Kidney Week

Abstract: SA-PO634

Safety and Single Ascending Dose Pharmacokinetic Study of DUR-928 in Patients with CKD versus Matched Control Subjects

Session Information

• Pharmacology
  October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

• 1700 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

• Shah, Jaymin C., DURECT Corporation, Cupertino, California, United States

Jaymin C. Shah,

• Ellis, David J., DURECT Corporation, Cupertino, California, United States

David J. Ellis,

• Miksztal, Andrew R., DURECT Corporation, Cupertino, California, United States

Andrew R. Miksztal,

• Lin, Wei Qi, DURECT Corporation, Cupertino, California, United States

Wei Qi Lin,

Background

DUR-928 ((5-cholesten-3β,25-diol 3-sulfate (25HC3S)) is an endogenous intracellular sulfated oxysterol that has been shown to regulate lipid metabolism, inflammatory response, and cell survival. This first-in-class investigational product is being developed for the treatment of various liver and kidney diseases. Animal ADME studies have shown that ≈ 17% of DUR-928 is eliminated through the urine. This study was to evaluate the impact of renal impairment in chronic kidney disease (CKD), on the safety and pharmacokinetics (PK) of DUR-928.

Methods

The study was a Phase 1b, open label, single ascending dose study to evaluate the safety and PK of IM injected DUR-928 in patients with moderate and severe kidney function impairment (Stage 3 and Stage 4 CKD) and matched control subjects (MCS), matched by age, BMI, and gender, with normal kidney function. The two doses of DUR-928 in the study were 30 mg and 120 mg. Biomarkers were also examined. All study subjects were followed through 7 days post dosing.

Results

Eleven CKD patients (Stage 3 (N=8), Stage 4 (N=3)) and six MCS completed the study. A total of 13 TEAEs were reported by 8 participants, mostly mild and none were severe. A clinically non-significant decrease (≈ 10%) in exposure was observed in CKD patients as compared to MCS at both dose levels of DUR-928. The AUC values for 30 and 120 mg doses in CKD patients were 1061 and 4304 ng*hr/mL vs. 1138 and 4766 ng*hr/mL in MCS. Similarly, the C_max values for 30 and 120 mg doses in CKD patients were 281 and 890 ng/mL vs. 345 and 997 ng/mL in MCS. The plasma half-life (T½) was in the range of 1.5 to 2 hours. Participants with elevated levels of CK-18 (markers of cell death) or bilirubin at baseline showed considerable reduction of these markers at 12 or 24 - 48 hours after a single IM injection of DUR-928.

Conclusion

Single IM doses of DUR-928 in CKD patients were found to be well tolerated. Kidney function impairment did not impact the PK of DUR-928. These data support further evaluation of DUR-928 in patients with kidney disease.