Novel antisense drug shows promise in slowing fatty liver disease

Date:
June 16, 2020
Source:
University of California - San Diego
Summary:
A first-in-class clinical trial suggests a novel treatment
measurably slowed progression of non-alcoholic fatty liver disease
to its more progressive and deadly form.



FULL STORY ========================================================================== 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. The findings are published in the June 15, 2020 online issue of The Lancet Gastroenterology and Hepatology.

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 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 United States," said the study's lead author Rohit Loomba, MD,
professor of medicine in the Division of Gastroenterology at UC San
Diego School of Medicine and director of the UC San Diego NAFLD Research Center. "Given its relative ubiquity and its potentially calamitous consequences, safe and effective treatments are absolutely needed."
In the double-blind, randomized, 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 percent 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."

========================================================================== Story Source: Materials provided by
University_of_California_-_San_Diego. Original written by Scott
LaFee. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Rohit Loomba, Erin Morgan, Lynnetta Watts, Shuting Xia, Lisa
A Hannan,
Richard S Geary, Brenda F Baker, Sanjay Bhanot. Novel
antisense inhibition of diacylglycerol O-acyltransferase
2 for treatment of non- alcoholic fatty liver disease: a
multicentre, double-blind, randomised, placebo-controlled phase
2 trial. The Lancet Gastroenterology & Hepatology, 2020; DOI:
10.1016/S2468-1253(20)30186-2 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/06/200616135737.htm

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