DUR-928

Alcoholic Hepatitis

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

In a Phase 2a clinical trial of DUR-928 in 19 patients with severe or moderate alcoholic hepatitis (AH), all patients treated with DUR-928 survived the 28-day follow-up period and there were no drug-related serious adverse events. Patients treated with DUR-928 in this trial had a statistically significant reduction from baseline in bilirubin at day 7 and 28 and MELD at day 28. Lille scores were also statistically significantly lower than those from a well-matched group of patients in a contemporary ongoing trial as well as several published historical controls. 74% of all DUR-928 treated patients and 67% of those with severe AH were discharged from the hospital within four days of receiving a single dose of DUR-928.

Lille

Lille scores are used in clinical practice to help determine the prognosis and response of AH patients after seven days of treatment. The lower the Lille score, the better the prognosis. Patients with a Lille score below 0.45 have a six-month survival rate of 85% compared to those with Lille scores above 0.45, with only a 25% six-month survival rate. 1The chart below shows the Lille scores for individual AH patients treated with DUR-928 plotted as a function of their baseline MELD scores. In our study, the median Lille score for patients treated with DUR-928 was 0.10. The median Lille score among a cohort of 15 patients treated with standard of care at the University of Louisville (UL) was 0.41 (shown as historical control).

1Louvet A et al. Hepatology 2007; 45: 1348-54.
 

The chart below shows individual patient Lille scores plotted as a function of their baseline MELD scores.

DUR-928 MELD vs Lille
 
1) Our advisor, Dr. Craig McClain from the University of Louisville (UL), shared anonymized data from his study, in which 15 AH patients with initial MELD scores ranging from 15-30 received either supportive care alone (n=8 moderate AH patients) or supportive care with corticosteroids (n=7 severe AH patients). Two of the UL patients died by day 28.
2)One patient in the DUR-928 group did not return for the day 7 visit.
3) Lille scores in the DUR-928 patients were significantly lower than that of the UL patients (p=0.01; Wilcoxon's Rank Sum Test). 
 

As shown below, 100% of patients in the 30mg and 90mg DUR-928 dosing groups were treatment responders based on their Lille scores. 89% of the overall DUR-928 patient population were treatment responders. Patients with severe AH, as defined by Maddrey’s Discriminant Function >32 or MELD 21-30, and baseline serum bilirubin above 8 mg/dL, had similarly high response rates to DUR-928 treatment.

AH Patient Category  n1

Responders

(Lille<0.45)

Lille Median

(Quartile)  

 All Patients2

30 or 90mg DUR-9283

18

14 

 89%

100%

 0.10 (0.04, 0.20)

0.05 (0.04, 0.19)

 

DF>32 (SAH)2

30 or 90mg DUR-9283

 

15

11 

 

87%

100%

 

0.19 (0.05, 0.22)

0.12 (0.05, 0.19) 

 

MELD 21-302

30 or 90mg DUR-9283

 

12

 

83%

100%

 

0.19 (0.11, 0.25)

0.19 (0.10, 0.19

 

Baseline bilirubin >8mg/dl2

30 or 90mg DUR-9283

 

11

 

82%

100%

 

0.10 (0.05, 0.20)

0.10 (0.05, 0.19)  

 
1 One patient did not return for Day 7 visit; 2 Including patients receiving 30, 90 and 150mg of DUR-928;3 Excluding patients receiving 150mg of DUR-928.
Maddrey’s Discriminant Function (DF) is calculated using the patient’s prothrombin time and serum bilirubin level.
 

The Lille scores of patients treated with DUR-928 in this trial were also significantly lower than several selected published historical studies (Hepatology 2007, 45:1348-1354; Gut 2011, 60:255-260), in which patients had similar baseline bilirubin, albumin, Creatinine, prothrombin time and DF scores, and were treated with standard of care with or without corticosteroids. Of course, due to the historical nature of these studies, such comparisons should be taken cautiously.

A sub-group analysis was conducted to compare severe AH patients in the 30mg and 90mg dosing groups (n=8) with well-matched severe AH patients (n=13) who received corticosteroids for 28 days in a contemporaneous study at the University of Louisville (UL). Patients shown below in the UL steroid group had a baseline mean MELD of 24.46 and baseline mean Maddrey’s DF score of 62.98. The 8 patients in the DUR-928 group had baseline mean MELD of 24.50 and baseline mean Maddrey’s DF score of 61.25. All patients treated with DUR-928 survived the 28-day follow up period, while 3 patients in the UL steroid group died within the first 28 days.

 
The steroid group in the above graph includes the 7 severe AH patients treated with steroids from the UL group shown in the MELD vs Lille graph above plus an additional 6 severe AH patients subsequently treated in the UL study
 

Bilirubin

Bilirubin is formed by the breakdown of red blood cells in the body. The level of total bilirubin in the blood is an indication of how the liver is functioning. In this trial, patients treated with DUR-928 had a significant early reduction from baseline in bilirubin by day 7. Patients with more elevated bilirubin at baseline (serum bilirubin >8 mg/dL) had a median reduction from baseline of 25% by day 7 and 48% by day 28.

 
*p<0.05 compared to baseline (Wilcoxon's Signed Rank Test)
 

Model of End-Stage Liver Disease (MELD)

MELD is another common scoring system used to assess the severity and prognosis of AH patients. Patients with MELD scores of 11-20 are classified as having moderate AH and patients with MELD scores of 21-30 are classified as having severe AH. As with Lille scores, the lower the MELD score, the better the prognosis for the AH patient. In this study (shown in the chart below), the median reduction from baseline in MELD among all DUR-928 treated patients was over 2 points and among those with baseline bilirubin levels >8 mg/dL was 5 points by day 28.

 
*p<0.05 compared to baseline (Wilcoxon's Signed Rank Test)
MELD is calculated based on (a) bilirubin, (b) serum creatinine (sCr), and (c) International Normalized Ratio (INR), which is a measure of prothrombin time.
 

Safety and Pharmacokinetics

DUR-928 was well tolerated at all doses tested. There were no drug-related serious adverse events and only three adverse events designated as possibly related to DUR-928: one occurrence of moderate generalized pruritus, one mild rash and one grade two alkaline phosphatase. There were no discontinuations, early withdrawals or termination of study drug or study participation due to adverse events. All patients treated with DUR-928 survived through the 28-day follow-up period. Drug exposures were dose proportional and were not affected by the severity of the disease.

About the DUR-928 Alcoholic Hepatitis Phase 2a Trial

The open-label, dose escalation, multi-center study was designed to determine the safety, pharmacokinetics and pharmacodynamics of DUR-928 in AH patients following treatment. This included assessing liver biochemistry, biomarkers, and prognostic scores such as the Lille score. Final enrollment included 19 patients with moderate and severe AH, who were administered DUR-928 intravenously at three different doses. Eight patients (four moderate and four severe) were dosed at 30mg, seven patients (three moderate and four severe) were dosed at 90mg and four patients (all severe) were dosed at 150mg. After being discharged on day two, one patient did not return for the scheduled day seven and day 28 follow-up visits; therefore Lille, bilirubin and model of end-stage liver disease (MELD) data reported above are based on 18 patients.

Next Steps

DURECT is planning to conduct a double-blind, placebo-controlled, Phase 2b clinical trial evaluating DUR-928 in AH patients beginning mid-2020. Assuming reasonable enrollment rates, top line data from this trial would be available in 2022.

AH is an acute form of alcoholic liver disease (ALD), associated with long-term heavy intake of alcohol, and often occurs after a recent period of increased alcohol consumption. AH is typically characterized by recent onset jaundice and hepatic failure. An analysis of 77 studies published between 1971 and 2016, which included data from a total of 8,184 patients, showed the overall mortality from AH was 26% at 28 days. According to the most recent data provided by the Agency for Healthcare Research and Quality (AHRQ), a part of the US Department of Health and Human Services (HHS), there were over 117,000 hospitalizations for patients with alcoholic hepatitis in 2016. From a recent publication analyzing the mortality and costs associated with alcoholic hepatitis, the cost per patient is estimated at over $50,000 in the first year. ALD is one of the leading causes of liver transplants in the U.S., each of which costs over $800,000.

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

There are risks and uncertainties associated with our business. Please see our most recent SEC filings (10-K or 10-Q) for a complete description of these risks and uncertainties, which are incorporated herein by reference.