DUR-928

Nonalcoholic Steatohepatitis (NASH)

DUR-928 is an investigational product and has not been approved by the FDA for marketing in the U.S. for any indication.

DUR-928 has been evaluated in a Phase 1b randomized, open-label, multi center US clinical trial to assess safety, pharmacokinetics, pharmacodynamics and signals of biological activity in NASH patients with stage 1-3 fibrosis, measured by clinical chemistry and biomarkers (e.g., liver enzymes and triglycerides) as well as liver fat content via non-invasive imaging.

DUR-928 was orally administered daily in 65 patients for 4 weeks at doses of 50 mg once a day (n=23), 150 mg once a day (n=21) and 300 mg twice a day (n=21) and followed up for an additional 4 weeks.

NASH Study Schematic

NASH Study Schematic

PO (by mouth); QD (once a day); BID (twice a day)

Topline data has shown significant improvements in liver function, including improvement in both serum liver enzymes and liver imaging and improvement in serum lipid profile. Together with a good safety profile with no significant adverse events reported, overall, these data support further development of DUR-928 in NASH.

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

Study Results (Topline)

DUR-928 showed positive results across all dose groups. Both the 50 mg and 600 mg (300 mg twice a day) dose groups showed a statistically significant median reduction at day 28 from baseline of serum alanine aminotransferase (ALT) levels at -16% and -17%, respectively (see Table below). 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.

For all tables below, * Indicates p-value <0.05; ** indicates p < 0.01; *** indicates p <0.001

Clinical Chemistry
Median 50 mg QD
150 mg QD
300 mg BID
ALT -16%*
(n=22)
-10%
(n=20)
-17%***
(n=20)
AST -14%
(n=22)
-9%
(n=20)
-18%**
(n=20)
GGT -6%
(n=23)
-1%
(n=20)
-8%*
(n=21)
LDL-C  -6%
(n=22)  
-11%*
(n=20)
-7%
(n=21)
 Non-HDL-C -8%
(n=23)  
-5%
(n=20)
 -1%
(n=21)
 Triglycerides -13%*
(n=23)
 -3%
(n=20)
 -2%
(n=21)
ALT (alanine aminotransferase); AST (aspartate aminotransferase); GGT (gamma-glutamyl transferase);
LDL-C ( Low-Density Lipoprotein – Cholesterol); Non-HDL-C (Total cholesterol excluding High-Density Lipoprotein-Cholesterol);
QD (once a day); BID (twice a day)

 

Non-Invasive Imaging
Median 50 mg QD
150 mg QD
300 mg BID
MRI-PDFF -7%
(n=21)
-7%
(n=21)
-4%
(n=21)
Fibroscan -10%**
(n=22)
-9%
(n=20)
-1%
(n=21)
MRI-PDFF (Magnetic Resonance Imaging - Proton Density Fat Fraction) is a non-invasive measure of the proportion of liver tissue which is composed of fat; FibroScan is a specialized ultrasound machine that measures the stiffness of liver tissue.


The following tables show Day 28 vs Baseline data from patients with ≥ 10% Reduction in MRI-PDFF

Clinical Chemistry
Patients with ≥ 10% Reduction in MRI-PDFF
Median 50 mg QD
(n=9)
150 mg QD
(n=9)
300 mg BID
(n=9)
ALT -21%** -19%* -32%***
AST -24%** -21% -39%***
GGT -13%*** -16%* -14%
LDL-C  -7% -11% -8%*
 Non-HDL-C -10% -8% -12%*
 Triglycerides -9% 0% -8%
ALT (alanine aminotransferase); AST (aspartate aminotransferase); GGT (gamma-glutamyl transferase);
LDL-C ( Low-Density Lipoprotein – Cholesterol); Non-HDL-C (Total cholesterol excluding High-Density Lipoprotein-Cholesterol);
QD (once a day); BID (twice a day)

 

Non-Invasive Imaging
Patients with ≥ 10% Reduction in MRI-PDFF
Median 50 mg QD
(n=9)
150 mg QD
(n=9)
300 mg BID
(n=9)
MRI-PDFF -18%*** -19%*** -23%***
Fibroscan -7% -9%** -9%
MRI-PDFF (Magnetic Resonance Imaging - Proton Density Fat Fraction) is a non-invasive measure of the proportion of liver tissue which is composed of fat; FibroScan is a specialized ultrasound machine that measures the stiffness of liver tissue.

Nonalcoholic steatohepatitis (NASH) is the most severe and progressive form of nonalcoholic fatty liver disease (NAFLD) and the most common chronic liver disease worldwide, with an estimated prevalence of more than 10% of adults in the United States, Europe, Japan, and other developed countries, expected to double by 2030. No drug is currently approved for treatment of NAFLD or NASH.

DURECT currently holds the worldwide development and commercialization rights to DUR-928 and other molecules identified as part of the Epigenetic Regulator Program.