Date: 2016-09-22
Type of information: Publication of results in a medical journal
phase: 1
Announcement: publication of results in The Lancet
Company: Isis Pharmaceuticals, now Ionis Pharmaceuticals (USA - CA) Akcea Therapeutics (USA - CA)
Product: ISIS-APO(a) Rx, now IONIS-APO(a) Rx
Action
mechanism: antisense oligonucleotide. ISIS-APO(a)Rx is an antisense drug targeting apolipoprotein(a) for the treatment of atherosclerosis. Based on its substantial experience and expertise in developing drugs to treat a variety of lipid disorders, Isis is currently developing ISIS-APO(a)Rx on its own. Apolipoprotein(a) contributes to the formation of plaque in arteries through its attachment to an LDL-C particle in a complex called Lp(a).
Disease: high lipoprotein(a), or Lp(a)
Therapeutic area: Cardiovascular diseases - Metabolic diseases
Country:
Trial details:
Latest
news: * On September. 22, 2016, Akcea Therapeutics, a wholly-owned subsidiary of Ionis Pharmaceuticals, announced the publication in The Lancet of key clinical results of two randomized, controlled studies of IONIS-APO(a)Rx and IONIS-APO(a)-LRx, the company's Lp(a)-lowering drugs designed to treat cardiovascular disease and aortic valve stenosis. Lipoprotein(a), or Lp(a), is an independent, causal, genetic risk factor for cardiovascular disease and aortic valve narrowing (stenosis). In these studies, substantial Lp(a) reductions of up to 99% were noted, regardless of starting Lp(a) levels. In addition, reductions in low-density lipoprotein-cholesterol - (LDL-C) and pro-inflammatory oxidized phospholipids were observed, as well as a decrease in the inflammatory effects of white blood cells, which can initiate and accelerate cardiovascular disease. The paper titled "Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials" (Viney et al., The Lancet) documents the results of two clinical studies testing the safety, tolerability and efficacy of antisense drugs designed to lower elevated Lp(a) levels. The published clinical findings are a result of a partnership with the Sulpizio Cardiovascular Center at the University of California San Diego School of Medicine. The IONIS-APO(a)Rx study is the first randomized clinical study to evaluate a specific Lp(a)-lowering therapy in patients with or at high risk for cardiovascular disease with elevated Lp(a) levels. Treatment with IONIS-APO(a)Rx in patients with high (50-175 mg/dL or 125-437 nmol/L) or very high (>175 mg/dL or >437 nmol/L) Lp(a) levels resulted in a mean reduction in Lp(a) of 67-72%, with up to a 94% reduction. In addition, a significant reduction was noted in pro-inflammatory oxidized phospholipids and the inflammatory effects of monocytes, as well LDL-C. The IONIS-APO(a)-LRx trial studied an optimized and more potent LICA drug that contains a GalNAc moiety that enhances delivery of drug to hepatocytes where Lp(a) is made and assembled. In this first-in-man study, multiple doses of IONIS-APO(a)-LRx resulted in mean reductions in Lp(a) of 66% in the 10 mg group, 80% in the 20 mg group, and 92% in the 40 mg group, and up to a 99% reduction. In these short-term studies, the drug was well tolerated. No side effects were noted in any laboratory tests and there were no injection site reactions. * On July 22, 2015, Isis Pharmaceuticals and Akcea Therapeutics announced that The Lancet has published clinical data evaluating ISIS-APO(a)Rx in healthy volunteers with elevated lipoprotein(a) or Lp(a). An accompanying editorial was also published. The paper titled "Antisense therapy targeting apolipoprotein(a): a randomized, double-blind, placebo-controlled phase 1 study" (Tsimikas et al, The Lancet 2015: published online today), reported data from the Phase 1 study evaluating single and multiple ascending doses of ISIS-APO(a)Rx in healthy volunteers with elevated Lp(a) concentrations of 25 nmol/L (100 mg/L) or more. Results of this study demonstrated potent, dose-dependent, selective reductions of plasma Lp(a) up to 89% (mean reduction up to 78%) in patients treated with ISIS-APO(a)Rx. In addition, up to 90 percent reduction (mean reduction up to 84%) was observed in Lp(a) associated oxidized phospholipids, which play an important role in proinflammatory and proatherogenic processes. The Lp(a) knockdown, together with safety and tolerability support continued clinical development of ISIS-APO(a)Rx as a potential therapeutic drug to reduce the risk of cardiovascular disease and calcific aortic valve stenosis in patients with elevated Lp(a) concentration. Isis and Akcea are currently evaluating ISIS-APO(a)Rx in a Phase 2 study in patients with elevated Lp(a) levels and plan to report data from this study around the year end.
