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Ionis Pharmaceuticals, Inc.

Partner : Akcea Therapeutics

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PLEASE SCROLL DOWN TO THE RESULTS SECTION (below) TO SEE THE OUTCOME OF THIS EVENT.

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Stanley T Crooke, MD, PhD, CEO, gave guidance for data from the ISIS-APO(a)Rx phase-II program. He stated, "We plan to complete and report data from the phase-II study on ISIS-APO(a)Rx in patients with elevated Lp(a) levels; and on ISIS-DMPK-2.5Rx in patients with myotonic dystrophy around year-end."
Source: Q4 2014 earnings conference call, 2/27/15.

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Isis Pharmaceuticals Initiates Phase 2 Study of ISIS-APO(a) Rx in Patients with High Lp(a)
CARLSBAD, Calif., July 17, 2014 /PRNewswire/ -- Isis Pharmaceuticals, Inc. (NASDAQ: ISIS) announced the initiation of a Phase 2 study evaluating ISIS-APO(a)Rx in patients with high lipoprotein(a), or Lp(a), an independent risk factor for cardiovascular disease. Patients with high levels of Lp(a) have an increased risk of atherosclerosis, coronary heart disease, aortic stenosis, heart attack and stroke. ISIS-APO(a)Rx is designed to reduce Lp(a) by inhibiting the production of apolipoprotein(a). Isis plans to develop ISIS-APO(a)Rx to treat patients with high Lp(a) levels who are at high risk of experiencing life-threatening cardiovascular events.

Isis Pharmaceuticals, Inc
"Until recently, the importance of evaluating Lp(a) as an independent risk factor for cardiovascular disease was largely underappreciated. Fortunately, there is a growing awareness within the cardiology community about Lp(a) and its role in cardiovascular disease. In fact, there are many patients who, despite having normal levels of LDL-cholesterol, have cardiovascular disease that is primarily caused by high Lp(a) levels. Because elevated Lp(a) is a genetically determined condition that is not responsive to lifestyle changes, patients are unable to adequately control their Lp(a) levels through improved diet or increased physical activity. Although Lp(a) can be measured by a routine lipid blood panel, the lack of drugs to effectively lower Lp(a) has made treating patients with Lp(a)-driven cardiovascular disease difficult," 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 and Leader of Cardiovascular Franchise at Isis. "By inhibiting the production of apolipoprotein(a), ISIS-APO(a)Rx is designed to directly reduce a patient's Lp(a) level, thereby offering a unique and specific approach to treating patients who have high cardiovascular risk due to high Lp(a) levels."

The Phase 2 study is a randomized, placebo-controlled, dose-titration study evaluating the safety and efficacy of ISIS-APO(a)Rx. The 12 week study will evaluate 100 mg, 200 mg and 300 mg doses of ISIS-APO(a)Rx in approximately 60 patients with Lp(a) levels of 50 mg/dL or greater. According to the National Institutes of Health, an average normal Lp(a) level is less than 30 mg/dL and the European Atherosclerosis Society recommends that Lp(a) levels be less than or equal to 50 mg/dL.

"We believe that ISIS-APO(a)Rx is the first drug specifically designed to treat patients with Lp(a)-caused cardiovascular disease. Because we do not expect ISIS-APO(a)Rx to have any drug-drug interactions with standard-of-care drugs, we believe that ISIS-APO(a)Rx could be added to the many other medications taken by patients with cardiovascular disease. In our Phase 1 study in healthy volunteers, we observed robust, dose-dependent reductions in Lp(a)," said Walter Singleton, M.D., vice president of development and chief medical officer at Isis. "We look forward to evaluating ISIS-APO(a)Rx in patients with cardiovascular disease and high Lp(a) levels."

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). Currently there are no drugs on the market that can effectively lower elevated Lp(a) to recommended Lp(a) levels. Isis plans to develop ISIS-APO(a)Rx to treat patients with high Lp(a) levels who have either coronary heart disease or aortic stenosis. Both of these groups of patients are at high risk of cardiovascular events. ISIS-APO(a)Rx is part of Isis' cardiovascular disease franchise comprised of drugs that target many of the key components of cardiovascular disease, including various atherogenic lipids, inflammation and thrombosis.
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Source: press release, 7/17/14. http://ir.isispharm.com/phoenix.zhtml?c=222170&p=irol-newsArticle&ID=194...

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A Randomized, Double Blind, Placebo-Controlled, Dose Titration, Phase 2 Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ISIS 494372 Administered Subcutaneously to Patients With High Lipoprotein(a)
Estimated Enrollment: 60
Study Start Date: June 2014
Estimated Study Completion Date: August 2016
Estimated Primary Completion Date: March 2016 (Final data collection date for primary outcome measure)
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Source: clinical trials.gov. http://clinicaltrials.gov/ct2/show/NCT02160899?term=APO&rank=4

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Compound/DeviceSpecialtyIndicationCompound ClassTarget
IONIS-APOARxCardiovascularAtherosclerosisapo(a) inhibitorapo(A)

Mechanism of action: IONIS-APOARx is an antisense drug that inhibits the production of apo(a) in the liver and is designed to offer a direct approach to reducing Lp(a), an independent risk factor for cardiovascular disease. High levels of Lp(a) are associated with an increased risk of atherosclerosis, coronary heart disease, heart attack and stroke. Lp(a) promotes premature plaque buildup, or atherosclerosis, in arteries.

Phase of Development: II

Event Type: Data: Phase II trial results

Dates: 2015-11-01 - 2015-12-31

Results:

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Isis Pharmaceuticals Reports Positive Clinical Data From Lp(a) Lowering Drugs

Webcast to review data scheduled for Sunday, November 8 at 1:00 p.m. Eastern Time

CARLSBAD, Calif., and CAMBRIDGE, Mass., Nov. 8, 2015 /PRNewswire/ -- Isis Pharmaceuticals, Inc. (NASDAQ: ISIS), and its subsidiary, Akcea Therapeutics, today 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 percent, with a mean reduction of 71 percent. 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 percent. 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 today 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.

Isis Pharmaceuticals, Inc.
"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."

Significant Reductions of Lp(a) in Phase 2 Study of ISIS-APO(a)Rx
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 percent with a mean reduction of 71 percent (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.

Significant, Sustained Lp(a) Reduction in Phase 1/2a Study of ISIS-APO(a)-LRx
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 percent (p ≤ 0.01) at 30 days. The long duration of effect resulted in significant Lp(a) reductions of nearly 50 percent 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 percent, and a mean reduction of up to 92 percent (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 program 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 commercialized by Akcea Therapeutics, Isis' wholly owned subsidiary.
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Source: press release, 11/08/15. http://ir.isispharm.com/phoenix.zhtml?c=222170&p=irol-newsArticle&ID=211...

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