Isis Pharmaceuticals, Inc., and its subsidiary, Akcea Therapeutics, announced positive results from a phase 2 study of ISIS-APO(a)Rx in which patients with high lipoprotein(a), or Lp(a), achieved reductions in Lp(a) of up to 94 per cent, with a mean reduction of 71 per cent. Lp(a) is a known driver of cardiovascular disease.

They also announced results from a phase 1/2a study of ISIS-APO(a)-LRx in which subjects with elevated Lp(a) achieved dose-dependent reductions in Lp(a) of up to 99 per cent. ISIS-APO(a)-LRx is a LIgand Conjugated Antisense (LICA) version of ISIS-APO(a)Rx. ISIS-APO(a)-LRx demonstrated a greater than 30-fold increase in potency in humans as compared to ISIS-APO(a)Rx. Data from both the phase 2 and phase 1/2a studies were presented at the American Heart Association Scientific Sessions by Joseph Witztum, M.D., distinguished professor of medicine and director of the atherosclerosis research group at the University of California, San Diego.

"Based on strong evidence, it is well accepted that elevated levels of Lp(a) are a key driver of cardiovascular disease. Because Lp(a) levels are largely unchanged throughout a person's lifetime, high Lp(a) levels present at birth can result in cumulative damage, which can be significant throughout the lifetime of a patient. ISIS-APO(a)-LRx is the only drug in clinical development that can specifically and robustly lower Lp(a) in patients with elevated Lp(a)," said Sotirios Tsimikas, M.D., professor of medicine and director of vascular medicine at the University of California, San Diego, and vice president of clinical development at Isis Pharmaceuticals. "In the studies presented today, patients achieved substantial reductions in Lp(a) that were irrespective of their incoming Lp(a) levels. These data support developing ISIS-APO(a)-LRx for patients with high Lp(a), especially patients with the highest Lp(a) levels, who are also at the greatest risk."

In the phase 2 study, patients with high or very high Lp(a) treated with ISIS-APO(a)Rx achieved substantial reductions in Lp(a) of up to 94 per cent with a mean reduction of 71 per cent (p = 0.001). In this study, patients treated with ISIS-APO(a)Rx achieved equal reductions of Lp(a) regardless of incoming Lp(a) levels. The phase 2 study was a randomized, double-blind, placebo-controlled, dose-titration 12 week study evaluating ISIS-APO(a)Rx in 65 patients with Lp(a) levels that were high (greater than or equal to 50 mg/dL and less than 175 mg/dL) or very high (greater than or equal to 175 mg/dL). In this study, treatment with ISIS-APO(a)Rx was generally well tolerated with no safety issues observed.

In the phase 1/2a study, subjects who received a single, low volume, subcutaneous injection of 10 mg, 20 mg, 40 mg or 80 mg of ISIS-APO(a)-LRx achieved robust, dose-dependent and durable reductions of Lp(a). Subjects who received a single dose of 80 mg ISIS-APO(a)-LRx achieved substantial reductions in Lp(a) of up to 97 percent and a mean reduction of 79 per cent (p = 0.01) at 30 days. The long duration of effect resulted in significant Lp(a) reductions of nearly 50 per cent at 90 days after the single dose.

Subjects who received multiple doses of 10 mg, 20 mg or 40 mg of ISIS-APO(a)-LRx achieved dose-dependent, significant reductions in Lp(a) of up to 99 per cent, and a mean reduction of up to 92 per cent (p =0.001). In this study, subjects treated with ISIS-APO(a)-LRx achieved similar reductions of Lp(a) regardless of incoming Lp(a) levels. The safety and tolerability profile of ISIS-APO(a)-LRx to date supports continued development, out of 159 injections, there were no injection site reactions or flu-like symptoms reported.

"The enhanced potency of ISIS-APO(a)-LRx, the opportunity for very infrequent dosing and the good safety and tolerability profile significantly expands the patient populations we plan to pursue for this drug. These data and our experience with ISIS-APO(a)Rx support our plans to rapidly move forward with the development of ISIS-APO(a)-LRx to treat patients with a variety of Lp(a)-driven cardiovascular diseases. We have a robust development programme that addresses near, mid and long-term commercial opportunities for ISIS-APO(a)-LRx by focusing initially on patients who have the greatest need and, in the long-term, on patients with more generalized Lp(a)-driven cardiovascular risk," said Paula Soteropoulos, president and chief executive officer of Akcea Therapeutics.

"Akcea is uniquely positioned to maximize the therapeutic and commercial potential of ISIS-APO(a)-LRx. We plan to rapidly advance this new drug to market for patients with high Lp(a) who have no effective treatment options today."

"ISIS-APO(a)-LRx is greater than 30-fold more potent in humans than the unconjugated drug, ISIS-APO(a)Rx. The significant increase in potency and the longer half-life of the drug support the potential for monthly, quarterly or even less frequent dosing. In addition, ISIS-APO(a)-LRx demonstrates a good tolerability profile. Given these data, we believe that the profile conferred by our LICA technology significantly broadens the patient populations we can target with our LICA drugs by supporting very low volume, infrequent and well tolerated subcutaneous dosing," said Richard Geary, Ph.D., senior vice president of clinical development at Isis Pharmaceuticals.

"We look forward to advancing ISIS-APO(a)-LRx and the seven other LICA drugs we have in our pipeline today and also adding new LICA drugs to our pipeline in the coming years."

ISIS-APO(a)-LRx is a LICA antisense drug, which is part of Isis' lipid franchise and is being developed and commercialised by Akcea Therapeutics, Isis' wholly owned subsidiary.

Lp(a) is considered a key driver 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.