ISIS 301012 Lowered LDL-C 62% as Single Agent Dosed for Three
Months
After Only Five Weeks of Treatment ISIS 301012 Coadministered
With Statins Lowered LDL-C 51% Beyond the Levels Achieved With
Statins Alone
ISIS 301012 Was Well-Tolerated in Both Studies
CARLSBAD, Calif., Nov. 12 /PRNewswire-FirstCall/ -- Isis Pharmaceuticals,
Inc. (Nasdaq: ISIS) announced exciting new results from two Phase
2 clinical trials of ISIS 301012 presented today 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% reduction in LDL-cholesterol (LDL-C), a 42% reduction
in total cholesterol (TC), and a 41% 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%, 46% and 43%, 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."
ISIS 301012 Coadministered with Statins
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% in LDL-C, 42% in
TC, 51% in non-HDL-C and 41% 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% while 300 mg/week lowered LDL-C by 51%).
ISIS 301012 as a Single Agent
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% in
LDL-C, 46% in TC, 54% in non-HDL-C and 43% 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.
More about Phase 2 Trials for ISIS 301012
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.
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.
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. |
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