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Isis Reports New Data for Mipomersen in Routine High CholesterolPatients and Provides Cumulative Safety Summary

Update: Kynamro (mipomersen) Now FDA Approved - January 29, 2013
- Patients on stable doses of statins treated for 3 months with 200 mg/week mipomersen experienced 48% further reduction in LDL-cholesterol

CARLSBAD, Calif., Nov. 13 /PRNewswire-FirstCall/ -- Isis Pharmaceuticals, Inc. announced new results from its Phase 2 clinical trial of mipomersen (ISIS 301012) in patients with routine high cholesterol, as well as providing an integrated Phase 1 & Phase 2 safety summary for the drug.

Eight patients with routine high cholesterol on stable doses of less than or equal to 40 mg/day of statins were treated with 200 mg/week mipomersen for three months. Results were compared with those from 14 placebo-treated patients. All patients remained on stable statin therapy throughout the study. Mipomersen treatment resulted in a 42% reduction in apoB and a 48% reduction in LDL-C, beyond reductions achieved with statin therapy alone. Previously, Isis reported results from the dose escalation portion of the study. With five weeks of treatment at 200 mg/week reductions in apoB and LDL-C were 24% and 30% respectively, so, as predicted, extending treatment with mipomersen from five weeks to 13 weeks led to further reductions in apoB and LDL-C. Mipomersen was well tolerated throughout the study.

Further, Isis reported results of an integrated safety analysis including data from more than 250 subjects treated with mipomersen in Phase 1 and Phase 2 studies. This analysis demonstrates that mipomersen has been well tolerated and that treatment with mipomersen did not result in evidence of liver toxicity. Among all subjects who received mipomersen, there were no instances of transaminase (ALT) elevations associated with two-fold increase in bilirubin or any other signs or symptoms of liver dysfunction. While on treatment, 3% of subjects treated with placebo and 3% of subjects treated with 200 mg/week mipomersen experienced ALT elevations of 150-250 IU/L. During the entire study periods, including dosing plus 90 day follow up, 5% and 7% of subjects treated with placebo or 200 mg/week of mipomersen, respectively, experienced ALT elevations of 150-250 IU/L. The most common adverse event was mild to moderate injection site reactions.

According to Jeffrey Jonas, M.D., Executive Vice President, Isis Pharmaceuticals, "Our clinical experience continues to demonstrate the lipid-lowering activity of mipomersen, which has been equally effective across multiple patient populations both as a single agent and in combination with lipid-lowering therapies. Furthermore, mipomersen's lipid-lowering effects have been highly predictable. As we expected, extending treatment from five to 13 weeks results in further lipid lowering, increasing LDL-C reductions from 30% to 48%.

"In addition, we have now dosed over 250 subjects with mipomersen and are able to present an extensive integrated safety summary. We have explored a full dose range for mipomersen as a single agent and in combination with moderate to maximal lipid-lowering therapies, and we have exposed subjects to aggressive loading and induction schedules. Mipomersen continues to display an attractive safety profile. The primary adverse event in our studies has been mild to moderate injection site reactions, which represent cosmetic inconveniences rather than safety concerns. We have not observed elevations in liver enzymes associated with increases in bilirubin or other signs or symptoms of liver dysfunction. During treatment and follow-up periods, subjects who received 200 mg/week mipomersen, our Phase 3 dose, experienced mild ALT elevations of 3-5xULN, similar to those in subjects who received placebo. These data are particularly impressive when one considers the fact that every subject was evaluated weekly and all ALT elevations were counted, whether confirmed or not. Based on this experience, we are very encouraged by mipomersen's overall safety and efficacy profile," concluded Dr. Jonas.



    Table 1: Mipomersen in Routine High Cholesterol Patients Coadministered

     with Statins

    Summary of Results. Median % changes from baseline at primary endpoint.*


    Per      Placebo   30       100       200       300      400**     200***

    Protocol         mg/week  mg/week   mg/week   mg/week   mg/week   mg/week

                     5 weeks  5 weeks   5 weeks   5 weeks   5 weeks   13 weeks

    # of

    patients   11         8        8        16          8         8         8


    ApoB       -1%        0%     -20%      -24%       -52%      -51%      -42%

                    (p=0.80) (p=0.03) (p=0.004) (p<0.0001)(p=0.0004)(p<0.0001)


    LDL-C      -4%        4%     -22%      -30%       -51%      -47%      -48%

                    (p=0.31) (p=0.01) (p=0.002) (p<0.0001) (p=0.008)(p<0.0001)


    VLDL-C      7%        8%      10%      -25%       -63%      -69%      -17%

                    (p=0.84) (p=0.66)  (p=0.38)   (p=0.08)  (p=0.02)  (p=0.80)


    Non-HDL-C  -1%        8%     -20%      -22%       -51%      -49%      -30%

                    (p=0.44) (p=0.02)  (p=0.02) (p<0.0001) (p=0.008) (p=0.006)


    HDL-C       9%        1%      -4%        6%         5%        6%       -4%

                    (p=0.24) (p=0.15)  (p=0.23)   (p=0.41)  (p=0.60)  (p=0.33)


    ApoA-1      0%        0%      -6%        1%         2%       -6%       -5%

                    (p=0.59) (p=0.66)  (p=0.93)   (p=0.67)  (p=0.43)  (p=0.04)


    TC          2%        5%     -15%      -13%       -42%      -34%      -23%

                    (p=0.72)(p=0.005) (p=0.009) (p<0.0001)(p=0.0001)(p=0.0001)


    TG          0%        4%       4%      -25%       -41%      -35%      -15%

                    (p=0.60) (p=0.52)  (p=0.38)   (p=0.04)  (p=0.02)  (p=0.92)


    P value = vs. placebo

    *   Primary endpoint analysis was 30 day post last dose, Day 59, in

        cohorts treated for 5 weeks and 14 days post last dose, Day 99, in the

        cohort treated for 13 weeks

    **  Per protocol, analysis excludes one patient enrolled in the

        400 mg/week cohort who dropped out after receiving only one dose of

        study drug

    *** Statistical analysis of the 200 mg/week dose group treated for 13

        weeks is versus a pooled placebo from all cohorts (n=14)




    Table 2: Mipomersen Phase 1 and Phase 2 Summary of On-Treatment ALT

     Elevations*

    Percentage of subjects with ALT elevations


    Max ALT**    Placebo      30/50         100         200        >=300

                            mg/week      mg/week     mg/week     mg/week

                (N=40)      (N=35)       (N=35)      (N=87)      (N=106)

    150-250     3%          3%            0%         3%           7%

     IU/L

     (3xULN-

     5xULN***)

    >250 IU/L    0%          0%            0%         0%           0%

     (>5xULN***)


    *   On-treatment period encompasses the treatment period from first dose

        to last dose

    **  Each subject is counted only once at maximum ALT reading

    *** ULN is defined to be 50 IU/L




    Table 3: Mipomersen Phase 1 and Phase 2 Summary of Entire Study ALT

     Elevations*

    Percentage of subjects with ALT elevations on-treatment or during 90 days

     following the last study dose


    Max ALT**    Placebo     30/50        100         200         >=300

                            mg/week      mg/week     mg/week     mg/week

                (N=40)      (N=35)       (N=35)      (N=87)      (N=106)

    150-250     5%          9%           0%          7%          14%

     IU/L

     (3xULN-

     5xULN***)

    >250 IU/L    0%          0%           0%          1%           4%

     (>5xULN***)


    **  Each subject is counted only once at maximum ALT reading

    *** ULN is defined to be 50 IU/L



About Mipomersen and Cholesterol

Mipomersen, formerly ISIS 301012, is a second-generation antisense drug that reduces the production of apoB-100, a protein critical to the synthesis and transport of "bad" cholesterol and a target that has proved to be undruggable using traditional, small-molecule approaches. Cholesterol can be carried in the bloodstream in a variety of forms, with high-density lipoprotein, or HDL-C, being the good form, and low-density lipoproteins, or LDL-C, and very low-density lipoproteins, or VLDL-C, being bad forms directly involved in heart disease. Collectively, LDL-C, VLDL-C, and other bad forms of cholesterol are referred to as "non-HDL-C." The lowering of non-HDL-C is a key component in the prevention and management of cardiovascular disease. Isis plans to develop mipomersen as the drug of choice for patients who are unable to achieve target cholesterol levels with statins alone or who are intolerant of statins. Isis is developing mipomersen at a dose of 200 mg/week in its ongoing and future studies.

Posted: November 2007

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