Isis Pharmaceuticals, Inc. has announced exciting new results from two phase 2 clinical trials of Isis 301012 presented at the American Heart Association Annual Scientific Sessions in Chicago. In the first study reported, patients with high cholesterol on stable doses of statins were treated with Isis 301012 for five weeks. Patients who received 300 mg/week of Isis 301012 in this study achieved a 51 per cent reduction in LDL-cholesterol (LDL-C), a 42 per cent reduction in total cholesterol (TC), and a 41 per cent reduction in triglycerides (TG) beyond the levels achieved with statins alone.
Isis also presented new results from an ongoing study in which patients with high cholesterol were treated for three months with 300 mg/week of Isis 301012 as a single agent. Data from this study for dose cohorts through 200 mg/week were previously reported. In this study, increasing the dose of Isis 301012 to 300 mg/week further reduced atherogenic lipids, with improvements in LDL-C, TC and TG of 62 per cent, 46 per cent and 43 per cent, respectively.
In addition, in these studies Isis 301012 continued to demonstrate a strong safety profile as a single agent and when coadministered with statins in every dose cohort presented. The drug was well tolerated in both studies.
According to John J.P. Kastelein, M.D., Ph.D., chairman, department of vascular medicine at the academic medical center in Amsterdam, The Netherlands, "These are quite remarkable results that are very encouraging for further development of Isis 301012. These new data demonstrate pronounced lipid-lowering effects of Isis 301012, both as a single agent and as an add-on to statin therapy. Further, the drug appears to have a positive safety profile, even at higher doses and when coadministered with statins.
"The guidelines for target cholesterol levels continue to be revised downward," Dr. Kastelein continued. "A significant percentage of at risk patients are simply not meeting LDL-C targets with current lipid lowering drugs, so there is a growing need for therapies that can be added to statins to achieve additional reductions in atherogenic lipids. ISIS 301012 shows promise for this group of patients."
Mark Wedel, M.D., J.D., Isis' chief medical officer, added, "We are pleased with the performance of Isis 301012 in patients, especially with its safety and activity when coadministered with statins, demonstrated after only five weeks of treatment. Because Isis 301012 has a half life of over 30 days, we are looking forward to seeing results from longer duration studies where we expect to see even better efficacy than that achieved over this short treatment period. These new data underscore the fact that by inhibiting the production of apoB 100, Isis 301012 works through a mechanism complementary to statins, enabling effective add on therapy in patients who have achieved maximal lipid lowering on statins but are unable to reach their desired LDL-C levels."
Isis' chairman of the board and chief executive officer, Stanley T. Crooke, M.D., Ph.D, commented, "With these studies, we have answered three important questions: first, with safe doses of Isis 301012 we can lower atherogenic lipids as or more effectively than any drug currently in use; second, we've shown that Isis 301012 as an add-on to ongoing statin therapy results in more than double the reduction in atherogenic lipids achieved with ezetimibe or other drugs typically added to statins; third, we have shown that Isis 301012 is well-tolerated as add-on therapy to statins. We're very excited about these recent results and they set the stage for continued development of this novel lipid-lowering drug."
This randomized, double-blinded, placebo-controlled, dose-escalation study calls for five weeks of therapy at doses of 30, 100, 200, 300 and 400 mg/week. It was recently expanded to include longer term treatment as well. Patients in the study have LDL-C levels between 100 and 220 mg/dL and have been on stable doses of 40 mg of simvastatin or atorvastatin for at least three months. The results of the five week dosing cohorts through 300 mg/week were presented yesterday. At a dose of 300 mg/week, patients receiving Isis 301012 achieved median reductions of 51 per cent in LDL-C, 42 per cent in TC, 51 per cent in non-HDL-C and 41 per cent in TG beyond the levels they had already achieved on stable statin doses. These results are comparable to the reductions achieved with Isis 301012 as a single agent and they are consistent with the data suggesting Isis 301012 acts through a mechanism of lipid lowering that is independent of and complementary to the statin mechanism. The data further demonstrate that when coadministered with a stable dose of statins, Isis 301012 displays a linear dose response relationship (200 mg/week lowered LDL-C by 30 per cent while 300 mg/week lowered LDL-C by 51 per cent).
This randomized, double-blinded, placebo-controlled, dose-escalation trial treated patients with high cholesterol (stable LDL-C 130 mg/dL) for three months with Isis 301012 as a single agent. In April, results for the first three dose cohorts through 200 mg/week were presented. Today the data from the 300-mg/week-dose cohort were presented, documenting median reductions of 62 per cent in LDL-C, 46 per cent in TC, 54 per cent in non-HDL-C and 43 per cent in TG. These data demonstrate that in contrast to statins, Isis 301012 causes linearly increasing reductions of atherogenic lipids as doses are increased.
The safety data for ISIS 301012 continue to show that the drug is well tolerated. In both studies, the most common adverse events were injection site reactions, categorized as mild and painless, that did not interfere with treatment. No clinically significant effects on liver function tests were observed.
Both studies for which data were presented are continuing with patients currently being enrolled in the 400-mg/week-dose cohort of the single agent study and the 400-mg/week-dose cohort for the five-week coadministration with statins study. Extended three-month treatment periods are planned for subsequent cohorts of 200 and 300 mg/week doses in the statin coadministration study.
In addition to the two studies described above, Isis 301012 is currently being evaluated in phase 2 dose escalation studies in patients with homozygous and heterozygous Familial Hypercholesterolemia (FH). Data from these trials, in which patients are being dosed with Isis 301012 as an add-on to their existing lipid-lowering therapies, are expected late in 2006 or early 2007. ISIS 301012 has been granted orphan drug status for the treatment of homozygous FH and Isis plans to begin registration-directed studies for FH in 2007.
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.
The national cholesterol education program's adult treatment panel updated LDL-C target for high-risk patients is less than 100 mg/dL. For moderately high-risk patients, the target is less than 130 mg/dL. Over 20 million Americans in the high-risk and Moderately high-risk categories are failing to meet their LDL-C targets using currently available lipid-lowering therapies.
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.