Abstract: SA-OR121

Tolvaptan Slows eGFR Decline in Later-Stage ADPKD

Session Information

Category: Genetic Diseases of the Kidney

  • 801 Cystic Kidney Diseases

Authors

  • Torres, Vicente E., Mayo Clinic, Rochester, Minnesota, United States
  • Czerwiec, Frank S., Otsuka Pharma. Devel. & Comm., Inc., Rockville, Maryland, United States
  • Sergeyeva, Olga, Otsuka Pharmaceuticals, Princeton, New Jersey, United States
  • Chapman, Arlene B., University of Chicago, Chicago, Illinois, United States
  • Devuyst, Olivier, University of Zurich, Zurich, Switzerland
  • Gansevoort, Ron T., UMC Groningen, Groningen, Netherlands
  • Perrone, Ronald D., Tufts Medical Center, Boston, Massachusetts, United States
  • Koch, Gary G, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
  • Ouyang, John, Otsuka Pharm. Dev. & Comm., Rockville, Maryland, United States
  • Mcquade, Robert D., Otsuka Pharmaceutical Development and Commercialization Inc, Rockville, Maryland, United States
  • Blais, Jaime, Otsuka Pharmaceutical Development and Commercialization, Princeton, New Jersey, United States

Group or Team Name

  • REPRISE Trial Investigators
Background

In subjects with autosomal dominant polycystic kidney disease (ADPKD) and relatively early disease (estimated creatinine clearance ≥60 mL/min) the vasopressin V2 receptor antagonist tolvaptan slowed kidney growth and estimated glomerular filtration rate (eGFR) decline, but also caused more frequently transaminase and bilirubin elevations. Tolvaptan efficacy and safety in later-stage ADPKD are unknown.

Methods

REPRISE is a phase 3, multi-center, randomized withdrawal, placebo controlled,double-blind trial. After an 8-week pre-randomization period including sequential placebo and tolvaptan treatments, 1,370 ADPKD subjects, 18–55 years with eGFR 25-65 mL/min/1.73 m2 or 56–65 years with eGFR 25-44 mL/min/1.73 m2, were randomized 1:1 to tolvaptan or placebo and treated for 12 months. Safety assessments were conducted monthly.

Results

The primary endpoint, annualized eGFR change from pre-treatment baseline to post-treatment follow-up, was -2.34 mL/min/1.73 m2 with tolvaptan versus -3.61 mL/min/1.73 m2 with placebo, indicating a 35% reduction in rate of eGFR decline (P<0.001). The secondary endpoint, annualized eGFR slope was -3.16 mL/min/1.73 m2 versus -4.17 mL/min/1.73 m2 (P<0.001). Alanine aminotransferase elevations (>3 x upper limit of normal, ULN) occurred in 5.6% or 1.2% of subjects receiving tolvaptan or placebo, respectively. Transaminase elevations were reversible and no subjects showed bilirubin elevations >2 x ULN.

Conclusion

Compared with placebo, tolvaptan slowed eGFR decline by 35% over 1-year in subjects with later-stage ADPKD. While transaminase elevations occurred more frequently with tolvaptan treatment, these were reversible after withdrawal of tolvaptan, without concurrent bilirubin elevation, and none met Hy’s laboratory criteria, likely due to more frequent transaminase monitoring and earlier discontinuation.

Funding

  • Commercial Support