Isis Reports Positive Phase 1 Data Demonstrating ISIS-APOCIIIRx Produces Significant Reductions in apoC-III Protein Levels and Triglycerides

CARLSBAD, Calif., Dec. 6, 2011 /PRNewswire/ -- Isis Pharmaceuticals, Inc. (NASDAQ: ISIS) announced today positive results from a Phase 1 study with ISIS-APOCIIIRx.  The results demonstrated that ISIS-APOCIIIRx treatment produced rapid, dose-dependent reductions of up to 78 percent in apolipoprotein C-III (apoC-III) protein and up to 44 percent in blood triglyceride levels.  In this study, the drug also demonstrated a good safety profile and was well tolerated.  These data will be presented today at the Cold Spring Harbor Laboratory 2^nd RNA Therapeutics conference in New York.  

"Patients with high levels of triglycerides are at significant risk of cardiovascular disease even if LDL-cholesterol levels are within acceptable/normal levels.   High-risk patients, such as those with diabetes or metabolic syndrome, may also benefit from lowering their triglycerides.  Unfortunately the needs of these patients are not adequately met and new treatment options are needed," said Frank Sacks, M.D., Professor of Cardiovascular Disease Prevention, Harvard School of Public Health. "ApoC-III itself is a pro-inflammatory protein and a key atherogenic lipid particle.  In addition, recent data suggest that the inclusion of apoC-III in LDL particles increases their atherogenicity and therefore increases the risk of coronary artery disease.  The combined benefit of lowering both apoC-III and triglycerides could potentially exceed that observed with current therapies that only reduce triglycerides."

The Phase 1 study of ISIS-APOCIIIRx was a blinded, randomized, placebo-controlled, dose-escalation study designed to assess the safety and pharmacokinetic profile of ISIS-APOCIIIRx in healthy volunteers and to assess the initial effects of the drug on baseline apoC-III and triglyceride levels.  ISIS-APOCIIIRx was evaluated in single and multiple doses ranging from 50 mg per week up to 400 mg per week in 32 subjects.  

After only four weeks of dosing, subjects in the 200 mg and 400 mg multiple-dose cohorts displayed a median reduction of 71 percent and 78 percent in apoC-III levels, respectively, with two of the three treated subjects at the 400 mg dose reaching undetectable levels of apoC-III.  Additionally, in the 200 mg and 400 mg dose cohorts, subjects that received ISIS-APOCIIIRx had a median reduction in blood triglyceride levels of 43 percent and 44 percent, respectively, from baseline.  These statistically significant reductions were sustained for up to four weeks after the last dose.  ISIS-APOCIIIRx demonstrated a good safety profile and was well tolerated in all subjects with no clinically meaningful elevations of transaminase enzymes and no significant adverse events.  Isis will report the full data from this study at an upcoming scientific conference in 2012.

"In this Phase 1 study we observed substantial dose-dependent reductions of apoC-III protein and triglycerides, two independent risk factors for cardiovascular disease.   This is very encouraging data and underscores the therapeutic potential that a selective apoC-III inhibitor could offer patients with elevated levels of triglycerides and other atherogenic lipids, such as apoC-III.  In addition, since ISIS-APOCIIIRx specifically reduces apoC-III, it should substantially reduce triglycerides without the undesirable side effects that are associated with current therapies," said Walter Singleton, M.D., Vice President, Development and Chief Medical Officer at Isis.  "ISIS-APOCIIIRx is a key component of our cardiovascular franchise strategy to treat all aspects of cardiovascular disease by targeting pro-inflammatory and other atherogenic particles.  We plan to initiate a proof-of-concept Phase 2 study evaluating the efficacy of ISIS-APOCIIIRx in treatment-naive patients with elevated triglycerides, which will begin in 2012."

ABOUT ISIS-APOCIIIRx
ISIS-APOCIIIRx targets apoC-III, a gene produced in the liver that plays a central role in the regulation of serum triglycerides.  Humans who do not produce apoC-III have lower levels of triglycerides and lower instances of cardiovascular disease.  ApoC-III is increased in patients with dyslipidemia associated with multiple metabolic abnormalities, such as insulin resistance and/or metabolic syndrome.  In clinical studies, patients with lower levels of apoC-III and triglycerides exhibit lower cardiovascular event rates.  In addition, apoC-III mediates insulin resistance, leading to worsening of the metabolic syndrome. 

ABOUT ISIS PHARMACEUTICALS, INC.
Isis is exploiting its leadership position in antisense technology to discover and develop novel drugs for its product pipeline and for its partners.  Isis' broad pipeline consists of 25 drugs to treat a wide variety of diseases with an emphasis on cardiovascular, metabolic and severe and rare/neurodegenerative diseases, and cancer.  Isis' partner, Genzyme, plans to commercialize Isis' lead product, mipomersen, following regulatory approval, which is expected in 2012.  Isis' patents provide strong and extensive protection for its drugs and technology.  Additional information about Isis is available at www.isispharm.com.

ISIS PHARMACEUTICALS' FORWARD-LOOKING STATEMENT
This press release includes forward-looking statements regarding the discovery, development and potential of drugs for cardiovascular diseases, and the development, activity, therapeutic potential and safety of ISIS-APOCIIIRx. Any statement describing Isis' goals, expectations, financial or other projections, intentions or beliefs, including the planned commercialization of mipomersen, is a forward-looking statement and should be considered an at-risk statement.  Such statements are subject to certain risks and uncertainties, particularly those inherent in the process of discovering, developing and commercializing drugs that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such drugs.  Isis' forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause its results to differ materially from those expressed or implied by such forward-looking statements.  Although Isis' forward-looking statements reflect the good faith judgment of its management, these statements are based only on facts and factors currently known by Isis.  As a result, you are cautioned not to rely on these forward-looking statements.  These and other risks concerning Isis' programs are described in additional detail in Isis' annual report on Form 10-K for the year ended December 31, 2010 and its most recent quarterly report on Form 10-Q, which are on file with the SEC. Copies of these and other documents are available from the Company.

In this press release, unless the context requires otherwise, "Isis," "Company," "we," "our," and "us" refers to Isis Pharmaceuticals and its subsidiaries, including Regulus Therapeutics Inc., its jointly owned subsidiary.

Isis Pharmaceuticals® is a registered trademark of Isis Pharmaceuticals, Inc. 

SOURCE Isis Pharmaceuticals, Inc.