March 30th, 2014
Stage Set for Phase IV Trials of PCSK9 Inhibition
Several Cardiology fellows who are attending ACC.14 in Washington, D.C. this week are blogging for CardioExchange. The fellows include Kumar Dharmarajan, Seth Martin, and Saurav Chatterjee. For more of our ACC.14 coverage of late-breaking clinical trials, interviews with the authors of the most important research, and blogs from our fellows on the most interesting presentations at the meeting, check out our ACC.14 Headquarters.
Surrounded by tall glowing curtains colored in purple, blue, orange, red, and hot pink, I’m sitting here in the main tent at the Sunday morning LBCT session feeling the enthusiasm build for PCSK9 inhibitors. I’m typing as the presentation of GAUSS-2 by Dr. Stroes completes a series of five phase III evolocumab (AMG 145) presentations here at ACC.14.
Yesterday, MENDEL-2 confirmed efficacy as monotherapy, DESCARTES showed durability out to 52 weeks, and RUTHERFORD-2 addressed the heterozygous FH population. Now I’ve just I watched Dr. Robinson present LAPLACE-2, showing that evolocumab significantly lowered LDL-C over the course of a few months in patients with hypercholesterolemia on background statin therapy. And now GAUSS-2 is showing efficacy and safety in a well-defined statin-intolerant population. Overall, the results are complementary, consistent, and favorable.
We are seeing that LDL-C consistently gets cut in half or more, but what’s also very cool here is that Lp(a) is going down by about 25-30%. To date, we haven’t had a good armamentarium against Lp(a), with niacin being the main option. Another potential tool for this predominantly genetic disorder, which predisposes families to premature cardiovascular disease, is warmly welcomed.
The stage is set for the phase IV trials of ASCVD outcomes. As Dr. Robinson mentioned, FOURIER is underway, using evolocumab on top of statin therapy in 22,500 patients with clinical ASCVD.
Will I be shocked if the phase IV trials don’t work? You better believe it. The biology makes sense. The epidemiology was consistent. The phase III trials look great. Are you also feeling the enthusiasm build? Do you agree that PCSK9 inhibitors are a likely game changer? Assuming the phase IV trials pan out, can you think of patients in your practice who will find this to be a useful option?
Regarding safety, we’re not seeing a signal for adverse effects in the realm of neurocognitive effects in the overall evolocumab program. However, the FDA has asked for neurocognitive sub-studies in the phase IV trials. Anyone out there have more insight into this? Is this really a good use of resources? Another approach: support n-of-1 trials in patients in whom a cognitive concern arises.