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Abstract: PO1534

A Post Hoc Analysis of Tolvaptan (TOL) Efficacy and Safety in Slowing Rate of Renal Function Decline in Subjects with Very Late-Stage Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic

Authors

  • Torres, Vicente E., Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • Gansevoort, Ron T., Rijksuniversiteit Groningen, Groningen, Groningen, Netherlands
  • Chapman, Arlene B., University of Chicago, Chicago, Illinois, United States
  • Perrone, Ronald D., Tufts Medical Center, Boston, Massachusetts, United States
  • Ouyang, John, Otsuka Pharmaceutical Development and Commercialization Inc, Rockville, Maryland, United States
  • Lee, Jennifer, Otsuka Pharmaceutical Development and Commercialization Inc, Rockville, Maryland, United States
  • Japes, Hina, Otsuka Pharmaceutical Development and Commercialization Inc, Rockville, Maryland, United States
  • Wang, Tao, Otsuka Pharmaceutical Development and Commercialization Inc, Rockville, Maryland, United States
Background

ADPKD is a progressive disease that causes end-stage renal disease in ~50% of the affected individuals by age 60. TOL, a selective vasopressin V2-receptor antagonist, has been shown to slow the progression of renal function decline in ADPKD subjects with an eGFR of 25 mL/min/1.73m2 or higher. The efficacy and safety of TOL in subjects with lower eGFR remain understudied. This post-hoc analysis evaluated the efficacy and safety of TOL in subjects with stage 4 CKD (eGFR of <30 mL/min/1.73m2).

Methods

This is a retrospective analysis of a subgroup of ADPKD subjects who enrolled in the TOL open-label extension (OLE) trial (NCT02251275). Included subjects had a baseline eGFR of <30 mL/min/1.73m2, received ≥ 1 TOL dose, and were randomized to the placebo group in the REPRISE trial (NCT02160145). Two subgroups of subjects were analyzed, one with baseline eGFR of 25-30 (Subgroup 1) and one <25 (Subgroup 2). The variables evaluated included demographics, adverse event (AE) profile, and intra-subject comparison of change in annualized eGFR decline during the OLE trial to that during placebo use in the REPRISE trial. Annualized eGFR change slopes in the treatment period were calculated using eGFR values between Month 1 and 12 visits to compensate for the acute hemodynamic effect of tolvaptan. Comparison was made by linear mixed model.

Results

Of 1,803 subjects enrolled, 159 (8.8%; 76 in Subgroup 1 and 83 in Subgroup 2) met the selection criteria. Annualized eGFR change slopes for all subjects (n=148) were -5.28 in the REPRISE trial and -3.16 in the OLE trial with a treatment effect of 2.11 (95% CI 1.56, 2.66), p<0.0001). The treatment effects were 1.99 and 2.17 for Subgroups 1 and 2, respectively (p<0.0001 for both subgroups). The 5 most common AEs were thirst (32%), polyuria (30%), renal pain (25%), blood creatinine increase (23%) and nocturia (22%); the rates were similar between the 2 subgroups. One incidence of hepatic enzyme increase, one of hemodialysis and one death (unrelated to TOL) was only observed in Subgroup 2.

Conclusion

This post-hoc analysis demonstrated that TOL significantly decreases the rate of eGFR decline in ADPKD subjects with stage 4 CKD, including those with an eGFR of <25 mL/min/1.73m2.

Funding

  • Commercial Support –