DUR-928

Overview

DUR-928 is the lead product candidate in DURECT’s Epigenomic Regulator Program. It is an endogenous, orally bioavailable small molecule that modulates the activity of nuclear receptors playing an important regulatory role in lipid homeostasis, inflammation, and cell survival.

Pharmacokinetics (PK) studies in mice, hamsters, and monkeys and PK/toxicity studies in rats and dogs have shown DUR-928 to be orally bioavailable and safe at plasma concentrations up to several thousand times naturally-occurring levels. Based on compelling efficacy data from 8 preclinical disease models involving 3 animal species, DURECT is examining the potential application of DUR-928 to human chronic metabolic diseases such as nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) and to the prevention or treatment of acute organ injury of various types.

  • Reduce lipid accumulation in the liver without inducing hyperlipidemia
  • Reduce liver fibrosis
  • Improve insulin sensitivity
  • Protect various organs from ischemic, chemical, or endotoxin-induced injuries

NAFLD affects approximately 30% of adults and 10% of children (about 81 million individuals) in the U.S. NASH, a more severe and progressive form of NAFLD, is one of the most common chronic liver diseases worldwide, with an estimated prevalence of more than 10% of adults in the U.S., Europe, Japan, and other developed countries. No drug is currently approved for the treatment of NAFLD or NASH.

Acute organ injury, including acute kidney injury (AKI) and other conditions, is another area of major unmet medical need for which effective pharmaceutical treatment is often lacking. AKI affects approximately 2.8 million patients per year in the U.S., and is associated with increased mortality, prolonged hospital stays, and worsening of chronic kidney disease.

Clinical studies

Oral and injectable formulations of DUR-928 are in Phase 1 clinical development.

  • DURECT is conducting a single-ascending-dose Phase 1b trial of DUR-928 in patients with nonalcoholic steatohepatitis (NASH).
  • DURECT is conducting another single-ascending-dose Phase 1b trial of DUR-928 in patients with impaired renal function.
  • The safety, tolerability, and pharmacokinetics of DUR-928 have been evaluated in healthy volunteers given both single and once-daily consecutive oral doses, and single and once-daily consecutive intramuscular doses.

Approximately 75 people have been exposed to DUR-928 in the clinical trial program as of the end of 2015. DUR-928 has been well tolerated at all studied dosages, with no treatment-related serious adverse events reported and no subject withdrawal. Peak plasma concentrations at least 100-fold higher than endogenous levels have been achieved, and no plasma accumulation has been observed with repeated dosing.

Animal studies

  • Chronic metabolic disease: Mice and hamsters fed high-fat-diets showed marked improvement in liver morphology and hepatic lipid levels after 6 weeks of treatment with DUR-928. In a widely used NASH mouse model, a reduction in NASH scores and fibrosis was seen after 4 weeks of treatment with DUR-928. Leptin-deficient obese rats demonstrated improvements in liver morphology and lipidosis after 3 weeks of treatment with DUR-928.
  • Acute organ injury: In a mouse liver-toxicity model (high-dose acetaminophen plus ethanol), DUR-928 demonstrated a significant impact on 10-day survival, with 90% of animals alive at 10 days compared with 10% of the untreated control group. In a mouse endotoxin shock model, DUR-928 had a similarly striking effect on survival. In a rat model of ischemic kidney injury, animals pretreated with DUR-928 showed significantly reduced post-ischemic creatinine concentrations, an indication of reduced functional loss. In a rat model of ischemic stroke, animals treated with DUR-928 showed improved brain cell viability.

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

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