for M1 | Maximum observed plasma concentration for M1 metabolite of lomitapide | 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose on Day 27 | 
| Tmax for M1 | Time to maximum observed concentration for M1 metabolite of lomitapide | 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose on Day 27 | 
| AUC0-t for M1 | Area under the plasma concentration versus time curve from hour 0 to the last measurable concentration for M1 metabolite of lomitapide | 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose on Day 27 | 
| t1/2 for M1 | Apparent terminal elimination half-life for M1 metabolite of lomitapide | 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose on Day 27 | 
| Cmax for M3 | Maximum observed plasma concentration for M3 metabolite of lomitapide | 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose on Day 27 | 
| Tmax for M3 | Time to maximum observed concentration for M3 metabolite of lomitapide | 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose on Day 27 | 
| AUC0-t for M3 | Area under the plasma concentration versus time curve from hour 0 to the last measurable concentration for M3 metabolite of lomitapide | 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose on Day 27 | 
| t1/2 for M3 | Apparent terminal elimination half-life for M3 metabolite of lomitapide | 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose on Day 27 |