Mipomersen

Reeskamp LF, et al. Atherosclerosis, 2019, 280, 109-117.

Mipomersen demonstrates efficacy in reducing atherogenic lipoproteins in patients with heterozygous familial hypercholesterolemia (HeFH). This double-blind, randomized trial assessed the safety and efficacy of two dosing regimens-200 mg once weekly and 70 mg thrice weekly-over 60 weeks in 309 HeFH patients with LDL-C >160 mg/dL despite maximal tolerated LDL-lowering therapy.
Both mipomersen regimens significantly reduced low-density lipoprotein cholesterol (LDL-C) by 21.0% and 18.8%, respectively, compared to placebo. ApoB levels decreased by 22.1% (200 mg) and 21.7% (70 mg), while lipoprotein(a) levels were markedly lowered by 27.7% with the thrice-weekly regimen (all p < 0.001). However, the therapeutic benefits were offset by tolerability challenges. Injection-site reactions and flu-like symptoms resulted in discontinuation rates of 21.2% and 17.6% for the 200 mg and 70 mg regimens, respectively, compared to 5.8% in the placebo group. Hepatic transaminase elevation (≥3× upper limit of normal) occurred in approximately 21% of mipomersen-treated patients.
The thrice-weekly regimen was associated with fewer flu-like symptoms, suggesting improved tolerability, though it offered no significant additional efficacy over the once-weekly dosing.
Mipomersen shows promise as an adjunctive therapy for HeFH patients failing to achieve LDL-C targets with standard regimens.

Furtado JD, et al. Journal of Lipid Research, 2012, 53(4), 784-791.

Mipomersen addresses critical pathways in dyslipidemia by inhibiting hepatic synthesis of apolipoprotein B (apoB). This mechanism reduces very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) particles, key contributors to cardiovascular disease (CVD). Clinical investigations have demonstrated its effectiveness in lowering plasma levels of apoB-containing lipoproteins, LDL cholesterol (LDL-C), and triglycerides.
Recent exploratory analyses indicate mipomersen's additional impact on apolipoprotein C-III (apoC-III), a protein that impairs lipoprotein clearance and fosters vascular inflammation. In a phase 2 randomized, controlled trial, mipomersen administered at doses of 100, 200, or 300 mg weekly over 13 weeks significantly reduced total plasma apoC-III levels by 38-42% compared to placebo (p < 0.01). ApoC-III concentrations in both apoB-containing lipoproteins and high-density lipoprotein (HDL) were markedly decreased. Mipomersen also reduced the apoB concentration in LDL particles containing apoC-III by up to 46% (p < 0.05).
The drug achieves these effects without altering apolipoprotein E levels, underscoring its selective action on lipid-regulating pathways. Epidemiological studies link lower levels of apoC-III and apoC-III-containing LDL to reduced coronary heart disease (CHD) risk, highlighting mipomersen's potential to address residual CVD risk in patients with hypercholesterolemia.