Alcoholic hepatitis drug candidate shows ‘life-saving potential’

Tarek I. Hassanein, MD
Tarek I. Hassanein

Data from a phase 2a clinical trial of DUR-928, an endogenous, small-molecule new chemical entity, for patients with alcoholic hepatitis demonstrated that the treatment led to greater reductions from baseline in bilirubin and MELD and improved Lille scores compared with a historical control group from a University of Louisville alcoholic hepatitis study, according to a company press release.

Healio Gastroenterology and Liver Disease spoke with study investigator Tarek I. Hassanein, MD, director of outreach services for liver transplantation at the University of California San Diego, about the results and the overall burden of alcoholic hepatitis worldwide.

The study comprised 12 patients with severe alcoholic hepatitis (MELD range, 21-30), seven patients with moderate alcoholic hepatitis (MELD range, 11-20), and a historical control group of 15 participants.

At day 7 and day 28, bilirubin levels were statistically significantly lower in treated patients than controls. Investigators observed the same for MELD at day 28. The median Lille score at day 7 was 0.1 and 16 patients achieved a Lille score less than 0.45 during the study. DUR-928 was well-tolerated with no serious adverse events.

James E. Brown, president and CEO of DURECT, noted in the press release that additional data from the trial will be presented at The Liver Meeting in Boston in November.

Healio: What is the current burden of alcoholic hepatitis in the U.S. and internationally?

Hassanein: Alcoholic hepatitis is the acute form of alcoholic liver disease caused by chronic alcohol abuse. While the true prevalence of the disease is difficult to calculate, a 2010 estimate of alcoholic hepatitis-related hospitalization was more than 320,000 and data reported by the U.S. Department of Health and Human Services’ Healthcare Cost and Utilization Project reports 117,000 patients hospitalized in 2016 that were diagnosed with alcoholic hepatitis. Additionally, costs related to alcoholic hepatitis in the United States were nearly $50,000 per patient. Alcoholic hepatitis has a very poor prognosis with a 28-day mortality ranging from 30% to 50% and is the second most common indication for liver transplant is the Western world.

Healio: How does improvement in bilirubin aid in treating patients with alcoholic hepatitis ?

Hassanein: While improvement in bilirubin does not directly aid in treating alcoholic hepatitis, bilirubin levels are used as a marker to identify hepatic function, or how healthy your liver is. Bilirubin is a biproduct of the normal breakdown of old red blood cells, and it is processed in the liver before it is excreted out of the body. Higher levels of total bilirubin than normal, which are usually around 1.2 mg/dL for adults, are a typical indicator of a liver malfunction. Severe alcoholic hepatitis, for instance, is represented by bilirubin levels over 10 mg/dL to 15 mg/dL. Results from DURECT’s phase 2a trial demonstrated that patients treated with DUR-928 experienced greater reductions from baseline in bilirubin after day 7 and day 28 than those in the control group, which suggest that treatment with DUR-928 has the potential to improve liver health and function.

Healio: What is the need for treatment options for alcoholic hepatitis ?

Despite the high impact of this acute condition there are limited and generally ineffective treatment options, which lead to a one-month mortality of 20% in moderate-stage patients and 40% in severe patients. In addition to stopping alcohol consumption, treatment options for alcoholic hepatitis patients are limited to medications to reduce liver inflammation, such as corticosteroids or pentoxifylline, which have large side effects and low therapeutic benefit. In addition, alcoholic hepatitis is currently a leading cause of liver transplant in the U.S.

There is a large unmet need for the development of effective and long-lasting therapies for alcoholic hepatitis patients. With a novel mechanism of action of epigenetically regulating metabolism, inflammation and cell survival, and the promising results of the phase 2a trial, DUR-928 has the potential to become a life-saving treatment alternative for alcoholic hepatitis patients. We are excited to continue to move this asset forward in the clinic.

Reference: www.durect.com

Disclosure: Hassanein reports he received grants or research support from DURECT.

Editor's note: This report was updated with a corrected data regarding comparison with a historical control group.
Tarek I. Hassanein, MD
Tarek I. Hassanein

Data from a phase 2a clinical trial of DUR-928, an endogenous, small-molecule new chemical entity, for patients with alcoholic hepatitis demonstrated that the treatment led to greater reductions from baseline in bilirubin and MELD and improved Lille scores compared with a historical control group from a University of Louisville alcoholic hepatitis study, according to a company press release.

Healio Gastroenterology and Liver Disease spoke with study investigator Tarek I. Hassanein, MD, director of outreach services for liver transplantation at the University of California San Diego, about the results and the overall burden of alcoholic hepatitis worldwide.

The study comprised 12 patients with severe alcoholic hepatitis (MELD range, 21-30), seven patients with moderate alcoholic hepatitis (MELD range, 11-20), and a historical control group of 15 participants.

At day 7 and day 28, bilirubin levels were statistically significantly lower in treated patients than controls. Investigators observed the same for MELD at day 28. The median Lille score at day 7 was 0.1 and 16 patients achieved a Lille score less than 0.45 during the study. DUR-928 was well-tolerated with no serious adverse events.

James E. Brown, president and CEO of DURECT, noted in the press release that additional data from the trial will be presented at The Liver Meeting in Boston in November.

Healio: What is the current burden of alcoholic hepatitis in the U.S. and internationally?

Hassanein: Alcoholic hepatitis is the acute form of alcoholic liver disease caused by chronic alcohol abuse. While the true prevalence of the disease is difficult to calculate, a 2010 estimate of alcoholic hepatitis-related hospitalization was more than 320,000 and data reported by the U.S. Department of Health and Human Services’ Healthcare Cost and Utilization Project reports 117,000 patients hospitalized in 2016 that were diagnosed with alcoholic hepatitis. Additionally, costs related to alcoholic hepatitis in the United States were nearly $50,000 per patient. Alcoholic hepatitis has a very poor prognosis with a 28-day mortality ranging from 30% to 50% and is the second most common indication for liver transplant is the Western world.

Healio: How does improvement in bilirubin aid in treating patients with alcoholic hepatitis ?

Hassanein: While improvement in bilirubin does not directly aid in treating alcoholic hepatitis, bilirubin levels are used as a marker to identify hepatic function, or how healthy your liver is. Bilirubin is a biproduct of the normal breakdown of old red blood cells, and it is processed in the liver before it is excreted out of the body. Higher levels of total bilirubin than normal, which are usually around 1.2 mg/dL for adults, are a typical indicator of a liver malfunction. Severe alcoholic hepatitis, for instance, is represented by bilirubin levels over 10 mg/dL to 15 mg/dL. Results from DURECT’s phase 2a trial demonstrated that patients treated with DUR-928 experienced greater reductions from baseline in bilirubin after day 7 and day 28 than those in the control group, which suggest that treatment with DUR-928 has the potential to improve liver health and function.

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Healio: What is the need for treatment options for alcoholic hepatitis ?

Despite the high impact of this acute condition there are limited and generally ineffective treatment options, which lead to a one-month mortality of 20% in moderate-stage patients and 40% in severe patients. In addition to stopping alcohol consumption, treatment options for alcoholic hepatitis patients are limited to medications to reduce liver inflammation, such as corticosteroids or pentoxifylline, which have large side effects and low therapeutic benefit. In addition, alcoholic hepatitis is currently a leading cause of liver transplant in the U.S.

There is a large unmet need for the development of effective and long-lasting therapies for alcoholic hepatitis patients. With a novel mechanism of action of epigenetically regulating metabolism, inflammation and cell survival, and the promising results of the phase 2a trial, DUR-928 has the potential to become a life-saving treatment alternative for alcoholic hepatitis patients. We are excited to continue to move this asset forward in the clinic.

Reference: www.durect.com

Disclosure: Hassanein reports he received grants or research support from DURECT.

Editor's note: This report was updated with a corrected data regarding comparison with a historical control group.