DURECT Corporation announced positive topline results from its Phase 1b clinical study of orally administered DUR-928 in nonalcoholic steatohepatitis (NASH) patients.

A total of 65 patients completed the study, in which DUR-928 was orally administered daily for 4 weeks at 50 mg (n=23), 150 mg (n=21), or 600 mg (300 mg BID (n=21)). Both the 50 mg and 600 mg dose groups showed a statistically significant median reduction at day 28 from baseline of serum alanine aminotransferase (ALT) levels at -16% and -17%, respectively. The 600 mg dose group also showed statistically significant median reductions at day 28 from baseline of serum aspartate aminotransferase (AST) (-18%) and gamma-glutamyl transferase (GGT) (-8%), and the 50 mg dose group had a statistically significant reduction at day 28 from baseline in liver stiffness as measured by Fibroscan (-10%).

Patients in the 50 mg or 150 mg dose groups also had statistically significant median reduction at day 28 from baseline of serum triglycerides (-13% in the 50 mg group) or LDL-C (-11% in the 150mg group). Patients with elevated baseline triglycerides (≥200 mg/dL; n=16) across all dose groups had a median reduction at day 28 from baseline of -24% (p <0.01).

At day 28, 43% of patients in all three dose groups showed ≥ 10% liver fat reduction from baseline as measured by magnetic resonance imaging - proton density fat fraction (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).

DUR-928 was well tolerated at all three doses evaluated. There were no serious adverse events reported during the study. Pharmacokinetic (PK) parameters after repeat dosing were comparable to those after a single dose (from a prior study), indicating no accumulation after repeat dosing.  Drug exposure was dose dependent.

Results, including biomarker data, are still being analyzed. DURECT plans to present additional results and data analyses at a future scientific meeting.

"The results from this trial are encouraging given the short treatment course of 4 weeks to establish proof of concept," said Dr. Eric Lawitz, Texas Liver Institute, University of Texas Health San Antonio and principal investigator of the study. "I look forward to further development of what appears to be a well-tolerated drug with the potential to treat NASH patients through modulation of multiple biologic pathways."

"It is impressive to see these improvements after such a short treatment period," said James E. Brown, D.V.M., President and CEO of DURECT. "Multiple important liver enzymes, plasma lipids and imaging results moving in the same direction is a very promising indication of DUR-928's potential in NASH."

The study was a randomized, open label, multi-center US study to evaluate safety, pharmacokinetics and signals of biological activity of DUR-928 in NASH patients with stage 1-3 fibrosis. A total of 65 patients completed the study. DUR-928 was orally administered daily at 50 mg (n=23), 150 mg (n=21), or 600 mg (300 mg BID (n=21)). Patients in this trial were dosed daily for 4 weeks and followed up for an additional 4 weeks.

DUR?928 is a new chemical entity and the first endogenous epigenetic regulator clinically tested for difficult-to-treat liver diseases. It is the lead candidate in DURECT's Epigenetic Regulator Program and is currently being tested in Phase 1 and Phase 2 development. An endogenous, orally bioavailable, small molecule, DUR-928 has been shown in preclinical studies to play an important regulatory role in lipid homeostasis, inflammation, and cell survival. Human applications may include acute organ injury such as alcoholic hepatitis (AH), acute liver or kidney injury in COVID-19 patients, and chronic metabolic diseases such as nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), and other liver diseases.