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