Research in context
Evidence before this study
We searched PubMed and ClinicalTrials.gov without language restrictions for trials published between Jan 1, 1990, and Feb 1, 2015, using the search terms “Lp(a)”, “lipoprotein(a)”, and “lipoprotein (a)”. No randomised controlled trials could be identified that randomly assigned a specific medical therapy that lowers only lipoprotein(a) (Lp[a]) versus placebo in patients with increased Lp(a) concentrations. Findings from the Specific Lp(a) Apheresis for Regression of Coronary and Carotid Atherosclerosis (LaRCA) study (NCT02133807) showed potent reductions of Lp(a) with an Lp(a)-specific apheresis column and angiographic evidence of atheroma regression. The Lipoprotein Apheresis in Refractory Angina study (NCT01796912) recruited patients with refractory angina and Lp(a) concentrations greater than 50 mg/dL (125 nmol/L) and LDL-C concentrations less than 80 mg/dL (2·072 nmol/L). Drugs with multiple effects on lipoproteins are being tested in trials with patients who have increased plasma Lp(a) concentrations. For example, the Early Aortic Valve Lipoprotein(a) Lowering Trial (EAVaLL, NCT02109614) is assessing niacin (nicotinic acid) versus placebo in patients with aortic sclerosis, and the study on the effects of TA-8995 on Lp(a) in patients with increased Lp(a) (NCT02241772) is assessing a cholesteryl ester transfer protein inhibitor.
Added value of this study
Antisense therapy is based on a unique pharmacological mechanism to mediate therapeutic effects, and joins small molecules and monoclonal antibodies as a third platform to modulate targets for therapeutic purposes. Its unique mechanism is to lower plasma Lp(a) concentrations by directly binding to apolipoprotein(a) (apo[a]) mRNA in the nucleus of hepatocytes, which then leads to destruction of the antisense:mRNA complex by RNase H1 and the specific inhibition of apo(a) synthesis. Lp(a) has no known enzymatic activity, and how it becomes degraded or causes atherosclerosis is unknown. Thus, it would be very difficult to develop a small molecule to either affect Lp(a) plasma concentrations or affect its atherogenic properties. Furthermore, Lp(a) cannot be easily targeted with biological drugs, such as monoclonal antibodies, because of the wide variability in plasma concentrations between individuals and its overall high plasma concentrations. Thus, the use of a second-generation antisense drug to inhibit apo(a) synthesis is theoretically an ideal mechanistic approach to reduce Lp(a) concentrations.
Implications of all the available evidence
The specialty of RNA therapeutics, and antisense drugs in particular, is a rapidly emerging field with about 50 companies developing drugs that target more than 150 disease-associated proteins. Only one RNA therapeutic (a second-generation antisense drug), Kynamro, which targets the production of apoB-100, is approved in the USA for the treatment of homozygous familial hypercholesterolaemia. However, there are multiple ongoing phase 1–3 trials of drugs that target RNA. ISIS-APO(a)Rx will allow the testing of the hypothesis that the reduction of Lp(a), without affecting other lipoproteins, will lead to therapeutic benefit.