FDA Grants Breakthrough Therapy Designation for Larsucosterol in Alcohol-Associated Hepatitis

The FDA has granted breakthrough therapy designation (BTD) to larsucosterol (DURECT Corporation) to treat individuals with severe alcohol-associated hepatitis (AH), an acute form of alcohol-associated liver disease (ALD). The BTD was granted based on clinical evidence found in the phase 2b double-blind, placebo-controlled, international, multi-center AHFIRM study, according to study authors.¹

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“We’re pleased with the FDA’s decision to grant breakthrough therapy designation to larsucosterol, as it further recognizes its potential to save the lives of AH patients,” said James E. Brown, DVM, president and CEO of DURECT, in a news release.¹

ALD is related to long-term heavy alcohol intake.¹ According to research published in the National Library of Medicine, even a shorter duration of heavy alcohol abuse could lead to AH. Researchers noted that the typical patient ranges from 40 to 60 years old with a history of more than 100 g of alcohol consumption per day, for a decade.²

The study authors noted that AH is characterized by severe inflammation and liver cell damage that could result in liver failure, acute kidney injury, and multi-organ failure. In a previous retrospective analysis of 77 studies published from 1971 to 2016, the researchers found that the overall mortality from AH was 26% at 28 days, 29% at 90 days, and 44% at 180 days, according to study authors. However, there are no current FDA-approved therapies for individuals with AH.¹

Despite the available studies and research, in an analysis conducted in 2022, individuals lacked awareness of risk between alcohol consumption and life-threatening diseases like cancer. This data suggest the need for further education on the impacts of alcohol consumption to shift the public perception.³

Individuals diagnosed with ALD and AH could receive a liver transplant and it has become a more common form of treatment for the conditions. However, study authors noted that the number of liver transplants is small due to limited organ availability and high cost of the procedure. The average cost for a liver transplant surpasses $875,000 followed by a lifetime of immunosuppressive therapy, according to study authors.¹

“AH has a high mortality rate and no currently approved treatments, so there is a great need for a safe and effective therapy,” said Brown, in a press release.¹

Larsucosterol is an endogenous sulfated oxysterol and an epigenetic modulator that “inhibits DNA methylation, which subsequently modulates the expression of genes that are involved in cell signaling pathways associated with stress responses, cell death and survival, and lipid biosynthesis.”¹

The AHFIRM phase 2b trial evaluated the safety and efficacy of larsucosterol treatment among individuals with AH. The study authors noted that 307 individuals were included in the study and were randomly assigned to receive either a placebo with or without methylprednisolone capsules, a 30 mg dose of larsucosterol, or a 90 mg dose of larsucosterol. Additionally, the individuals who received larsucosterol all were given the same supportive care without the use of steroids.¹

The primary outcome was a 90-day incidence of mortality or liver transplant for individuals that received larsucosterol, compared to the placebo group, and the key secondary endpoint was 90-day survival.¹

“We continue to finalize the design of our planned registrational Phase 3 trial for larsucosterol, incorporating the recent FDA feedback and promising data from our completed Phase 2b AHFIRM trial. We look forward to releasing additional clinical data on larsucosterol and potentially bringing this therapy to patients as soon as possible,” said Brown, in a press release.¹

References

1. DURECT Corporation Receives FDA Breakthrough Therapy Designation for Larsucosterol in Alcohol-Associated Hepatitis. Durect. News release. May 21, 2024. Accessed May 21, 2024. https://www.durect.com/2024/05/durect-corporation-receives-fda-breakthrough-therapy-designation-for-larsucosterol-in-alcohol-associated-hepatitis/.

2. Alcoholic Hepatitis. National Library of Medicine. News release. June 5, 2023. Accessed May 21, 2024. https://www.ncbi.nlm.nih.gov/books/NBK470217/.

3. Study: More Than Half of US Adults Not Aware of Link Between Alcohol, Cancer. Pharmacy Times. News release. December 1, 2023. Accessed May 21, 2024. https://www.pharmacytimes.com/view/study-more-than-half-of-us-adults-not-aware-of-link-between-alcohol-cancer.