Recent publications on Residual Risk

Lipids were very much in the news at this year’s meeting. Not only was there a report from GLAGOV, the first intravascular ultrasound study evaluating the effects of treatment with a PCSK9 monoclonal antibody on top of statin on progression of coronary atherosclerosis (see Landmark study), but there was also news of other approaches to targeting PCSK9. In the ORION study in high risk patients with elevated low-density lipoprotein cholesterol (LDL-C), 1 or 2 subcutaneous injections of the PCSK9 RNA interference agent inclisiran reduced LDL-C levels by 55-60%. This approach has obvious benefits for adherence, offering the possibility in the future of a single depot injection per year to manage elevated LDL-C levels.
 
On the downside, there were disappointing results from the MILANO-PILOT Study. In this study, infusion of the apoA-IMilano high-density lipoprotein (HDL) mimetic did not significantly change the percent atheroma volume (PAV) in acute coronary syndrome patients, leading to termination of this agent. However, some may question why the placebo response in this study differed with that observed in GLAGOV; in the MILANO-PILOT Study there was -0.8% change in PAV (vs. -0.5% with active drug) whereas in GLAGOV, there was +0.05% change with placebo vs. -0.95% with active drug. Perhaps a case of throwing the baby out with the bathwater?
 
Furthermore, there were early clinical (Phase I) data with Ionis-angptl3-lRx, an antisense inhibitor to angiopoietin-like protein 3 (ANGPTL3). Genetic studies have previously identified ANGPTL3 variants that were associated with very low plasma levels of LDL-C, triglycerides and HDL cholesterol. Together with other evidence, there was a strong rationale that ANGPTL3 may be a novel target for managing dyslipidaemia, with multiple beneficial effects on lipoprotein metabolism. These findings were the catalyst for the development of Ionis-angptl3-lRx. In a phase I study in healthy volunteers with elevated triglycerides, there were significant mean reductions in triglycerides (by 66%), apolipoprotein CIII (by 68%), and LDL-C (by 35%). Safety data were also encouraging.