Clinical pharmacological properties of mipomersen (Kynamro), a second generation antisense inhibitor of apolipoprotein B.
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TLDR
Mipomersen reduces all apolipoprotein B containing atherogenic particles and displays dose dependent reductions between 50–400 mg week−1, both as a single agent and in the presence of maximal lipid lowering therapy.Abstract:
Mipomersen is a second generation antisense oligonucleotide that targets apolipoprotein B. It has been studied thoroughly in clinical trials (more than 800 subjects), including four randomized double-blind placebo controlled phase 3 studies involving 391 patients, and is in registration for the treatment of severe hypercholesterolaemia. The pharmacokinetic and pharmacodynamic properties of mipomersen are well characterized. Mipomersen is rapidly and extensively absorbed after subcutaneous administration and has an elimination half-life of approximately 30 days across species. It is cleared by nuclease metabolism and renal excretion of the metabolites. Mipomersen reduces all apolipoprotein B containing atherogenic particles and displays dose dependent reductions between 50-400 mg week⁻¹ , both as a single agent and in the presence of maximal lipid lowering therapy. No drug-drug interactions have been identified. Mipomersen is a representative of second generation antisense drugs, all of which have similar properties, and is thus representative of the behaviour of the class of drugs.read more
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References
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Journal ArticleDOI
Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial.
Frederick J. Raal,Raul D. Santos,Dirk J. Blom,A. David Marais,Min-Ji Charng,William C. Cromwell,Robin H. Lachmann,Daniel Gaudet,Ju L. Tan,Scott Chasan-Taber,Diane Tribble,JoAnn Flaim,Stanley T. Crooke +12 more
TL;DR: Inhibition of apolipoprotein B synthesis by mipomersen represents a novel, effective therapy to reduce LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia who are already receiving lipid-lowering drugs, including high-dose statins.
Journal ArticleDOI
Potent Reduction of Apolipoprotein B and Low-Density Lipoprotein Cholesterol by Short-Term Administration of an Antisense Inhibitor of Apolipoprotein B
John J.P. Kastelein,Mark Wedel,Brenda F. Baker,John Su,Joann D. Bradley,Rosie Z. Yu,Emil Chuang,Mark J. Graham,Rosanne M. Crooke +8 more
TL;DR: Although injection-site reactions were common, adherence to protocol was unaffected, and Administration of an antisense oligonucleotide to human apoB resulted in a significant, prolonged, and dose-dependent reduction in apolipoprotein B and LDL-C.
Journal ArticleDOI
Apolipoprotein B: mRNA Editing, Lipoprotein Assembly, and Presecretory Degradation
TL;DR: Although control of lipid secretion in vivo is primarily achieved at the level of lipoprotein particle size, regulation of apoB production by presecretory degradation may be relevant in some dyslipidemic states.
Journal ArticleDOI
An apolipoprotein B antisense oligonucleotide lowers LDL cholesterol in hyperlipidemic mice without causing hepatic steatosis
Rosanne M. Crooke,Mark J. Graham,Kristina M. Lemonidis,Charles P. Whipple,Seonjoon Koo,Ranjan J. Perera +5 more
TL;DR: Findings, as well as those derived from interim phase I data with a human apoB-100 antisense drug, suggest that antisense inhibition of this target may be a safe and effective approach for the treatment of humans with hyperlipidemia.
Journal ArticleDOI
Cross-species pharmacokinetic comparison from mouse to man of a second-generation antisense oligonucleotide, ISIS 301012, targeting human apolipoprotein B-100
TL;DR: The pharmacokinetic properties of ISIS 301012 provide guidance for clinical development and support infrequent dose administration, as demonstrated by 32% of dose recovered in total excreta by 14 days in a rat mass balance study.
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