Key result
ARO-ANG3 administered to healthy volunteers reduced ANGPTL3 levels by 83-93%, triglycerides and VLDL-C by 61-65%, and LDL-C by 45-54%, with effects lasting at least 12 weeks after the second dose.
Why the study?
Single doses of ARO-ANG3 reduced ANGPTL3 and atherogenic lipoproteins in healthy volunteers, but the effects and duration of action of multiple doses remained to be reported.
Does ARO-ANG3 reduce ANGPTL3 and atherogenic lipids in healthy volunteers?
Does ARO-ANG3 reduce ANGPTL3 and atherogenic lipids in healthy volunteers?
RNAi inhibition of ANGPTL3 with ARO-ANG3 significantly reduces ANGPTL3, LDL-C, and triglycerides in healthy volunteers with a duration of action of at least 12 weeks following a second dose.
Answers are grounded in this paper and cite their sources.
May support ANGPTL3 RNAi development for dyslipidemia; leaves open long-term efficacy, safety, and outcomes.
Background Elevated LDL-C and triglyceride rich lipoproteins (TRLs) are independent risk factors for cardiovascular disease (CVD). Genetic deficiency of angiopoietin-like protein 3 (ANGPTL3) is associated with reduced circulating levels of LDL-C, triglycerides (TGs), VLDL-C, HDL-C and reduced CVD risk, with no described adverse phenotype. ARO-ANG3 is a RNA interference drug designed to silence expression of ANGPTL3. Single doses of ARO-ANG3 have been shown to reduce ANGPTL3, TGs, VLDL-C and LDL-C in healthy volunteers (HVs, AHA 2019). We report the effects of multiple doses of ARO-ANG3 in HVs with a focus on the duration of action. Methods ARO-ANG3 was administered subcutaneously to HVs on days 1 and 29 at doses of 100, 200 or 300 mg (n=4 per group). Measured parameters included ANGPTL3, LDL-C, TGs, VLDL-C and HDL-C. Follow up is ongoing. Results All HVs have received both doses and follow-up is currently through week 16 (12 weeks after second dose). Mean nadir for ANGPTL3 levels occurred 2 weeks after the second dose (−83–93%) with minimal change for 200 and 300 mg but 16% recovery for 100 mg at week 16. Mean TGs and VLDL-C reached nadir earlier (3 wks, −61–65%) without apparent dose response and minimal change for any dose at wk 16. LDL-C nadir occurred 4–6 wks after the second dose (−45–54%), again with minimal evidence for dose response or change through wk 16. HDL-C was reduced 14–37% at wk 16. ARO-ANG3 was well tolerated without serious or severe adverse events or dropouts related to drug. The most common adverse events have been headache and upper respiratory infections. Conclusions Genetic deficiency of ANGPTL3 is a cause of familial combined hypolipemia and is associated with a decreased risk of CVD. Using RNAi to selectively suppress ANGPTL3 production reproduces these genetic effects with a duration of at least 12 weeks following a second dose and with good tolerability over 16 wks. ANGPTL3 inhibition results in lowering of LDL-C and TRLs which may confer protection against CVD in patients with atherogenic mixed dyslipidemia. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Arrowhead Pharmaceuticals
No takes yet. Share an insight, caveat, or question.
Watts et al. (2020) studied Healthy volunteers (n=12). ARO-ANG3 was evaluated on ANGPTL3, LDL-C, TGs, VLDL-C and HDL-C levels. ARO-ANG3 administered to healthy volunteers reduced ANGPTL3 levels by 83-93%, triglycerides and VLDL-C by 61-65%, and LDL-C by 45-54%, with effects lasting at least 12 weeks after the second dose.
Synapse has enriched 10 related papers. Consider them for comparative context: