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HomeHepatologyNovel antisense drug shows promise in slowing fatty liver disease

Novel antisense drug shows promise in slowing fatty liver disease

Using a first-of-its-class drug in a clinical trial, an international research effort headed by a scientist at University of California San Diego School of Medicine reports that inhibition of a key enzyme safely and effectively improved the health of persons with non-alcoholic fatty liver disease (NAFLD), a chronic metabolic disorder that affects hundreds of millions of people worldwide.

The gene silencing approach represents a novel way to reverse NAFLD.

NAFLD occurs when fat accumulates in liver cells due to causes other than excessive alcohol intake. The precise cause is not known, but diet and genetics are believed to play substantial roles. The condition is typically not noticed until the disease is well-advanced, and perhaps has transitioned to non-alcoholic steatohepatitis (NASH), a progressive form that can lead to cirrhosis, liver cancer and liver failure.

There is no cure. Treatment primarily consists of ameliorating contributory factors, such as losing weight, improving diet, exercising more and controlling for other conditions, such as diabetes and hypertension. No US Food and Drug Administration-approved medications exist. In worst cases, a liver transplant may be required.

“NAFLD wasn’t even recognized as a disease three decades ago; now it is alarmingly prevalent, affecting roughly one-quarter of all Americans and emerging as one of the leading causes for liver transplant in the US,” said the study’s lead author Dr Rohit Loomba, professor of medicine in the division of gastroenterology at UC San Diego School of Medicine and director of the UC San Diego NAFLD Research Centre. “Given its relative ubiquity and its potentially calamitous consequences, safe and effective treatments are absolutely needed.”

In the double-blind, randomised, placebo-controlled Phase II trial, Loomba and colleagues enrolled 44 qualifying participants at 16 sites in Canada, Poland and Hungary.

For 13 weeks, participants were injected with either an antisense inhibitor called IONIS-DGAT2 or a placebo. The inhibitor, produced by Carlsbad-based Ionis Pharmaceuticals, interferes with Diacylglycerol-O-acyltransferace or DGAT2, one of two enzyme forms required to catalyze or accelerate the production of triglycerides, a type of fat found in blood. High levels of triglycerides boost fat storage throughout the body, including the liver.

The researchers found that after 13 weeks of treatment, participants who received the enzyme inhibitor experienced measurable reductions in fatty liver levels compared to baseline, without elevated levels of fats, enzymes or sugars in the blood. There were six reported serious adverse events, including a cardiac arrest and deep vein thrombosis, but the researchers determined the events were unrelated to the study drug.

“These findings showed robust reduction in liver fat by MRI without corresponding increases in blood lipids,” said Loomba. “Given significant proportion of patients achieving roughly a 30% reduction in MRI-PDFF, the threshold that corresponds with higher odds of histologic response when treated for a longer duration, it looks like after just 13 weeks of treatment, the drug was actually slowing progression of NAFLD to NASH.

“All of this is very encouraging and argues for the next step: longer term trials to further investigate the potential of this drug in improvement of liver histologic features associated with NASH, the progressive sub-type of NAFLD.”

Abstract
Background: Diacylglycerol- O-acyltransferase 2 (DGAT2) is one of two enzyme isoforms that catalyse the final step in the synthesis of triglycerides. IONIS-DGAT2 Rx is an antisense oligonucleotide inhibitor of DGAT2 that is under clinical investigation for the treatment of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). The aim of this trial was to examine the safety, tolerability, and efficacy of IONIS-DGAT2 Rx versus placebo in reducing liver fat in patients with type 2 diabetes and NAFLD.
Methods: This double-blind, randomised, placebo-controlled, phase 2 study consisted of a 2-week screening period, a run-in period of up to 4 weeks, a 13-week treatment period of once-weekly dosing, and a 13-week post-treatment follow-up period. The study was done at 16 clinical research sites in Canada, Poland, and Hungary. Eligible participants were aged 18–75 years, had a body-mass index at screening between 27 kg/m 2 and 39 kg/m 2, haemoglobin A 1c (HbA 1c) levels from 7·3% to 9·5%, and liver fat content 10% or greater before randomisation, and agreed to maintain a stable diet and exercise routine throughout the study. Enrolled participants were stratified on the basis of liver fat content during the run-in period (<20% or ≥20%) and then centrally randomised (2:1) to receive once weekly subcutaneous injection of 250 mg IONIS-DGAT2 Rx or placebo for 13 weeks. Participants, investigators, funder personnel, and the clinical research organisation staff, including central readers of MRI scans, were all masked to treatment identity. The primary endpoints were the safety, tolerability, and pharmacodynamic effect of IONIS-DGAT2 Rx on hepatic steatosis, according to absolute reduction from baseline in liver fat percentage as quantified by MRI-estimated proton density fat fraction and assessed in the per-protocol population. Pharmacodynamic performance was determined in the per-protocol population by the change in liver fat content from baseline to 2 weeks after the last dose. The per-protocol population included all randomised participants who received at least ten doses of study drug, with the first four doses administered in the first 5 weeks, did not miss more than three consecutive weekly doses, and who had no protocol deviations that might affect efficacy. All randomised participants who received at least one dose of study drug were included in the safety analysis. This study is registered with ClinicalTrials.gov, NCT03334214.
Findings: Between Nov 3, 2017, and Nov 28, 2018, we screened 173 people for eligibility. 44 were enrolled and randomly assigned to receive either IONIS-DGAT2 Rx (29 participants) or placebo (15 participants). After 13 weeks of treatment, the mean absolute reduction from baseline was −5·2% (SD 5·4) in the IONIS-DGAT2 Rx group compared with −0·6% (6·1) in the placebo group (treatment difference −4·2%, 95% CI −7·8 to −0·5, p=0·026). Reductions in liver fat were not accompanied by hyperlipidaemia, elevations in serum aminotransferases or plasma glucose, changes in bodyweight, or gastrointestinal side-effects compared with placebo. Six serious adverse events occurred in four patients treated with IONIS-DGAT2 Rx. No serious adverse events were reported in the placebo group. One of four patients reported three serious adverse events: acute exacerbation of chronic obstructive pulmonary disease, cardiac arrest, and ischaemic cerebral infarction, each considered severe and not related to study drug. Three of four patients reported one serious adverse event of increased blood triglycerides (severe, unrelated to study drug), deep-vein thrombosis (severe, unlikely to be related to study drug), and acute pancreatitis (mild, unrelated to study drug).
Interpretation: Our results suggest that DGAT2 antisense inhibition could be a safe and efficacious strategy for treatment of NAFLD and support further investigation in patients with biopsy-proven NASH. Based on the pharmacological target, the response to treatment observed in this study population could extend to the broader population of patients with NAFLD.
Funding: Ionis Pharmaceuticals.

Authors
Rohit Loomba, Erin Morgan, Lynnetta Watts, Shuting Xia, Lisa A Hannan, Richard S Geary, Brenda F Baker, Sanjay Bhanot

 

[link url="https://ucsdnews.ucsd.edu/pressrelease/novel-antisense-drug-shows-promise-in-slowing-fatty-liver-disease"]University of California San Diego School of Medicine material[/link]

 

[link url="https://www.thelancet.com/journals/langas/article/PIIS2468-1253(20)30186-2/fulltext"]The Lancet Gastroenterology & Hepatology abstract[/link]

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