Apolipoprotein B synthesis inhibition: results from clinical trials.
OBJECTIVE
Mipomersen is a second-generation antisense oligonucleotide developed to inhibit the synthesis of apolipoprotein B-100 in the liver. In this review we will summarize the results of recent preclinical and clinical studies addressing safety and low-density lipoprotein-cholesterol (LDL-c) lowering efficacy of this new compound.


RESULTS
In phase 3 clinical trials, mipomersen has been shown to significantly reduce LDL-c in patients with homozygous and heterozygous familial hypercholesterolemia on maximally tolerated lipid-lowering therapy. Injection site reactions, flu-like symptoms and increases in liver transaminases were the main adverse events. A recent safety study, designed to investigate the effects of mipomersen on intrahepatic triglyceride content, failed to show evidence of clinically relevant hepatic steatosis after 13 weeks of treatment.


CONCLUSIONS
Mipomersen is a new agent to lower LDL-c in patients at increased risk of cardiovascular disease and/or intolerant to statins. Whereas safety concerns have focused on hepatic fat accumulation, to date no evidence of clinically relevant increases of intrahepatic triglyceride content are reported. Ongoing and future studies are eagerly awaited to assess the impact of mipomersen on hepatic triglyceride content after prolonged exposure.
Visser
Maartje E
ME
Department of Vascular Medicine, Academic Medical Center Amsterdam, The Netherlands.
Kastelein
John J P
JJ
Stroes
Erik S G
ES
D000818:Animals; D001055:Apolipoproteins B / Q000096:biosynthesis* / Q000378:metabolism; D002986:Clinical Trials as Topic; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D009841:Oligonucleotides / Q000009:adverse effects / Q000494:pharmacology; D014176:Protein Biosynthesis / Q000187:drug effects*
D001055:Apolipoproteins B; D009841:Oligonucleotides; C524142:mipomersen