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DGAT2 a potential therapeutic target for fatty liver?

Audrey Abella
05 Aug 2020

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-DGAT2Rx, 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-DGAT2Rx 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-DGAT2Rx 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-DGAT2Rx is being developed.

 

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Most Read Articles
01 Dec 2020
Tetanus toxoid 5 Lf, diphtheria toxoid 2 Lf, pertussis toxoid 2.5 mcg, filamentous haemagglutinin 5 mcg, fimbriae types 2 and 3 5 mcg, pertactin 3 mcg
Dr. Hsu Li Yang, Dr. Tan Thuan Tong, Dr. Andrea Kwa, 08 Jan 2021
Antimicrobial resistance has become increasingly dire as the rapid emergence of drug resistance, especially gram-negative pathogens, has outpaced the development of new antibiotics. At a recent virtual symposium, Dr Hsu Li Yang, Vice Dean (Global Health) and Programme Leader (Infectious Diseases), NUS Saw Swee Hock School of Public Health, presented epidemiological data on multidrug-resistant (MDR) gram-negative bacteria (GNB) in Asia, while Dr Tan Thuan Tong, Head and Senior Consultant, Department of Infectious Diseases, Singapore General Hospital (SGH), focused on the role of ceftazidime-avibactam in MDR GNB infections. Dr Andrea Kwa, Assistant Director of Research, Department of Pharmacy, SGH, joined the panel in an interactive fireside chat, to discuss challenges, practical considerations, and solutions in MDR gram-negative infections. This Pfizer-sponsored symposium was chaired by Dr Ng Shin Yi, Head and Senior Consultant of Surgical Intensive Care, SGH.
Tristan Manalac, Yesterday
While antibody titres against SARS-CoV-2 wane with time, the immune system is capable of producing memory B-cells that can last for at least 6 months after infection, suggesting that the body will be able to protect itself in the case of re-exposure, according to a new study.
Jairia Dela Cruz, 5 days ago
Spending too much time sitting cannot be good for the body, and rising to one's feet breaks up such a behaviour and yields small, but meaningful, reductions in certain cardiovascular disease (CVD) risk factors, according to the results of a meta-analysis.