Discussant Daniel J. Rader, MD, noted that there is an unmet need for hypertriglyceridemia-lowering therapies, because elevated triglycerides can cause pancreatitis as well as coronary disease.
“These siRNA molecules are catalytic: They can go around and destroy multiple aspects of the target RNAs in a way that provides substantial longevity of effect, which is quite remarkable,” explained Dr. Rader, professor of molecular medicine and director of the preventive cardiology program at the University of Pennsylvania, Philadelphia.
Hypertriglyceridemia is often a challenge to treat successfully in clinical practice, so the siRNA studies drew considerable attention, not only for the impressive size and durability of the lipid changes, but also because of the way in which the target genes were identified, a process that began by genetic analysis of individuals with inherently low levels of APOC3 and ANG3.
“One of the really interesting parts of this story is the rapidity with which we went from target identification to therapeutics, now moving into phase 1 and 2 trials. It’s happening much more rapidly than we’ve ever seen before,” commented AHA scientific sessions program chair Donald Lloyd-Jones, MD, senior associate dean for clinical and translational research and chair of the department of preventive medicine at Northwestern University, Chicago.
Still, he was quick to inject a cautionary note. “These genomic studies can show us that having lower levels of these proteins is associated with lower risk. But that doesn’t necessarily mean that lowering levels of these proteins will lower risk, and it certainly doesn’t tell us anything about potential safety concerns.”
In an interview, AHA spokesperson Jennifer Robinson, MD, made a similar point: “We have had lots of fibrate trials in which we’ve lowered triglycerides, and they didn’t really work.”
Yet she, too, was clearly caught up in the thrill of the early evidence of a novel means of treating new targets in dyslipidemia.
“We’re on the cusp of the genetic revolution,” declared Dr. Robinson, professor of epidemiology and director of the preventive and intervention center at the University of Iowa, Iowa City. “For us science nerds, this is so exciting. It’s so cool. The brilliance of these compounds is they have a very focused target in a very focused organ. If you’re just in the liver, you’re limiting off-target effects, so the safety issue should be better than with what we have now.”
Bruce Jancin/MDedge News
Dr. Daniel J. Rader
Dr. Rader commented that plenty of questions remain to be answered about siRNA therapy for hyperlipidemia. These include which target – APOC3 or ANG3 – is the more effective for treating severe hypertriglyceridemia and/or for preventing major cardiovascular events, how frequently these agents will need to be dosed, whether there’s a clinical downside to the substantial HDL cholesterol lowering seen with silencing of ANG3, and whether the APOC3 that’s produced in the intestine – and which isn’t touched by hepatocentric ARO-APOC3 – will cause problems.
Dr. Ballantyne reported serving as a consultant to Arrowhead Pharmaceutics, which is developing the RNA inhibitors for hypertriglyceridemia, as well as numerous other pharmaceutical companies. Dr. Watts has received research grants from Amgen and Sanofi-Regeneron.