DUR-928

Overview

DUR-928 is the lead product candidate in DURECT’s Epigenetic Regulator Program. It is an endogenous, orally bioavailable small molecule that has been shown in nonclinical studies to modulate 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 nontoxic at plasma concentrations up to several thousand times naturally-occurring levels. Based on data from 10 nonclinical 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), several nonmetabolic liver disorders, acute organ injury, and inflammatory conditions such as psoriasis.

DUR-928 is being studied for its ability to:

  • 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
  • Reduce inflammation

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

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 has yet been approved for the treatment of NAFLD or NASH.

Acute organ injury, including acute kidney injury (AKI) and other conditions, is an 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.

Psoriasis is an immune-mediated chronic inflammatory skin condition that affects approximately 7.5 million Americans. It is considered undertreated, and there is general dissatisfaction with current treatment options.

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

Clinical studies

Phase 1 studies of oral and injectable formulations of DUR-928 have been initiated.

  • DURECT has conducted 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.
  • DURECT has conducted a single-dose Phase 1b trial of DUR-928 in patients with psoriasis.
  • 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 100 healthy volunteers have been exposed to DUR-928 in the clinical program as of the end of 2016. Peak plasma concentrations at least 100-fold higher than endogenous levels were achieved and no plasma drug accumulation was seen 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 currently holds the worldwide development and commercialization rights to DUR-928 and other molecules identified as part of the Epigenetic Regulator Program.

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