RNAi strategy to silence ANGPTL3 safely lowers triglyceridesNews - Nov. 18, 2019
RNA Interference Targeting Hepatic Angiopoietin-Like Protein 3 Results in Prolonged Reductions in Plasma Triglycerides and LDL-C in Human Subjects (AROANG1001 study)
Presented during the AHA Scientific Sessions 2019 by Gerald F Watts (Univ of Western Australia, Royal Perth Hosp, Perth, Australia).
Introduction and methods
ANGPTL3 is a key regulator of lipid and lipoprotein metabolism with multiple potential nodes of action. Loss-of-function mutations in ANGPTL3 have been found to lead to low LDL-C, VLDL-C, HDL-C and triglycerides (TG), and genome-wide association studies suggested that these mutations are associated with lower risk of CVD. There is no known adverse phenotype associated with a genetic deficiency in ANGPTL3.
ANGPTL3 is primarily synthesized in hepatocytes. ANGPTL3 can be silenced by RNA interference with the specific siRNA ARO-ANG3 (with Arrowhead’s TRiM platform). ARO-ANG3 is administered subcutaneously and is targeted at the liver, where it specifically induces degradation of the ANGPLT3 mRNA. This induces deep and durable silencing of the ANGPTL3, while avoiding off-target effects.
The AROANG1001 study was a phase 1/2a clinical study to test the safety and tolerability of ARO-ANG3 in healthy volunteers. A single dose was tested in normal healthy volunteers (NHV) with TG>100 mg/dL and LDL-c >70 mg/dL (cohorts 1-4, 10 persons each: 6 active, 4 placebo).
- Mean maximum reductions from baseline in ANGPTL3 ranged from 55% (50 ng/mL) [35 mg] (P<0.0001) to 83% (63 ng/mL) [300 mg] (P<0.0001). Reductions were maintained through end of the study, at week 16 (43% (42 ng/mL) [35 mg] to 75% (57 ng/mL) [300 mg]).
- Mean maximum TG reduction from baseline ranged from 31% (38 mg/dL)[35 mg] (P=0.06) to 66% (167 mg/dL) [200 mg] (P=0.0002), and VLDL-c concentration from 30% (8 mg/dL)[35 mg] (P=0.006) to 65% (33 mg/dL) [200 mg] (P<0.0001). Reductions were maintained, with reductions of 47% to 53% for TG and 49% to 51% for VLDL-c.
- LDL-c showed a significant reduction with 300 mg (30%, P=0.0004), but not with 200 mg (9%, P=0.40). HDL-c was reduced by 8% with 35mg (P=0.02) to 26% with 300 mg (P<0.0001).
- No serious adverse effects or drop-outs were seen in subjects receiving the study drug. Two subjects had mild transient elevations in ALT (1 active, 1 placebo, 1 confounded by concomitant ingestion of herbal supplement with known liver toxicity). 1 mild drug-related local injection site reaction was seen.
This single ascending dose study of ARO-ANG3, an RNAi therapeutic that specifically silences ANGPTL3 mRNA in the liver, showed dose-dependent reductions in fasting serum ANGPTL3. Moreover, reductions in fasting TG, VLDL-c, LDL-c and HDL-c were seen, similar to those reported in ANGPTL3 loss-of-function carriers. ARO-ANG3 had a favourable safety and tolerability profile. Multi-dose studies in patients with NAFLD, hyperlipidemia on statins , familial hypercholesterolemia, and severe hypertriglyceridemia 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 -