Mipomersen Sodium: First Global Approval

Abstract

Mipomersen sodium (Kynamro™) (henceforth mipomersen) is a second-generation antisense oligonucleotide inhibitor of apolipoprotein B-100, which is the main structural component of atherogenic lipid particles. Mipomersen is administered via subcutaneous injection and is indicated as adjunctive treatment for homozygous familial hypercholesterolaemia (HoFH). The drug was developed by Isis Pharmaceuticals, which now collaborates with Genzyme Corporation for on-going development and product marketing. Multinational phase III trials of mipomersen as adjunctive therapy were completed in patients with HoFH, severe FH, heterozygous FH (HeFH) with coronary artery disease (CAD), and in those with hypercholesterolaemia at high risk of CAD. Mipomersen 200 mg once weekly has been approved in the USA as an adjunct to lipid-lowering medications and diet in HoFH patients and is undergoing regulatory review in the EU for the same indication. Genzyme is also conducting a multinational phase III, open-label extension study to evaluate long-term treatment in HoFH and HeFH patients, as well as a multinational trial to evaluate a three-times-per-week mipomersen regimen in patients with severe FH. This article summarises the milestones in the development of once-weekly, subcutaneous mipomersen leading to this first approval.

The delivery of therapeutic oligonucleotides

“…This is due to the convergence of several developments including improved chemistries, better understanding of the basic biology of oligonucleotides, more sophisticated delivery systems and most importantly, increasing success in the clinic. The 2013 approval of the first major antisense drug, Kynamro ® (2), an inhibitor of apolipoprotein B expression, was accompanied by promising clinical trials involving siRNA (3) and splice switching oligonucleotides (SSOs) (4). More recently, a number of clinical trials utilizing various types of oligonucleotides have reported impressive results.…”

Caged oligonucleotides for studying biological systems

“…In 2013, the FDA approved the second RNA-based drug, mipomersen, which is a 2′-O-methoxyethyl phosphorothioate antisense oligonucleotide targeting apolipoprotein B expressed in the liver [74]. By reducing the amount of this protein that is secreted from the liver into the blood stream, mipomersen successfully decreases low-density lipoprotein cholesterol levels in patients with homozygous familial hypercholesterolemia [75].…”

Emerging treatments for amyloidosis

“…[56][57][58] ISIS-TTR RX is a second-generation chimeric antisense inhibitor of TTR. It binds selectively and with high affinity to the nontranslated portion of the human TTR mRNA and results in its degradation, preventing production of both wt and variant TTR protein.…”