Isis Reports Positive Results of Phase 2 Study of ISIS 301012 inHeterozygous FH Patients- HeFH Patients on Maximally Tolerated Lipid-Lowering Therapies Experienced 46% Further Reductions in LDL-C when Treated with 300 mg/week ISIS 301012 for 13 Weeks
CARLSBAD, Calif., October 04, 2007 /PRNewswire-FirstCall/ -- Isis Pharmaceuticals, Inc. announced new results from its Phase 2 clinical trial of ISIS 301012 in patients with heterozygous familial hypercholesterolemia (HeFH) on stable maximally tolerated lipid-lowering therapies presented in a poster session today at the Drugs Affecting Lipid Metabolism (DALM) XVI International Symposium in New York City. These results will also be presented by Dr. John J.P. Kastelein in an oral session at DALM on Saturday at 3:45 p.m. E.T., and Isis will host a conference call Monday morning at 8:00 a.m. E.T. to further discuss the results.
In a randomized, double-blind, placebo-controlled study, HeFH patients being treated with maximally tolerated lipid-lowering therapies were treated with ISIS 301012 for 6 or 13 weeks. Median baseline LDL-C levels for the dose cohorts ranged from 159 - 204 mg/dL. ISIS 301012 add-on treatment produced potent, dose-dependent, prolonged reductions in all atherogenic lipids, and results were consistent with those reported for patients with routine high cholesterol. Furthermore, this study confirmed that ISIS 301012 treatment results in meaningful reductions in Lp(a), another important predictor of cardiovascular disease. These reductions and accompanying improvements in other atherogenic lipid levels were all relative to baseline levels which already reflected the impact of ongoing maximally tolerated lipid-lowering therapies. ISIS 301012 was well tolerated in the study.
According to Evan Stein, M.D., Ph.D., Director, Metabolic and Atherosclerosis Research Center, Cincinnati, Ohio, a principal investigator for the studies, "The performance of ISIS 301012 continues to be extremely encouraging, especially for those of us who care for the many heterozygous FH patients who aren't able to achieve target lipid levels despite being treated with all that we currently have to offer them. The attributes of ISIS 301012, including its effects not only on LDL-C but also on triglycerides and Lp(a) -- other important markers of cardiovascular risk, make it all the more promising as a new drug with a unique and complementary profile to available therapies."
ISIS 301012 Coadministered with Maximally Tolerated Lipid-Lowering Therapies
This randomized, placebo-controlled, double-blind, sequential dose-escalation trial included cohorts receiving 6 weeks of treatment at doses of 50, 100, 200 or 300 mg/week. Because ISIS 301012 was well tolerated in the lower dose cohorts and in other ongoing Phase 2 studies, the dosing period for the 300 mg/week cohort was extended to 13 weeks. All patients in the study were diagnosed with heterozygous FH with median baseline levels of LDL-C ranging from 159 - 204 mg/dL while being treated with maximally tolerated doses of lipid-lowering therapies including high-dose statins either alone or in combination with cholesterol absorption inhibitors, bile acid sequestrants or fish oil capsules. At a dose of 300 mg/week for 13 weeks, patients receiving ISIS 301012 achieved median reductions of 43% in apoB and 46% in LDL-C beyond the levels they had already achieved on stable lipid-lowering therapies. ISIS 301012 treatment did not affect HDL-cholesterol (HDL-C) levels.
Table 1: ISIS 301012 in HeFH Patients on Maximally Tolerated Lipid-Lowering Therapies, Summary of Results. Median % changes from baseline at primary endpoint* Per Protocol Placebo 50 mg/week 100 mg/week # of patients 8 (8 for 6 weeks, 7 (6 weeks) 8 (6 weeks) (treatment duration) 2 for 13 weeks) ApoB -6 % -9% (p=0.69) -9% (p=0.57) LDL-C -5 % -12% (p=0.12) -11% (p=0.19) Non-HDL-C -6 % -10% (p=0.23) -6% (p=0.57) HDL-C 11 % -7% (p=0.28) -1% (p=0.28) ApoA-1 -1 % -1% (p=0.78) 0% (p=0.88) TC -2 % -11% (p=0.19) -5% (p=0.44) TG -17 % 5% (p=1.00) 6% (p=0.16) Lp(a) -3 % 0% (p=0.84) -19% (p=0.16) Per Protocol 200 mg/week 300 mg/week # of patients 9 (6 weeks) 8 (6 weeks) 8 (13 weeks) (treatment duration) ApoB -20% (p=0.02) -33% (p=0.01) -43% (p=0.02) LDL-C -20% (p=0.03) -36% (p=0.003) -46% (p=0.03) Non-HDL-C -26% (p=0.04) -30% (p=0.01) -39% (p=0.03) HDL-C -4% (p=0.28) 10% (p=0.88) 5% (p=0.97) ApoA-1 -5% (p=0.56) 1% (p=0.96) -2% (p=0.81) TC -24% (p=0.04) -22% (p=0.007) -31% (p=0.03) TG -25% (p=0.14) -27% (p=0.51) -24% (p=0.46) Lp(a) -17% (p=0.14) -25% (p=0.03) -37% (p=0.37) p value = vs. placebo *Primary endpoint analysis was Study Day 43 for the 6 week treatment cohorts, and Day 99 for the 13 week treatment cohort.
There were no Serious Adverse Events in the study, and the most common Adverse Event was transient, painless erythema at the site of injection. There was no effect on liver synthetic function as indicated by changes in bilirubin and albumin levels and prothrombin time. Three patients treated with the 300 mg/week dose experienced mild elevations of liver transaminases above three times the upper limit of normal; the maximal ALT observed in the study was 216 IU/L. Patients in this study remain in follow-up or are participants in the ongoing Open-Label Extension study.
About ISIS 301012 and Cholesterol
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 ISIS 301012 as the drug of choice for patients who are unable to achieve target cholesterol levels with statins alone or who are intolerant of statins. 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.span>
Posted: October 2007