15289-s-bos

7 107 | Latest developments in the treatment of lipoprotein (a) been published yet. Evacetrapib, (Eli Lilly, Indianapolis, Indiana, USA) , another CETP currently under investigation, reduces LDL-C (22%), increases HDL-C (136%) and TG (7%), but Lp(a) levels were not investigated[35]. Recently Dezima Pharma , announced a phase 1 trial to investigate the effect of their CETP inhibitor TA-8995 (Dezima Pharma, Naarden, The Netherlands) ) on Lp(a) levels [http://www.dezimapharma.com/dezima- pharma-extends-clinical-development]. The mechanism of the Lp(a) lowering effect of the CETP inhibitors is not clear, and if CETP inhibition will prove to lower CVD risk it will be a challenge to determine to which extent Lp(a) will contribute to the reduction of CVD outcome, given its other beneficial effect on other lipoproteins. PCSK9-inhibitors Proprotein convertase subtilisin/kexin type 9 (PCKS-9) is secreted by the liver and regulates expression of the LDL-receptor by targeting it for lysosomal degradation [36]. To inhibit PCSK-9 activity, monoclonal antibodies have been developed that specifically target the PCSK-9 protein [36-38]. In recent phase 2 trials ( AMGEN: MENDEL (Monoclonal Antibody Against PCSK9 to Reduce Elevated LDL-C in Patients Currently Not Receiving Drug Therapy for Easing Lipid Levels) / LAPLACE-TIMI 57 (LDL-C Assessment With PCSK9 Monoclonal Antibody Inhibition Combined With Statin Therapy) / RUTHERFORD (Reduction of LDL-C With PCSK9 Inhibition in Heterozygous Familial Hypercholesterolaemia Disorder) /GAUSS (Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin-Intolerant Subjects), REGENERON/SANOFI: ODYSSEY (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With SAR236553) programs) the compounds of Amgen and Regeneron/ Sanofi showed that PCSK-9 inhibition on top of statin therapy reduces LDL-C by 55-65% , and Lp(a) by 30-40% [36-38]. This is also confirmed in a recently published phase III trial were after 52 weeks, there was a decrease in TG (4-23%), VLDL-C (20-79%), LDL-C (48- 61%), Lp(a) (23-33%), and in increase in HDL-C (4-11%)[39]. As with CETP inhibition the question how PCSK9 influences Lp(a) levels remains to be answered. It is hypothesized that PCSK-9 inhibition improves clearance either through an unknown receptor, directly from the circulation, or reduces synthesis by a decrease in substrate availability [37]. Although the phase 3 outcome trials are ongoing, PCSK-9 inhibition can be potentially important for Lp(a) reduction. However, because of the multiple actions of PCSK- 9 inhibition, the contribution of the direct effect of reduced Lp(a) on lowering CVD incidence will be a challenge to investigate.