APOC3 RNA silencing therapeutic safely lowers triglycerides

RNA Interference Targeting Apolipoprotein C-III Results in Deep and Prolonged Reductions in Plasma Triglycerides (AROAPOC31001 study)

News - Nov. 25, 2019

Presented during the AHA Scientific Sessions 2019 by Christie Ballantyne (Baylor College of Medicine, Houston, TX) .

Introduction and methods

Plasma triglyceride (TG) levels are an independent risk factor for cardiovascular disease and pancreatitis. Apolipoprotein C-III (APOC3) is a component of VLDL and chylomicrons and functions to inhibit lipoprotein lipase (LPL) and non-LPL-driven TG metabolism. APOC3 has been validated in human genetic studies as a target for hypertriglyceridemia and CVD, and APOC3 loss-of-function results in lower TG levels. An APOC3 -targeted antisense oligonucleotide has been shown to be effective in lowering TG levels. After initial testing, the toxicity profile was considered adverse, with Q1 week dose intervals required.

Because APOC3 is predominantly synthesized in hepatocytes (~80-90%), it is an ideal target gene for RNA interference (RNAi). A therapeutic agent directed against APOC3 mRNA was developed using Arrowhead’s Targeted RNAi Molecule (TriM) platform, yielding the hepatocyte-targeted ARO-APOC3 siRNA. ARO-APOC3 is designed to induce deep and durable gene specific silencing while avoiding off-target effects.

Two areas related to hypertriglyceridemia of high unmet medical need include familial chylomicronemia syndrome (FCS) and severe high triglycerides (sHTG) with pancreatitis. For both of these conditions, strict diet and lifestyle changes are important, but adherence is challenging.

The AROAPOC31001 Study was a phase 1/2a clinical study that evaluated the safety and tolerability of a single dose ARO-APOC3 in normal healthy volunteers (NHV) with fasting TG>80 mg/dL (cohorts 1-4, 10 persons each: 6 active, 4 placebo). Safety was assessed in all NHV of cohorts 1 -4 (24 active, 16 placebo).

Main results

  • In the safety analysis, no serious or severe adverse events were reported.
  • One person, with elevated ALT at baseline (65 U/L), had moderate transient ALT elevation (peak of 210 U/L) after treatment with ARO-APOC3, with return to baseline by end-of-study (45 U/L at day 113). No other lab abnormalities were observed.
  • 8 Local injection site reactions were noted, all rated mild. They were more common at higher doses.
  • Dose-dependent reductions of APOC3 were noted. Because the dose response between 25 and 100 mg was minimal, a 10 mg dose was added to the study.
  • Mean maximum reduction from baseline in serum APOC3 levels ranged from 72% [10 mg dose] (P<0.0001) to 94% [100 mg dose] (P<0.0001). For serum TG, mean maximum reductions ranged from 53% (77 mg/dL)(p=0.002) to 64% (92 mg/dL) (p=0.0001) and for serum VLDL-c, they ranged from 53% (16 mg/dL) [10 mg dose] (P=0.0005) to 68% (19 mg/dL) [50 mg dose] (P<0.0001).
  • Reduction in serum APOC3 levels was maintained through the end of study (week 16), with week 16 mean reductions of 70% [25 mg dose] to 91% [100 mg dose]. Reductions in serum TG and VLDL-c were also maintained, with mean reductions at week 16 of 41% to 55% for TG and 42-53% for VLDL-C.
  • The 25 and 10 mg dose showed significant mean maximum reductions in LDL-c of 12% and 25%, respectively. Serum HDL-c was increased by 30% with 10 mg, to 69% with the 100 mg dose.


A single dose of an RNAi therapeutic directed against hepatocyte APOC3 mRNA in healthy volunteers showed potent and durable reductions in serum APOC3 and reductions in triglycerides, up to week 16. Reductions in triglycerides, VLDL-c and LDL-c and an increase in HDL-c were also seen. ARO-APOC3 had a favourable safety and tolerability profile. These data suggest an opportunity for quarterly or 6-monthly dose intervals. Multiple dose evaluations in patients with severe hypertriglyceridemia and/or familial chylomicronemia syndrome are underway.


Daniel Rader (Perelman School of medicine, University of Pennsylvania) commented on the two presented siRNA studies aimed at lowering triglyceride levels (targeting APOC3 and ANGLPT3). He noted that with siRNA technology, one molecule can continue to inhibit protein synthesis, allowing for continuity of the therapeutic effects. Both APOC3 and ANGPT3 have been genetically validated, and the rationale to study them as therapeutic targets comes from human genetics research. Both proteins inhibit LPL, which normally serves to transform triglyceride-rich lipoproteins (TRLs) to TRL remnants.

Both agents showed over 60% maximum reduction in serum TG after a single dose. APOC3 silencing showed more LDL-c reduction, and while APOC3 inhibition led to an HDL-c increase, ANGPTL3 silencing was associated with lower HDL-c.

Rader pointed out that the studied persons were not selected for hypertriglyceridemia, which will ultimately be the target population. It remains to be established which target is more likely to be efficacious in treating severe hypertriglyceridemia, or in preventing major acute CV events? In light of APOC3, the role of intestinally-derived APOC3 needs to be studied, as this is not targeted by the hepatocyte-driven siRNA. The next few years will be interesting, as we will find out what these agents can mean for the relevant populations.

- Our reporting is based on the information provided during AHA Scientific Sessions 2019 -

Read our summary of the results with siRNA directed against ANGPTL3

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