Cardiovascular Clinical Trialists (CVCT) Forum – Paris 2012 - Workshop 5 : Identifying new targets: The value of omics and mendelian randomization studies (Daniel SWERDLOW)

MODIGLIANI Workshop 5 - Saturday December 1st, 2012
THE ATHEROSCLEROSIS TRIALISTS FORUM

Chairpersons: Wolfgang KOENIG, Ulm, GER - Anthony WIERZBICKI, London, GBR
Webcast: Tabassome SIMON, Paris, FRA

Will new compounds be able to reduce the residual risk in high risk patients when treatment targets based on new ESC guidelines have been achieved (e.g. LDL-C < 70mg/dl)?
Despite widespread early intervention in acute coronary syndromes and complete revascularization of stenotic lesions complemented by aggressive polypharmacotherapy, still a high percentage of patients develop a secondary event.
This has been shown in various registries and recent data from the GRACE registry have suggested that we grossly underestimate long-term risk in these patients. Thus, despite all our current efforts there is room for improvement.
➢ A very active clinical research programme is delivering an important number of new potential therapeutic targets that
may be ready for trial testing.
 • Can OMICS technology help us out here in terms of new specific biomarkers taking advantage of the proteome, metabolome or the transcriptome?
 • What is the relevance of Mendelian Randomisation studies to investigate the potential causal role of biomarkers in the pathophysiology of disease and to identify and select new drug biotargets.
➢ One major question relates to the value of biomarker-guided and/or risk guided therapy and how to design appropriate trials to test these therapeutic strategies. Should therapy be targeted to patients with specific biomarkers profiles? e.g. low HDL, high inflammatory burden (elevated CRP), high Lp-PLA2 activity etc.?
➢ A fairly large number of lipid-associated new targets or targets reflecting other pathways of the complex atherosclerotic process are being evaluated in mechanistic imaging studies but also in large randomised controlled clinical trials looking for important cardiovascular endpoints. In all of these trials the standard of care is much better than seen in the real world situation. Thus, the question arises, whether these additional compounds will lead to a clinically significant reduction in cardiovascular events on top of optimal standard care.

Trials (Interventions)
➢ CETP inhibitors: dalcetrapib, anacetrapib, evacetrapib (DAL-Outcomes I, DAL-Outcomes II, DEFINE, REVEAL, evacetrapib, ApoA1 mimetics, ApoA1 Milano, AIM-HIGH, HPS-Thrive)
➢ Directly augmenting apo A-I: Intravenous apo A-I therapy, Recombinant apo A-I Milano/phospholipids (ETC-216), Purified native apo A-I/phospholipids (CSL-111/112)
➢ Oral upregulators of endogenous apo A-I production RVX-208: ASSURE, SUSTAIN
➢ Phospholipase inhibitors: VISTA-16, SOLID, STABILITY
➢ Anti-inflammatory therapy: CANTOS (IL-1β antibody), CIRT (MTX), Anakinra (IL1 RA), IL-6 RA (Taxilicumab)
➢ New LDL-lowering compounds: PCSK9 inhibitors, apoB antisense, ISIS

Session program:
Will we be able to answer the question of HDL as a therapeutic target after the CETP inhibitor trials?
Speaker: Eric STROES, Amsterdam, NED
Discussant: Robert ROSENSON, New York, USA
Identifying new targets: The value of omics and mendelian randomization studies
Speaker: Juan Pablo CASAS, London, GBR
Identifying new targets: Monoclonal Antibody Inhibitor of PCSK9
Speakers: Wolfgang KOENIG, Ulm, GER - Robert SCOTT, Amgen, USA