First-of-Its-Kind Antisense Drug May Become Novel Treatment for Fatty Liver Disease

A new drug in its second phase of trials may become part of treating fatty liver disease. Before a recent breakthrough, there had been no FDA-approved drugs for this disease which caused doctors to prescribe the antioxidant vitamin E and pioglitazone, medicine for diabetes.

The antisense inhibitor is the first of its kind, developed by an international team led by the University of California San Diego School of Medicine. Antisense therapy has been a focus for pharmaceuticals to develop US Food and Drug Administration (FDA)-approved medicine for diseases such as arthritis, Alzheimer's, and Parkinson's.

Antisense is a DNA strand within a gene that does not code and becomes a template for producing messenger RNA (mRNA). In this case, scientists use the same term meaning to silence genes, such as damaged DNA from diseases and cancer.

The international team focused on one illness, non-alcoholic fatty liver disease (NAFLD) which is a chronic illness that damages hundreds of millions of people's metabolism function. This occurs when harmful amounts of fat accumulate in liver cells from reasons aside from excessive alcohol consumption.

There is No Cure to Fatty Liver Disease.. Just Yet

Although genetics and an individual's diet are factors of the disease, the cause remains unknown. Moreover, it is only when the illness is already well-advanced that symptoms appear and may have even evolved into non-alcoholic steatohepatitis (NASH) which can lead to cirrhosis. Liver cancer and failure may even lead to a liver transplant since there is no cure.

Doctor 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 Center, said '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.'

'Given its relative ubiquity and its potentially calamitous consequences, safe and effective treatments are absolutely needed.' Common treatment involved programs for patients to have healthier diets, more exercise, losing weight, and controlling other factors.

Significant Results

In the study's Phase II trial, 44 participants at 16 locations in Canada, Hungary, and Poland took part in a 13-week experiment. Half of the participants were injected with the antisense inhibitor IONIS-DGAT2 while the other half was treated with a placebo. Produced by Carlsbad-based Ionis Pharmaceuticals, the inhibitor interferes with Diacylglycerol-O-acyltransferase (DGAT2) an enzyme that accelerates triglyceride production, the fat that the body stores. 'High levels of triglycerides boost fat storage throughout the body, including the liver.'

Those who received IONIS-DGAT2 had a significant reduction in fatty liver levels after 13 weeks without an increase in sugar levels. However, during the trial, six participants experienced harmful events that the team determined was unrelated to the drug. One participant had a cardiac arrest while another experienced deep vein thrombosis or a blood clot.

Loomba explained that their 'These findings showed [a] robust reduction in liver fat by MRI without corresponding increases in blood lipids. A majority of the patients achieved '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 [the] 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 the improvement of liver histologic features associated with NASH, the progressive subtype of NAFLD,' she said