Patient meeting with doctor

Clinical Development

Clinical Trials

Alcohol-Associated Hepatitis (AHFIRM)

AHFIRM Logo

We are currently conducting a Phase 2b study (AHFIRM) in subjects with Alcohol-associated Hepatitis to evaluate saFety and effIcacy of  LaRsucosterol treatMent.

AHFIRM is a randomized, double-blind, placebo-controlled trial targeting more than 60 clinical trial sites across the U.S., EU, U.K., and Australia.

The outcomes measured will be 90-day mortality or liver transplant, 90-day mortality, 28-day mortality or liver transplant, and 28-day mortality in patients treated with larsucosterol compared to those treated with placebo plus standard of care.

Download AHFIRM Poster Presentation (PDF)
View More Information on ClinicalTrials.gov

Expanded Access Policy

After careful review, DURECT has determined that it cannot offer its product candidates for expanded access (sometimes called “compassionate use”) at this time. DURECT believes that investigational products should be studied in patients as part of clinical trials designed to obtain data on safety and efficacy.

If you have questions about DURECT’s expanded access policy, please email us at medaffairs@DURECT.com.

Pipeline

Preclinical

Phase 1

Phase 2

Phase 3

Marketed

Larsucosterol

Alcohol-Associated Hepatitis (AH)
Intraveneous administration

Preclinical

Phase 1

Phase 2

Phase 3

Marketed

Nonalcoholic Steatohepatitis (NASH)
Oral administration

Preclinical

Phase 1

Phase 2

Phase 3

Marketed

New Chemical Entities

Hematology/Oncology
Small molecules

Preclinical

Phase 1

Phase 2

Phase 3

Marketed

Larsucosterol has demonstrated encouraging results in human studies, including a Phase 2a clinical trial in AH and an open label Phase 1b trial in NASH.

A randomized, controlled, potentially pivotal Phase 2b trial in AH patients (AHFIRM) is currently underway.

Given the clinical profile to date, we believe larsucosterol has the potential to treat multiple acute organ injuries and chronic liver diseases.

Preclinical

Phase 1-3

Marketed

POSIMIR®
(Non-opioid bupivacaine solution)

Post surgical pain (following arthroscopic subacromial decompression)

Preclinical

Phase 1-3

Marketed

POSIMIR® is sold in the U.S. by Innocoll Pharmaceuticals
DURECT maintains ex-U.S. rights

Alcohol-Associated Hepatitis (AH)

AH is an acute life-threatening form of alcohol-associated liver disease (ALD), which can occur in individuals who chronically misuse alcohol – frequently after increased consumption – regardless of age, gender, education or income. It is characterized by severe inflammation and destruction of liver tissue (i.e., necrosis). AH accounts for roughly 158,000 hospitalizations in the U.S. per year.1 Approximately 30% of patients die within 90 days of hospitalization.2 The charges for each hospitalization episode resulting in death are approximately $167,000.1 There is currently no FDA or EMA approved treatment for AH, and novel therapeutic strategies are needed to improve survival.3,4 A number of clinical practice guidelines, including from AASLD and ACG, recommend corticosteroids as first-line treatment for severe AH despite limited and inconsistent survival benefits and widely acknowledged contraindications.5,6,7 Although liver transplantation is indicated for patients with severe AH, the procedure is costly ($875,000 per patient on average8), requires lifelong immunosuppression, and may be limited by the availability of donated organs.6,9 Despite these drawbacks, the rate of liver transplantation for AH has increased rapidly in the U.S.10

Epigenetic modulation in AH

One form of epigenetic modulation is DNA methylation. The enzymes responsible for DNA methylation are known as DNA methyltransferases (DNMTs). Studies have shown increased expression of two DNMTs (DNMT1 and DNMT3a) in patients with severe AH, but not in normal subjects or in patients with milder disease or other types of liver disease.11 Given larsucosterol’s proposed mechanism of action of inhibiting DNMTs, there is strong rationale for investigating larsucosterol for the treatment of AH.12
Read More About Epigenetic Modulation

Larsucosterol potential in AH

Larsucosterol demonstrated its potential to improve liver health and function as well as the clinical profile of AH patients in a Phase 2a, open-label, multicenter, dose escalation study. This study was conducted in 19 patients with severe or moderate AH.13

  • Survival: All patients treated with larsucosterol survived the 28-day follow-up period compared to a 26% historical 28-day mortality rate
  • Time to discharge: 74% of patients treated with larsucosterol were discharged within 3 days of treatment after one dose
  • Prognostic indicators of AH mortality: Significantly improved after larsucosterol treatment, including Lille score and bilirubin, which were significantly reduced from baseline in larsucosterol-treated patients
  • Safety: Larsucosterol was well tolerated at all doses tested, with no drug-related serious adverse events

Learn more about the Phase 2a trial results in our AH factsheet or a peer-reviewed American Journal of Gastroenterology article.

Factsheet

Article

The AHFIRM Trial

We are currently conducting a Phase 2b study (AHFIRM) to evaluate the safety, efficacy, and potential lifesaving capacity of larsucosterol treatment in patients with severe AH.

Learn More About the Clinical Trial

Additional Evidence of Larsucosterol’s Clinical Potential

The potential of larsucosterol has been demonstrated in human studies beyond AH. Larsucosterol was evaluated in a Phase 1b clinical trial in patients with nonalcoholic steatohepatitis (NASH) with stage 1 to 3 fibrosis, showing signals of potential efficacy with no drug related serious adverse events to date.14 Data showed significant improvements in liver function following larsucosterol treatment, including improvement from baseline in serum liver enzymes, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT), in serum lipid profiles such as low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDLC), and triglycerides, in certain biomarkers of liver health, such as CK-18, and in liver fat. It demonstrated improvement from baseline in insulin resistance and liver stiffness. Larsucosterol was well tolerated in all subjects.

Larsucosterol potential in NASH

Larsucosterol has shown a positive safety profile and signals of potential efficacy in a completed Phase 1b clinical trial in NASH patients with stage 1 to 3 fibrosis. The randomized, open-label, multicenter US clinical trial assessed safety, pharmacokinetics, pharmacodynamics, and signals of biological activity, measured by clinical chemistry and biomarkers (eg, liver enzymes and triglycerides) as well as liver fat content via noninvasive imaging.

Data showed significant improvements in liver function following larsucosterol treatment, including:

  • Improvement from baseline in serum liver enzymes, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT), in serum lipid profiles such as low-density lipoprotein cholesterol (LDL-C), non–high-density lipoprotein cholesterol (HDLC), and triglycerides, in certain biomarkers of liver health, such as CK-18 and in liver fat, measured by MRI-PDFF imaging
  • Improvement from baseline in insulin resistance
  • Improvements from baseline in liver stiffness
  • A positive safety profile: Larsucosterol was well tolerated in all subjects

Overall, these data support further development of larsucosterol in NASH.

Read More in Our EASL Presentation

References

  1. Data on File
  2. Hughes E, Hopkins LJ, Parker R. Correction: Survival from alcoholic hepatitis has not improved over time. PLoS One. 2018;13:e0195857.
  3. Thanda Han MA, Pyrsopoulos N. Emerging therapies for alcoholic hepatitis. Clin Liver Dis. 2021;25:603-624.
  4. Vergis N, Atkinson SR, Thursz MR. The future of therapy for alcoholic hepatitis – Beyond corticosteroids. J Hepatol. 2019;70:785-787.
  5. Crabb DW, Im GY, Szabo G, Mellinger JL, Lucey MR. Diagnosis and treatment of alcohol-associated liver diseases: 2019 practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2020;71:306-333.
  6. Singal AK, Bataller R, Ahn J, Kamath PS, Shah VH. ACG clinical guideline: alcoholic liver disease. Am J Gastroenterol. 2018;113:175-194.
  7. Shipley LC, Singal AK. Liver transplantation for alcoholic hepatitis. Transl Gastroenterol Hepatol. 2020;5:26.
  8. Bentley TS, Ortner NJ. 2020 U.S. organ and tissue transplant: cost estimates, discussion, and emerging issues. February 18, 2020. Accessed April 9, 2022. https://www.milliman.com/-/media/milliman/pdfs/articles/2020-us-organ-tissue-transplants.ashx
  9. Tornai D, Szabo G. Emerging medical therapies for severe alcoholic hepatitis. Clin Mol Hepatol. 2020;26:686-696.
  10. Cotter TG, Sandıkçı B, Paul S, et al. Liver transplantation for alcoholic hepatitis in the United States: Excellent outcomes with profound temporal and geographic variation in frequency. Am J Transplant. 2021;21:1039-1055.
  11. Argemi J, Latasa MU, Atkinson SR, et al. Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis. Nat Commun. 2019;10(1):3126. doi:10.1038/s41467-019-11004-3
  12. Wang Y, Lin W, Brown JE, et al. 25-Hydroxycholesterol 3-sulfate is an endogenous ligand of DNA methyltransferases in hepatocytes. J Lipid Res. 2021;62:100063. doi:10.1016/j.jlr.2021.100063
  13. Hassanein T, McClain CJ, Vatsalya V, et al. Safety, Pharmacokinetics, and Efficacy Signals of Larsucosterol (DUR-928) in Alcohol-Associated Hepatitis. Am J Gastroenterol. 2023;10.14309/ajg.0000000000002275.
  14. Lawitz E, Hassanein T, Denham D, et al. Efficacy signals of 4-week oral DUR-928 in NASH subjects. Presented at: 2021 International Liver Conference; June 23-26, 2021; virtual. Poster no. 1198.
Scroll to Top