James Hamilton, MD: Managing Triglycerides via Liver Protein

A pair of phase 1 trials assessing a 2 investigative compounds designed to hypertriglyceridemia and high LDL cholesterol, presented at the American Heart Association (AHA) 2019 Scientific Sessions in Philadelphia this month, showed ARO-APOC3 and ARO-ANG3may have positive, safe, and tolerable benefits for patients over weeks following a single dose.

That said, more needs to be understood of the compounds’ overall effects on patients.

In an interview with MD Magazine® while at AHA 2019, James Hamilton, MD, vice president of Clinical Development for Arrowhead Pharmaceuticals, detailed the 2 investigative therapy’s effect on liver proteins, and what the early phase 1 data entailed.

MD Mag: What were the findings of the ANGPTL3-APOC3 trials for hypertriglyceridemia?

Hamilton: These were 2 studies, 2 separate compounds—one targeting the protein made by the liver called angiopoietin-like protein 3, or ANGPTL3. And so, this study started in healthy volunteers. We administered a single dose at the beginning of this study. We required that the healthy volunteers had slightly elevated triglycerides and LDL cholesterol at baseline.

And what the study demonstrated was, first and foremost, a favorable safety and tolerability profile. In terms of drug activity, we were able to show with a single dose, reduction in serum ANGPTL3 levels of about 80% main reduction.

That translated into reductions in triglycerides of about 60 to 70% after a single dose, and reductions in LDL cholesterol of about 30%. And the duration also was what's important to us—the durability of effect after a single dose is administered. Those reductions can last outwards of 16 weeks.

So, from the standpoint of later-stage trials and how this might be used in the clinic, potentially we're looking at very infrequent dose administration—maybe quarterly, or even less frequent. That's the ANGPTL3 study.

The other study was targeting another liver protein called APOC3, similarly involved in triglyceride metabolism—a very similar study design starting in healthy volunteers, and then we're in the process of progressing into patients with very high triglycerides. And what we showed in that study, even with some of the lower doses, a reduction after a single dose—again—in APOC3 blood levels of upwards of 94%.

So, very deep reductions, and that translated into triglyceride reductions of about 60 to 70%, with a similar long duration of effect. So, reduced triglycerides after a single dose, lasting 16 weeks or so. And that's about where the time points are right now.

MD Mag: How well do we understand liver protein’s function in cardiometabolic outcomes?

Hamilton: For both of these proteins, they're both involved in triglyceride metabolism, in terms of peripheral metabolism of triglycerides, how the triglycerides shuttled between the tissues where they're used or stored—like adipose tissue, cardiac muscle, skeletal muscle that burn triglycerides for fuel, and the particles that carry triglycerides around in the blood.

So, ANGPTL3 is involved in that that relationship and that transfer. It's also involved in how triglyceride-rich particles are synthesized and cleared by the liver.

ANGPTL3, the understanding of how it's involved in triglyceride and LDL cholesterol metabolism is not perfectly understood. There's still a lot of work to be done in that area. I think it’s a similar story for APOC3, however it's more of a triglyceride target rather than an LDL cholesterol target. APOC3 is involved in inhibiting peripheral hydrolysis of triglycerides, and then it's also important for inhibition of uptake by the liver of triglyceride-rich lipoproteins.

So, by silencing the production of APOC3, one is able to release, sort of take the foot off the brakes of apadosite clearance and liver clearance—and also of peripheral metabolism. And that results in lower triglycerides—at least that's the theory. There's still, again, a lot of work to be done on understanding that mechanism of action.