Safety and Efficacy Study of ISIS 301012 (Mipomersen) Administration in High Risk Statin Intolerant Subjects (ASSIST)

Safety and Efficacy Study of ISIS 301012 (Mipomersen) Administration in High Risk Statin Intolerant Subjects

A Randomized, Double-Blind, Placebo-Controlled Study to Assess Safety and Efficacy of ISIS 301012 Administration in High Risk Statin Intolerant Subjects

The purpose of this study is to determine safety and efficacy of mipomersen (ISIS 301012) in the reduction of total cholesterol, low density lipoprotein cholesterol (LDL-C), and apolipoprotein B (apoB) in high risk subjects intolerant to statins.

In humans, apoB is the principal apolipoprotein of the atherogenic lipoproteins, comprising very low-density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and low density lipoprotein (LDL). ApoB messenger ribonucleic acid (mRNA) is abundantly present in the liver. Within the endoplasmatic reticulum, apoB requires lipidation by microsomal triglyceride transfer protein, which allows apoB to be incorporated in the VLDL particle within the lumen of the endoplasmatic reticulum. Non-lipidated apoB is readily degraded via ubiquitination. Notably, apoB within the VLDL particle is obligatory for hepatic secretion of VLDL. ApoB remains present within the VLDL-metabolism pathway, from secretion to clearance of the end product LDL by the liver LDL receptor. As a consequence, apoB reliably reflects the total burden of atherogenic lipoproteins. Thus, apoB carries strong prognostic value for cardiovascular events, which exceeds the predictive value of LDL-C. Conversely, decreased levels of apoB (e.g. in familial hypobetalipoproteinemia) have been associated with reduced levels of atherosclerosis. These genetic observations have prompted interest in pharmacologic inhibition of apoB synthesis. Mipomersen (ISIS 301012) is an antisense drug targeted to human apoB, the principal apolipoprotein of LDL and its metabolic precursor, VLDL. Mipomersen (ISIS 301012) is complementary to the coding region of the mRNA for apoB, binding by Watson and Crick base pairing. The hybridization (binding) of mipomersen (ISIS 301012) to the cognate mRNA results in Ribonuclease (RNase) H-mediated degradation of the cognate mRNA, thus inhibiting translation of the apoB protein. This was a randomized, double-blind, placebo-controlled Phase 2 study to assess the safety and efficacy of mipomersen administration in high-risk statin-intolerant patients with hypercholesterolemia. This study consisted of a ≤3-week screening period, 26 weeks of treatment, and a 24-week post-treatment follow-up period. Eligible patients were randomized in a 2:1 ratio to receive mipomersen 200 mg or matching volume placebo subcutaneous (SC) injections weekly. Following the screening visit, eligible patients returned to the study center for clinical evaluation every week for study drug administration and assessments.

Metabolic Diseases, Hyperlipidemias, Metabolic Disorder, Hypercholesterolemia, Dyslipidemias, Lipid Metabolism Disorders

Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) at the Primary Efficacy Time Point

LDL-C was measured in mg/dL. Samples were taken following an overnight fast. For patients with triglycerides <400 mg/dL, LDL-C was obtained using Friedewald's calculation; and for patients with triglycerides ≥400 mg/dL, LDL-C was directly measured by the central laboratory using ultracentrifugation. The primary efficacy time point was the post-baseline visit closest to 14 days after the last dose of study treatment.

Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose).

The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment.

Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose).

The on-treatment time frame spanned the time during which the study drug was administered until the later of the primary efficacy time point and 14 days beyond the last study drug date. Adverse events (AEs) were considered related if assessed by the Investigator as possibly, probably or definitely related to study drug. Severity was assessed as: Mild-symptom barely noticeable to the patient or do not make the patient uncomfortable; Moderate-symptom makes the patient uncomfortable, affects performance of daily activities; Severe-symptom causes the patient severe discomfort, may cause cessation of treatment with the study drug. Serious AEs (SAEs) are those that resulted in death, were life-threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant disability/incapacity, congenital anomaly, or resulted in an important medical event that may have jeopardized the patient or required medical or surgical intervention.

Apolipoprotein B was measured in mg/dL. Samples were taken following an overnight fast. The primary efficacy time point was the post-baseline visit closest to 14 days after the last dose of study treatment.

Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose).

The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment.

Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose).

Total cholesterol was measured in mg/dL. Samples were taken following an overnight fast. The primary efficacy time point was the post-baseline visit closest to 14 days after the last dose of study treatment.

Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose).

The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment.

Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose).

Percent Change From Baseline in Non-High-Density Lipoprotein Cholesterol at the Primary Efficacy Time Point

Non-high-density lipoprotein cholesterol was measured in mg/dL. Samples were taken following an overnight fast. The primary efficacy time point was the post-baseline visit closest to 14 days after the last dose of study treatment.

Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose).

The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment.

Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose).

Triglycerides were measured in mg/dL. Samples were taken following an overnight fast. The primary efficacy time point was the post-baseline visit closest to 14 days after the last dose of study treatment.

Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose).

The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment.

Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose).

Lipoprotein (a) was measured in mg/dL. Samples were taken following an overnight fast. The primary efficacy time point was the post-baseline visit closest to 14 days after the last dose of study treatment.

Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose).

The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment.

Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose).

Percent Change From Baseline in Very Low Density Lipoprotein Cholesterol at the Primary Efficacy Time Point

Very low density lipoprotein cholesterol was measured in mg/dL. Samples were taken following an overnight fast. The primary efficacy time point was the post-baseline visit closest to 14 days after the last dose of study treatment.

Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose).

The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment.

Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose).

Percent Change From Baseline in the Ratio of Low-Density Lipoprotein Cholesterol to High-Density Lipoprotein Cholesterol at the Primary Efficacy Time Point

The ratio of low-density lipoprotein (LDL) cholesterol to high-density lipoprotein (HDL) cholesterol was measured in mg/dL. Samples were taken following an overnight fast. The primary efficacy time point was the post-baseline visit closest to 14 days after the last dose of study treatment.

Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose).

Ratio of Low-Density Lipoprotein Cholesterol to High-Density Lipoprotein Cholesterol at Baseline and at the Primary Efficacy Time Point

The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment.

Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose).

Apolipoprotein A1 was measured in mg/dL. Samples were taken following an overnight fast. The primary efficacy time point was the post-baseline visit closest to 14 days after the last dose of study treatment.

Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose).

The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment.

Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose).

Percent Change From Baseline in High-Density Lipoprotein Cholesterol at the Primary Efficacy Time Point

High-density lipoprotein cholesterol (HDL-C) was measured in mg/dL. Samples were taken following an overnight fast. The primary efficacy time point was the post-baseline visit closest to 14 days after the last dose of study treatment.

Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose).

The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment.

Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose).

Inclusion Criteria: Diagnosis of statin intolerance Diagnosis of Coronary Artery Disease (CAD) Diagnosis of hypercholesterolemia Stable weight for > 6 weeks Exclusion Criteria: Significant health problems in the recent past (≤24 weeks) including heart attack, heart surgery, heart failure, uncontrolled hypothyroidism, blood disorders, digestive problems, disease of central nervous system, cancer, liver or renal disease

Visser ME, Wagener G, Baker BF, Geary RS, Donovan JM, Beuers UH, Nederveen AJ, Verheij J, Trip MD, Basart DC, Kastelein JJ, Stroes ES. Mipomersen, an apolipoprotein B synthesis inhibitor, lowers low-density lipoprotein cholesterol in high-risk statin-intolerant patients: a randomized, double-blind, placebo-controlled trial. Eur Heart J. 2012 May;33(9):1142-9. doi: 10.1093/eurheartj/ehs023. Epub 2012 Apr 16.

Patel N, Hegele RA. Mipomersen as a potential adjunctive therapy for hypercholesterolemia. Expert Opin Pharmacother. 2010 Oct;11(15):2569-72. doi: 10.1517/14656566.2010.512006.