seems to hint from fda the science have change since the spa.
page 9 bd
During a pre-IND meeting with the applicant in July 2008, however, the Division noted
that there was a lack of prospective, controlled clinical trial data demonstrating that
pharmacological reduction of non-HDL-C (or TG) with a second drug, in patients with
elevated TG levels at LDL goal on statin therapy, significantly reduces residual
cardiovascular risk. The Division referenced trials ongoing at the time (e.g., AIM-HIGH,
ACCORD-Lipid) that, while not able to assess the effect of specifically lowering
non-HDL-C (or TG) on clinical outcomes, would be expected to provide important
information on the incremental benefit of adding a second lipid-active drug to statin
therapy. It was stated that before an indication would be entertained for Ethyl-EPA as
add-on to statin therapy in patients with elevated TG levels, the applicant at a minimum
would have to provide results from a 12-week study with lipid endpoints as well as
initiate an appropriately designed cardiovascular outcomes study. This outcomes study,
known as REDUCE-IT, is ongoing and is investigating whether the addition of AMR101
4 g daily ameliorates residual cardiovascular risk among patients at high CV risk who
have moderate hypertriglyceridemia at LDL-C goal on statin therapy. The study designs
for both ANCHOR and REDUCE-IT were agreed to by the Division under special
protocol assessments.
Several cardiovascular outcome trials of non-statin lipid-modulating therapy, such as
those referenced by the Division in 2008, have since completed. ACCORD-Lipid, AIMHIGH,
and HPS2-THRIVE, which were designed to target residual cardiovascular risk
by improving lipid parameters other than LDL-C (e.g., HDL-C and/or TG) in patients
optimally treated with statin therapy, failed to demonstrate unequivocally additional
cardiovascular benefit from non-statin lipid-modulating drugs. Several hypotheses could
be put forward regarding the failures of these large, carefully designed trials to
demonstrate benefit on their primary endpoints, but the evidence to date certainly
challenges the hypothesis that adding lipid-modulating therapies to patients optimally
treated with statins will reduce residual cardiovascular risk. Although it can be argued
that lipid and/or lipoprotein parameters can be used to define subpopulations of statintreated
patients who would be expected to benefit from various non-statin lipidmodulating
agents, contemporary trials have not yet prospectively tested this hypothesis.
Members of the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC)
are asked to consider the results of the ANCHOR trial in the context of the available
science when recommending whether to approve the proposed treatment indication for 4
grams AMR101 daily to be co-administered with statin therapy for the treatment of
patients with mixed dyslipidemia and coronary heart disease (CHD) or its risk equivalent.
