DGAT2 a potential therapeutic target for fatty liver?

Antisense inhibition of DGAT2* – one of two vital enzymes in triglyceride synthesis – may be a favourable strategy for reversing nonalcoholic fatty liver disease (NAFLD), suggesting that targeting this pathway may mitigate NAFLD progression to its more severe form, nonalcoholic steatohepatitis (NASH), a phase II study has shown.

“NAFLD wasn’t even recognized as a disease 3 decades ago. [N]ow, it is alarmingly prevalent … emerging as one of the leading causes for liver transplant in the US,” said lead author Professor Rohit Loomba from the University of California San Diego School of Medicine, US, in a press release.

“Given its relative ubiquity and its potentially calamitous consequences … there is an unmet global need for effective treatments for NAFLD,” added Loomba. The need for pharmacologic intervention is also underpinned by poor adherence to lifestyle change (ie, diet, exercise), which is the standard approach for reversing NAFLD. [Hepatology 2018;67:328-357]

Disruption of triglyceride synthesis presents a novel mechanism for managing NAFLD. By inhibiting hepatic lipogenesis, the primary hit of hepatic steatosis may be reduced, subsequently attenuating the secondary hits ultimately leading to irreversible disease, explained the investigators.

IONIS-DGAT2_Rx, an antisense oligonucleotide (ASO) inhibitor of DGAT2, is under clinical investigation for NAFLD and NASH treatment. The team sought to evaluate its efficacy and safety in 44 participants who were randomized 2:1 to receive IONIS-DGAT2_Rx 250 mg (SC 1.25 mL; active arm) or placebo once-weekly for 13 weeks. [Lancet Gastroenterol Hepatol 2020;doi:10.1016/S2468-1253(20)30186-2]

Liver fat reduction

After 13 weeks, the active vs the placebo arm had greater absolute (mean, –5.2 percent vs –0.6 percent; p=0.026) and relative reductions in liver fat content (mean, –25.5 percent vs –2.4 percent; p=0.024), with no corresponding increases in other lipid parameters**.

“[These imply that] IONIS-DGAT2_Rx ameliorates hepatic steatosis without adversely affecting hepatic function [and] plasma lipid profiles … Our data suggest that reduction in steatosis by affecting de-novo lipogenesis can be achieved without any increase in circulating triglycerides, validating this therapeutic strategy in patients with NAFLD,” they said.

Twelve active agent recipients had ≥30-percent reduction in liver fat content, as opposed to only two in the placebo arm (p=0.077).

A 30-percent drop in fat percentage apparently signifies histologic improvements tied to NASH. [Therap Adv Gastroenterol 2016;9:692-701] “Therefore, our findings suggest that DGAT2 inhibition using an antisense approach should be assessed as treatment in patients with biopsy-proven NASH,” said the researchers.

Six serious adverse events (SAEs) were noted in four patients receiving the study drug, three of which occurring in one patient (ie, acute exacerbation of COPD***, cardiac arrest, ischaemic cerebral infarction). The other three patients reported one SAE each (ie, increased blood triglycerides, deep vein thrombosis, acute pancreatitis). Nonetheless, all were not drug-related.

Nip in the bud

Patients with NASH are at higher risk for developing decompensated cirrhosis and HCC^#. “The risk of progression to [the] advanced stages … provides a strong rationale to intervene at the initial stages, before the development of cirrhosis,” said Loomba.

“All of this is very encouraging and argues for the next step: longer term trials to further investigate the potential of this drug in [improving] liver histologic features associated with NASH,” he added.

Combining an ASO with a GalNAc3^## moiety reportedly increases productive delivery to hepatocytes through receptor-mediated uptake by the asialoglycoprotein receptor. [Nucleic Acid Ther 2019;29:16-32] This approach, as per the researchers, amplifies ASO potency up to 30 times vs unconjugated ASO, allowing for reduced doses and dosing frequency. As such, a GalNAc3-conjugated form of IONIS-DGAT2_Rx is being developed.