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Isis Reports Final Phase 2 Data on ISIS-APOCIII Rx

David Johnson

Isis Pharmaceuticals, Inc. (NASDAQ: ISIS) announced the final results from its Phase 2 study of ISIS-APOCIIIRx in patients with high to severely high triglycerides on stable doses of fibrates. In this study, patients treated with ISIS-APOCIIIRx achieved average reductions of up to 71 percent in apolipoprotein C-III (apoC-III) and up to 64 percent in triglycerides, and average increases of up to 52 percent in high-density lipoprotein cholesterol (HDL-C), the 'good' cholesterol. While the starting average triglyceride level in the 300 mg group was 384 mg/dL, 70% of these patients reduced their triglyceride level to below the normal level of 150 mg/dL. In addition, lipoprotein particle analysis showed significant dose-dependent reductions in the number of very low-density lipoprotein (VLDL) particles and significant increases in the number of HDL particles. These new data for ISIS-APOCIIIRx were presented today by Dr. Vickie Alexander at the American College of Cardiology meeting in Washington DC.

Isis Pharmaceuticals, Inc "Fibrates are widely used to lower triglyceride levels, but this therapy is frequently not sufficiently effective and new and better therapies are needed," said Joseph L. Witztum, M.D., professor of medicine at the University of California, San Diego. "In this new study, ISIS-APOCIIIRx was shown to robustly lower both plasma apoC-III and triglycerides, and raise HDL cholesterol levels, even in subjects who were already on standard doses of fibrate therapy. This ability of ISIS-APOCIIIRx to positively impact these parameters should significantly enhance the profile of the drug to treat patients with severely elevated triglycerides."

The Phase 2 study of ISIS-APOCIIIRx was a double-blind, randomized, placebo-controlled 13 week study designed to assess the safety and activity of 200 mg and 300 mg doses of ISIS-APOCIIIRx. The data reported today are the final data analysis (including treatment and follow up period through day 176) in patients with high to severely high triglyceride levels on stable doses of fibrates. Isis reported an interim analysis of these data in July 2013. Consistent with the interim analysis, ISIS-APOCIIIRx produced statistically significant mean percent reductions from baseline in triglycerides and apoC-III and apoC-III-associated VLDL in both dose cohorts. Furthermore, patients treated with ISIS-APOCIIIRx demonstrated a rapid, prolonged and statistically significant mean percent increase from baseline in HDL-cholesterol in both dose cohorts. The effects of ISIS-APOCIIIRx observed on these lipid parameters were sustained for at least six weeks after the last dose and in addition to those achieved with each patient's existing therapeutic regimen of fibrates.

Table 1: ISIS-APOCIIIRx Produced Statistically Significant Reductions of Triglycerides, ApoC-III and ApoC-III Associated VLDL in a Phase 2 Study in Patients with High Triglyceride Levels Treated With Stable Doses of Fibrates. Mean % Changes From Baseline at Primary Endpoint.

Placebo + Fibrate

(n=8) ISIS-APOCIIIRx 200 mg + Fibrate (n=8) ISIS-APOCIIIRx 300 mg + Fibrate (n=10) ApoC-III -2% -60% (p<0.001) -71% (p<0.001) Triglycerides

[% patients achieving triglyceride level <150 mg/dL] -8%

[0%] -51% (p=0.008)

[63%] -64% (p=0.002)

[70%] ApoC-III VLDL +8% -66% (p<0.001) -77% (p<0.001) HDL-C +6% +51% (p=0.02) +52% (p=0.008) P value = vs. placebo + fibrate.

In addition to measuring changes in lipoprotein cholesterol levels in the blood, changes in lipoprotein particle numbers were evaluated in these patients. In this study, patients treated with ISIS-APOCIIIRx demonstrated dose-dependent reductions in atherogenic particle numbers and increases in HDL-C particle numbers compared to placebo. These results are consistent with the observed changes in lipoprotein cholesterol levels in the blood and provide further evidence of enhanced clearance of triglycerides associated with reduction of apoC-III.

In this study 28 patients received either 200 mg or 300 mg dose of ISIS-APOCIIIRx or placebo via weekly subcutaneous injections. All patients were on stable doses of fibrates with average baseline levels of fasting triglycerides between 282 and 457 mg/dL. The three groups of patients were reasonably well balanced in baseline characteristics. In this study, ISIS-APOCIIIRx was found to be generally safe and well tolerated. The most common adverse event was injection site reactions, which were infrequent and consisted of mild erythema that typically resolved within one to two days. In this study, there were no flu-like symptoms, no elevations of liver enzymes greater than three times upper limit of normal, no abnormalities in renal function and no clinically meaningful changes in other laboratory values. As previously reported in July, there was one treatment-related serious adverse event reported, which resolved completely.

"We have shown that ISIS-APOCIIIRx has lowered triglycerides equally well in patients with high to severely high triglycerides as well as in patients with high triglycerides and type 2 diabetes. We observed significant reductions in apoC-III and triglycerides and increased HDL-C both when ISIS-APOCIIIRx is administered as a single agent and in combination with fibrates. We also observed significant reductions in the number of VLDL particles and increases in the number of HDL particles. These data are consistent with a mechanism of reducing ApoC-III and exactly what we would expect given the significant reductions of triglycerides and other lipid parameters in patients treated with ISIS-APOCIIIRx we have observed in our Phase 2 clinical trials," said Richard Geary, Ph.D., senior vice president of development at Isis. "We look forward to advancing ISIS-APOCIIIRx into Phase 3 clinical studies this year."

ISIS-APOCIIIRx is an antisense drug intended to treat patients with severely high triglycerides either as a single agent or in combination with other triglyceride-lowering agents. ISIS-APOCIIIRx targets apoC-III, a protein 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. Humans with elevated levels of apoC-III have high triglycerides associated with multiple metabolic abnormalities, such as insulin resistance and/or metabolic syndrome. In addition, the prevalence of type 2 diabetes is increased in patients with elevated triglycerides. Humans with severely elevated levels of triglycerides are at risk of many serious health conditions, including pancreatitis, which can be life-threatening and require hospitalization.

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 31 drugs to treat a wide variety of diseases with an emphasis on cardiovascular, metabolic, severe and rare diseases, including neurological disorders, and cancer. Isis' partner, Genzyme, is commercializing Isis' lead product, KYNAMRO®, in the United States and other countries for the treatment of patients with homozygous FH. 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 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, 2013, which is on file with the SEC. Copies of this 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.

Isis Pharmaceuticals® is a registered trademark of Isis Pharmaceuticals, Inc. KYNAMRO® is a registered trademark of Genzyme Corporation.

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SOURCE Isis Pharmaceuticals, Inc.

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