New RNAi therapies to reduce triglycerides: 2 studies show favourable results

According to preliminary data from 2 new therapies utilising RNA interference (RNAi) to reduce cellular levels of proteins involved in lipoprotein metabolism (apolipoprotein C-III [APOC3] or angiopoietin-like protein 3 [ANGPTL3]), plasma triglycerides and cholesterol levels were reduced in healthy volunteers for prolonged periods of time. Furthermore, in the case of the APOC3-silencing therapy, these reductions were coupled with an increase in high-density lipoprotein cholesterol (HDL-C).

Presenting the phase 1 and 2 study targeting APOC3, Prof. Christie Ballantyne (Baylor College of Medicine, USA) focused on the safety and tolerability of the RNAi therapy given as a single dose or 2 monthly doses [1]. Likewise, presenting the phase 1 and 2 study targeting ANGPTL3, Prof. Gerald Watts (University of Western Australia, Australia) showed the durability of that RNAi [2].

Invited discussant for both presentations, Prof. Daniel J. Rader (University of Pennsylvania, USA), compared the 2 studies head-to-head. The dose ranges were 10-100 mg for APOC3 silencing and 35-300 mg for ANGPTL3 silencing, which resulted in a maximum reduction in serum APOC3 protein levels of 94% versus 83% for ANGPTL3 protein levels. At the highest doses, silencing APOC3 reduced triglyceride levels by 64%, whereas silencing the ANGPTL3 gene did so by 66%. In both cases, these reductions were durable for at least 16 weeks. Silencing of APOC3 and ANGPTL3 decreased the mean maximum low-density lipoprotein (LDL) levels by 30% and 25%, respectively. One point of difference was that silencing APOC3 was associated with an HDL-C increase of 52%, whereas ANGPTL3 silencing decreased HDL levels by up to 16%. It is unclear what this discrepancy may indicate.

No serious adverse events were reported for either study. Although rare in frequency, reactions at the injection site did occur but were all mild. It remains to be investigated how these RNAi therapies compare to antibody- and antisense oligonucleotide-based methods that target the same proteins.

Prof. Radar concluded: “We are in a brave new world of RNAi therapeutics, a very interesting technology that is similar to but mechanistically different than antisense oligonucleotides.” Here, the process is ‘catalytic,’ in that “the same molecule can go around and destroy multiple aspects of the RNAs in a way that provides substantial longevity in terms of their duration of effect.”

1. Ballantyne C, et al. RNA interference targeting apolipoprotein C-III results in deep and prolonged reductions in plasma triglycerides. LBS06, AHA Scientific Sessions 2019, 14-18 November, Philadelphia, USA.
2. Watts GF, et al. RNA interference targeting hepatic angiopoietin-like protein 3 results in prolonged reductions in plasma triglycerides and LDL-C in human subjects. LBS06, AHA Scientific Sessions 2019, 14-18 November, Philadelphia, USA.

Posted on 26 February 202016 May 2024