Hypercholesterolemia Clinical Trial
Official title:
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.
;
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
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