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DRRX: Update on DUR-928 Development Program

02/15/2017
By Grant Zeng, CFA

NASDAQ:DRRX

Among Durect’s (NASDAQ:DRRX) multiple candidates, DUR-928 may be the most promising one in our view because this compound has the potential to target multiple indications including NAFLD/NASH and acute kidney injury.

The Background

DUR-928 came from DURECT's Epigenomic Regulator Program, which is a collaborative effort between DURECT and the Department of Internal Medicine at Virginia Commonwealth University (VCU), the VCU Medical Center, and the McGuire VA Medical Center.  During the course of this program, a number of compounds that may have therapeutic utility have been identified, including the lead molecule DUR-928. DURECT holds the exclusive worldwide right to develop and commercialize DUR-928 and related molecules discovered in the program.

DUR-928 is an endogenous (produced naturally by the body), orally bioavailable small molecule that modulates the activity of several nuclear receptors that play an important regulatory role in lipid homeostasis, inflammation and cell survival.  Studies have showed that DUR-928 modulates the activity of more than 240 genes, including ACC, FAS, HMGR, Cyp7A1, LXR, PPARγ, NFκB/IκB, TNFα, IL-1α, IL-6, COX-2, PCSK9, and others.

The broad biologic activities indicate that DUR-925 may have a broad range of clinical applications including acute organ injury, ischemia or reperfusion injury, and chronic liver disease such as non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

Phase Ib Oral Study of DUR-928 for NASH

In January, 2016, Durect initiated a single-ascending-dose Phase Ib clinical trial with oral DUR-928 in patients with nonalcoholic steatohepatitis (NASH) in Australia.

This Phase Ib trial of DUR-928 is a dose ranging, single-ascending-dose safety and pharmacokinetic study of oral DUR-928 in subjects with NASH and matched control subjects. This study was conducted in successive cohorts evaluating single-dose levels (first a low dose and then a high dose) of oral DUR-928.

The company has completed 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.

Major findings from the first 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, 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.

These preliminary results from the low dose cohort are especially encouraging in our view. Collectively, the reduction of these biomarkers plus results from the company’s animal and cell culture studies suggest potential therapeutic activity of DUR-928 for patients with liver disease.

The high dose cohort consisted of 10 subjects with NASH (of which 2 were cirrhotic and 8 were not cirrhotic) and 6 matched control subjects.  One patient (with a prior history of arrhythmia and an ongoing viral infection) in the high dose cohort experienced a serious adverse event (shortness of breath) which occurred without unusual biochemical changes and resolved without intervention but was considered possibly treatment related by the physician due to its temporal association with dosing.  In both the low and high dose cohorts, the PK parameters were comparable between the NASH patients and the matched control subjects.  In addition, the systemic exposure following the low and high doses of DUR-928 was dose dependent.

While this study was not designed to assess efficacy, the trial did observe a dose dependent reduction of certain biomarkers after a single oral dose of DUR-928.  In both cohorts, IL-18, an inflammatory mediator implicated in both liver and kidney diseases, decreased in the NASH patients.  In addition, both full length CK-18 (a generalized cell death marker) and cleaved CK-18 (a cell apoptosis marker) were reduced after DUR-928 treatment, with the effect more pronounced in NASH patients.

An abstract for this study has been accepted and data from the study will be presented at the International Liver Congress™ 2017 organized by the European Association for the Study of the Liver (EASL) in Amsterdam, April 19-23, 2017.

This single-ascending-dose Phase Ib trial will enable and inform future studies in patients with liver diseases.  Durect has requested a pre-IND meeting with the FDA with respect to a future liver disease clinical trial in the United States.

Phase Ib Injectable DUR-928 for Kidney Disease

This ongoing trial is also conducted in Australia.

This Phase Ib trial of DUR-928 is an open-label single-ascending-dose safety and pharmacokinetic study in patients with impaired kidney function (stage 3 and 4 chronic kidney disease) and matched control subjects.  This study will be conducted in successive cohorts (first a low dose and then a high dose) evaluating single-dose levels of DUR-928 administered by injection.

The low dose cohort consisted of 6 kidney function impaired patients and 3 matched control subjects.  After a PK/safety review of this cohort, the study has proceeded to the high dose cohort utilizing a dose four times larger than the low dose cohort.  Data from the low dose cohort showed the PK parameters between the kidney function impaired patients and the matched control subjects were comparable.

The high dose cohort of this study is currently enrolling patients.

In addition, Durect has held a pre-IND meeting with the Cardiovascular and Renal Products Division of the FDA, and the company is utilizing feedback from that meeting as well as from its clinical advisors to prepare an IND which is required to enable a future kidney disease clinical trial in the United States.

Future Development Plans

Durect is working with its clinical advisors to design several Phase II studies and is planning to submit INDs which are required to enable these studies to take place in the United States in 2017.

The company submitted an initial IND in late December 2016 for a proposed Phase II liver study.  The FDA has requested additional non-clinical information (drug-drug interaction data) and has made suggestions as to modifications to the proposed protocol.  The company is working to address FDA's request and consulting with its clinical advisors to finalize the study protocol.

READ THE FULL RESEARCH REPORT HERE

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