"We are pleased to report data from cohort one of the first patient study with DUR-928, and that a single dose provided signals of DUR-928 activity in cirrhotic and non-cirrhotic NASH patients," stated
"I recently reviewed data from the Phase 1b trial and am impressed to see this kind of signal with just a single dose," stated
Update on the Epigenetic Regulator Program
DUR-928, our Epigenetic Regulator Program's lead product candidate, is an endogenous, small molecule, new chemical entity (NCE), which may have broad applicability in several metabolic diseases such as nonalcoholic steatohepatitis (NASH), and in acute organ injuries such as acute kidney injury.
Phase 1b trial in patients with NASH
Our first patient trial utilizing DUR-928 is an open-label, single-ascending-dose safety and pharmacokinetic (PK) Phase 1b trial in liver function impaired (NASH) patients and matched control subjects (matched by age, body mass index and gender with normal liver function). This study is being conducted in successive cohorts evaluating single-dose levels of orally administered DUR-928. The first, low dose, cohort consisted of 10 subjects with NASH (of which 4 were cirrhotic and 6 were not cirrhotic) and 6 matched control subjects. After a PK/safety review of this cohort, the study has proceeded to the higher dose cohort utilizing a dose four times larger than the low dose cohort. Data from the first cohort showed the PK parameters between the NASH patients and the matched control subjects were comparable.
While this study was not designed to assess the efficacy of DUR-928 as a therapy for NASH, certain clinical chemistry biomarkers for liver function and liver injury were reduced 12 hours after dosing with DUR-928 as compared to before dosing. Furthermore, high sensitivity C-Reactive Protein (hsCRP), a marker of inflammation, was reduced after dosing with DUR-928. IL-18, an inflammatory mediator implicated in both liver and kidney diseases, decreased in the NASH patients as soon as a few hours after dosing, with the effect more pronounced in cirrhotic subjects at 12 hours after dosing; there was little or no change of IL-18 levels in matched control subjects. In addition, both full length CK18 (a generalized cell death marker) and cleaved CK18 (a cell apoptosis marker) were reduced after DUR-928 treatment in the NASH patients, with the effect more pronounced in cirrhotic subjects, and little or no change in matched control subjects. Collectively, the reduction of these biomarkers plus results from our animal and cell culture studies suggest potential therapeutic activity of DUR-928 for patients with liver disease. However, additional studies are required to evaluate the safety and efficacy of DUR-928, and there is no assurance that these biomarker effects will be observed in a statistically significant manner, or that DUR-928 will demonstrate safety or efficacy in treating NASH or other liver diseases, in larger controlled trials.
We are currently enrolling and dosing patients in the higher dose cohort, which we expect to complete in 2016, and we expect that this single-ascending-dose Phase 1b trial will enable and inform future studies in patients with liver diseases. We have also recently requested a pre-IND meeting with the
Phase 1b trial in patients with impaired kidney function
Our second Phase 1b study with DUR-928, also being conducted in
Results from additional animal studies
Previously we communicated that the biological activity of DUR-928 has been demonstrated in 8 different animal disease models involving three animal species. These models represent acute organ injuries and chronic disorders involving kidney, liver, brain and multi-organ injuries. Today we are reporting on two additional animal disease models:
- A second study in a mouse model of advanced NASH (STAM model). In this model, conducted by a Contract Research Organization (CRO) in
Japan, NASH is induced in diabetic mice fed a high fat diet. In a previously reported study with this model, the treatment with DUR-928 was initiated when fatty liver had formed and stopped after fibrosis developed. Daily oral administration of DUR-928 for 4 weeks resulted in inhibition of the progression of liver inflammation, hepatocyte ballooning and fibrosis. In this newer study, the treatment was initiated after fibrosis had formed and stopped after nodules had developed. Daily oral administration of DUR-928 for 4 weeks resulted in statistically significant reduction of fibrosis and hepatocyte ballooning as compared to placebo control. The fibrosis seen at the end of the study in DUR-928 treated animals was less than that seen at the beginning of the treatment. The hepatocyte ballooning seen at the end of the study in the DUR-928 group was significantly lower than at the beginning of the treatment.
- Bile duct ligation rat model (a model for cholestatic liver diseases such as Primary Sclerosing Cholangitis or PSC). In two studies, conducted by a CRO in
Canada, the bile duct was surgically ligated, resulting in cholestatic inflammatory liver injury. Daily oral administration for nine days of DUR-928 showed significant improvement in body temperature and body weight, as well as a statistically significant reduction of total bilirubin (including both direct and indirect bilirubin).
These results will be discussed during a live audio webcast of a conference call to discuss third quarter 2016 results that will be broadcast live over the internet at
NOTE: POSIMIR®, SABER®, and ORADUR® are trademarks of
DURECT Forward-Looking Statement
The statements in this press release regarding the potential benefits and uses of our drug candidates, including the potential use of DUR-928 to treat NASH, other liver disease or kidney disease, the potential use of POSIMIR to treat pain, clinical trial plans for DUR-928 and potential markets for DUR-928 and POSIMIR, are forward-looking statements involving risks and uncertainties that can cause actual results to differ materially from those in such forward-looking statements. Potential risks and uncertainties include, but are not limited to, the risks that future clinical trials of DUR-928 do not demonstrate the safety or efficacy of DUR-928 in a statistically significant manner, that the PERSIST clinical trial of POSIMIR will take longer to conduct than anticipated or result in data that will not support a successful NDA resubmission or product approval, the risk of delays in the commencement, enrollment or completion of other clinical trials, the risk that prior clinical trials will not be confirmed in subsequent trials, the potential failure of clinical trials to meet their intended endpoints, the risk of adverse decisions by regulatory agencies or delays and additional costs due to requirements imposed by regulatory agencies, additional time and resources that may be required for development, testing and regulatory approval of DUR-928, potential adverse effects arising from the testing or use of our drug candidates, and risks related to our ability to obtain capital to fund operations and expenses. Further information regarding these and other risks is included in
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Matt Hogan, Chief Financial Officer, DURECT Corporation, 408-777-4936