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Isis Pharmaceuticals Updates Its Positive Phase 2 Data for ISIS,301012 in Familial Hypercholesterolemia Patients

* Treatment with ISIS 301012 produced at least 45% additional reduction in patients' LDL-cholesterol when added to maximally-tolerated lipid-lowering therapies

CARLSBAD, Calif., May 17, 2007 /PRNewswire-FirstCall/ -- Isis Pharmaceuticals, Inc. announced updated results from its ongoing Phase 2 clinical trial of ISIS 301012 in patients with homozygous familial hypercholesterolemia (HoFH), initial results of which were presented in March at the of Cardiology Annual Scientific Session (ACC) in New Orleans. The three HoFH patients dosed with 300 mg/week of ISIS 301012 for twelve weeks have now completed treatment. With ISIS 301012, the patients achieved 45%, 50% and 51% additional reductions in LDL-cholesterol beyond that achieved with maximally-tolerated lipid-lowering therapy, with similar reductions in apoB of 45%, 43% and 54%. ISIS 301012 continued to be well tolerated in the study.

"The magnitude of LDL-cholesterol response in these three HoFH patients has surpassed anything I have seen in the last 30 years, including with statins," stated Evan Stein, M.D., Ph.D., Director, Metabolic and Atherosclerosis Research Center, Cincinnati, Ohio, lead investigator in the study. "It offers for the first time the potential for good, life-long control of LDL without expensive and invasive therapies such as apheresis, liver transplantation and other heroic measures we have tried over the years."

ISIS 301012 has been granted orphan drug status for the treatment of homozygous FH, one of the most severe forms of hypercholesterolemia and one that is highly resistant to treatment. Patients with this genetic condition typically suffer heart attacks at an early age. Isis plans to begin registration-directed studies for FH in 2007.

ISIS 301012 in Homozygous Familial Hypercholesterolemia

The data presented are part of a single-arm, open-label, dose-escalation study. Because the study was designed princip ally to assess the safety of ISIS 301012 in HoFH and in combination with high-dose concurrent lipid-lowering therapies, the protocol initially called for five weeks of dosing. Based on a strong safety profile at five weeks with doses through 200 mg/week, the study was amended to include a cohort of patients dosed at 300 mg/week for three months, and it is that cohort for which Isis is updating the interim data presented at the ACC. Because HoFH is an extremely rare condition affecting one person per million, clinical trials in this disease are generally quite small.

The study included three HoFH patients with very high incoming LDL-cholesterol levels despite being treated with maximally-tolerated lipid-lowering therapies. Throughout the study, all patients remained on their other lipid-lowering drugs at constant doses. With this update, all patients completed 12 weeks of study treatment and reached the primary endpoint for analysis at Day 99, 14 days after receiving their last dose of ISIS 301012. The patients continue in follow-up. The data are summarized in tabular form below.

    Table 1: ISIS 301012 in HoFH, Summary of Results

    Lipid values are presented in mg/dL and % change from baseline.

                  Patient 1         Patient 2          Patient 3

                                      80 mg

                                   atorvastatin +

    Concurrent                   10 mg ezetimibe +

    Lipid-                            3.75 g              40 mg

    lowering        80 mg          colesevelam +      rosuvastatin +

    Therapies    atorvastatin       1 g niacin        10 mg ezetimibe


     (years)        23                  48                  32

    Lipids: Base-   Day    %     Base- Day    %     Base-  Day    %

            line    99   change  line  99   change  line   99   change

    ApoB     369    171   -54%   180   103   -43%   283    156   -45%

    LDL-C    651    318   -51%   197    99   -50%   4
45    246   -45%

    VLDL-C    18     10   -44%    33    24   -26%    30     20   -33%

    Non-HDL  669    328   -51%   230   123   -46%   475    266   -44%

    HDL-C     27     35    32%    29    28    -2%    27     31    15%

    ApoA-1    86     92     7%   109   109     0%    89     90     2%

    TC       695    363   -48%   258   151   -41%   502    297   -41%

    TG        90     49   -45%   163   118   -28%   151     99   -34%

    Lp(a)    104     36   -65%   140   128    -9%   108     54   -50%

ISIS 301012 was well tolerated and there were no serious adverse events in the study. A single patient had a transient increase in liver transaminase (ALT) that exceeded three times the upper limit of normal (3xULN), which the investigator attributed to alcohol as documented by patient's admission.

Jeff Jonas, M.D., Executive Vice President, Isis Pharmaceuticals, commented, "We are pleased to have successfully completed this initial evaluation of ISIS 301012 in the extreme disease setting of homozygous FH and in combination with the high doses of other lipid-lowering drugs typically prescribed to these patients. We are preparing to initiate our registration studies for FH shortly, and we look forward to presenting more FH data later in the year."

More about Phase 2 Trials for ISIS 301012

Isis has presented results of two double-blind, placebo-controlled Phase 2 dosing studies in patients with routine high cholesterol (polygenic hypercholesterolemia): a monotherapy study and a five-week coadministration with statins study. Ongoing studies include an extended three-month 200 mg/week treatment cohort in the statin coadministration study in polygenic hypercholesterolemia, and a dose-escalation study in patients with heterozygous FH. Data for each of these studies will be reported later in the year. For future studies, including the registration studies for FH and the long-term coadministration study planned for patients with routine high cholesterol, both expected to begin this year, Isis has selected 200 mg/week as its development dose.

About Familial Hypercholesterolemia

Familial hypercholesterolemia is a genetic condition that results in markedly elevated LDL-C levels beginning at birth and heart attacks at an early age. People with the disease have consistently high levels of LDL-C, which leads to premature atherosclerosis of the coronary arteries. Current therapies for FH are inadequate, and the most severely affected patients may need apheresis, an expensive and time-consuming procedure that removes the "bad" cholesterol from the blood. Homozygous FH is rare, affecting about one in one million people, but heterozygous FH is much more common with a prevalence of approximately one in every 500 people.


Isis is exploiting its expertise in RNA to discover and develop novel drugs for its product pipeline and for its partners. The Company has successfully commercialized the world's first antisense drug and has 17 drugs in development. Isis' drug development programs are focused on treating cardiovascular and metabolic diseases. Isis' partners are developing drugs for cancer, and inflammatory and other diseases. Ibis Biosciences, Inc., Isis' wholly owned subsidiary, is developing and commercializing the Ibis T5000 Biosensor System, a revolutionary system to identify infectious organisms. As an innovator in RNA-based drug discovery and development, Isis is the owner or exclusive licensee of over 1,500 issued patents worldwide. Additional information about Isis is available at

This press release includes forward-looking statements regarding the development, activity, therapeutic potential and safety of ISIS 301012 in treating high cholesterol. Any statement describing Isis' goals, expectations, financial or other projections, intentions or beliefs is a for ward-looking statement and should be considered an at-risk statement, including those statements that are described as Isis' goals. 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 products. 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, 2006, and its quarterly report on Form 10-Q for the quarter ended March 31, 2007, which are on file with the SEC. Copies of this and other documents are available from the Company.

CONTACT: Kate Corcoran, Ph.D., Vice President, Corp. Development of IsisPharmaceuticals, Inc., +1-760-603-2331

Web site:

Ticker Symbol: (NASDAQ-NMS:ISIS)

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