Q&A: DUR-928 ‘well tolerated’ for NASH in Phase 1b study
Nonalcoholic steatohepatitis is a severe form of fatty liver disease that affects 3% to 5% of the population in the United States and currently no approved drugs are available for treatment, according to a press release from Durect Corporation.
Durect announced positive data from a phase 1b trial of orally administered DUR-928 in NASH that demonstrated significant improvement in liver function. DUR-928 is reportedly the first endogenous epigenetic regulator that was clinically tested for difficult-to-treat liver diseases.
Healio Gastroenterology spoke with Eric Lawitz, MD, from the Texas Liver Institute, The University of Texas Health San Antonio and principal investigator of the phase 1b study to discuss the study design and its results. – by Monica Jaramillo
Healio: What was the purpose and design of the study?
Lawitz: The study was a randomized, open label, multicenter U.S. study designed to evaluate the safety, pharmacokinetic (PK), pharmacodynamic (PD) signals of biological activity of DUR-928 in NASH patients with stage 1 to 3 fibrosis, measured by clinical chemistry (including liver enzymes and metabolic panels)and biomarkers, as well as liver fat content via non-invasive imaging. DUR-928 was administered daily orally for 4 weeks at 3 different doses in 65 patients (50 mg once daily, n = 23;, 150 mg once daily, n = 21; or 600 mg, 300 mg twice daily, n=21). Patients were then followed up for an additional 4 weeks after dosing. DUR-928 is an orally available small molecule and the first endogenous epigenetic regulator clinically tested for difficult-to-treat acute organ injury and chronic liver diseases.
Healio: What were the results and key findings?
Lawitz: We saw an overall statistically significant improvement in serum liver enzymes, serum lipid profiles and liver imaging, suggesting an improvement in the liver and metabolic profile in these patients.
Both the 50 mg and 600 mg groups showed a statistically significant median reduction at day 28 from baseline of serum alanine aminotransferase levels with a decline of 16% and 17%, respectively. The 600 mg group also showed statistically significant median reductions at day 28 from baseline of serum aspartate aminotransferase with an 18% decline and gamma-glutamyl transferase reduction of 8%. Additionally, the 50 mg group had a statistically significant reduction at day 28 from baseline in liver stiffness as measured by Fibroscan with a reduced kPA by 10%.
Patients in the 50 mg group also had statistically significant median reduction at day 28 from baseline of serum triglycerides (–13%). Those in the 150 mg group saw statistically significant median reduction in LDL (–11%). With the evaluation of all patients with a baseline elevated triglyceride level above 200 mg/dL (n = 16) across the study we demonstrated a triglyceride median reduction of 24% at day 28 from baseline.
At day 28, 43% of patients in all three dose groups showed 10% or greater liver fat reduction from baseline as measured by MRI-PDFF. In this subgroup, there was a significant reduction from baseline in median liver fat content (–18%, –19%, and –23% in the 50 mg, 150 mg and 600 mg groups, respectively). The reduction of liver fat content was accompanied by a significant median reduction from baseline of serum ALT (–21%, –19%, and –32%, in the 50 mg, 150 mg and 600 mg groups, respectively).
Overall, DUR-928 was well tolerated at all dose levels with no serious adverse events reported.
We look forward to presenting the full data analysis at a future scientific meeting.
Healio: Will the results impact treatment of patients with NASH?
Lawitz: The results from this trial demonstrated improvements in liver and metabolic profiles in addition to imaging. DUR-928 was well tolerated. These results are encouraging especially considering the short treatment course of 4 weeks. The data have helped to establish proof of concept of the potential of DUR-928 to treat NASH patients through modulation of multiple biologic pathways and support further development of this epigenetic regulator in NASH. There are no treatment options currently approved for the treatment for NASH, one of the most common chronic liver diseases worldwide, with an estimated prevalence of more than 10% of adults in the United States, Europe, Japan and other developed countries. There is certainly great unmet need to develop a safe and effective treatment for these patients. These topline results for this 4-week proof of concept study suggest DUR-928 should be studied further to understand its potential role in NASH therapeutics.
Healio: What was the conclusion?
Lawitz: Both the efficacy and safety profiles of DUR-928 are encouraging especially considering the short treatment course of 4 weeks. The results provide a proof of concept of DUR-928’s activity in NASH and future trials will further define DUR-928’s role in NASH.
Healio: What is the take-home message of the study?
Lawitz: Seeing multiple hepatic markers moving in a positive direction is very promising, especially given the duration of 4 weeks of treatment. Not long ago, the same drug candidate, DUR-928, demonstrated positive safety and efficacy signals in alcoholic hepatitis patients in a phase 2a trial in which all 19 AH patients dosed survived the 28-day follow-up in contrast to a 26% historical mortality rate. Additionally, 74% of patients treated with DUR-928 were discharged within 4 days or less of treatment after one dose. These positive results from both trials validate the potential of DUR-928 and its ability to regulate lipid metabolism, inflammatory responses and cell survival. I am excited about further development of DUR-928 in NASH and other indications.
Healio: What is the next step in research?
Lawitz: We are going to complete the analysis of the full data set. Once the full data are finalized, they will be submitted for presentation at a future scientific meeting. We are also working with the trial sponsor, Durect Corporation, to determine next steps for potential future studies.