Positive Clinical Data From Lp(a) Lowering Drug ISIS-APO(a) Rx Published in The Lancet

Publication highlights importance of Lp(a) as a risk factor for cardiovascular disease and the therapeutic potential of antisense drugs 

CARLSBAD, Calif. and CAMBRIDGE, Mass., Isis Pharmaceuticals, the leader in RNA-targeted therapeutics, and Akcea Therapeutics announced today 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.  ISIS-APO(a)_Rx is a Generation 2.0+ antisense drug that is part of Isis' lipid franchise, which is being developed and commercialized by Akcea Therapeutics, Isis' wholly owned subsidiary.  

"Although not as widely recognized as LDL-cholesterol, a growing body of scientific and medical evidence has identified Lp(a) as an important and independent, genetically caused risk factor for cardiovascular disease," said Joseph Witztum, M.D., distinguished professor of medicine and director of the atherosclerosis research group at the University of California, San Diego and co-author on the paper. "There is no drug available today to specifically and effectively lower elevated Lp(a) levels in patients with high Lp(a) levels. The publication of these study results today in The Lancet shows the therapeutic potential of antisense drugs, such as ISIS-APO(a)_Rx, to specifically affect important, newly identified therapeutic targets like Lp(a)."

"The introduction of a selective Lp(a)-lowering therapy is very exciting," said Erik Stroes, M.D., Ph.D., professor of internal medicine, department of vascular medicine, University of Amsterdam. "It is estimated that up to 20% of the population have elevated Lp(a) levels that put them at higher risk for cardiovascular disease but because there has been no therapeutic option for lowering elevated Lp(a) levels, most healthcare providers have not been monitoring this important risk factor. However, the availability of a therapeutic agent capable of lowering Lp(a) should lead to the widespread testing of Lp(a) levels."

"Several seminal publications over the past five years, including human genetic studies, have established Lp(a) as an important risk factor for cardiovascular disease. It is a testament to the efficiency of antisense technology that we were able to create ISIS-APO(a)_Rx and advance it into human clinical trials so rapidly. We are looking forward to the results from our Phase 2 clinical trials in patients with very high Lp(a) later this year," saidRosanne M. Crooke, vice president of cardiovascular research at Isis Pharmaceuticals.  "ISIS-APO(a)_Rx is a Generation 2.0+ antisense drug that specifically and potently reduces  Lp(a) without affecting other lipoproteins."

"ISIS-APO(a)_Rx, as well as its next generation LICA version, ISIS-APO(a)-L_Rx, are the first drugs in development to directly target Lp(a), and among the various drugs in the Akcea pipeline to treat patients with serious cardiometabolic lipid disorders," said Paula Soteropoulos, president and chief executive officer of Akcea Therapeutics. "Akcea is uniquely positioned to drive development and rapidly advance these drugs to market for these patients who are underserved with today's therapies."

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. Isis and Akcea are also developing ISIS-APO(a)-L_Rx.

ABOUT Lp(a) 
Lp(a) is considered an independent risk factor for cardiovascular disease due to its association with an increased risk of coronary heart disease, atherosclerotic plaque formation and calcific aortic valve stenosis.  Lp(a) is a lipoprotein particle that is assembled in the liver and consists of the apolipoprotein(a) protein covalently linked to LDL-cholesterol.  Lp(a) levels in blood can vary greatly between individuals due primarily to genetic variations in the gene that encodes for apolipoprotein(a).  As a result, Lp(a) levels are genetically determined and remain constant throughout the life of the individual.  Diet and lifestyle changes have little impact on Lp(a) levels and current therapies are not able to adequately reduce elevated levels of Lp(a) to acceptable levels in patients who have severely elevated Lp(a).  As a general guideline for ideal Lp(a) levels, the European Atherosclerosis Society recommends that Lp(a) levels be less than or equal to 50 mg/dL. 

Source:  Isis Pharmaceuticals, Inc