Kidney Week

Abstract: SA-OR121

Tolvaptan Slows eGFR Decline in Later-Stage ADPKD

Session Information

• High-Impact Clinical Trials
  November 02, 2017 | Location: Hall J, Morial Convention Center
  Abstract Time: 10:30 AM - 10:45 AM

Category: Genetic Diseases of the Kidney

• 801 Cystic Kidney Diseases

Authors

• Torres, Vicente E., Mayo Clinic, Rochester, Minnesota, United States

Vicente E. Torres,

• Chapman, Arlene B., University of Chicago, Chicago, Illinois, United States

Arlene B. Chapman,

• Devuyst, Olivier, University of Zurich, Zurich, Switzerland

Olivier Devuyst,

• Gansevoort, Ron T., UMC Groningen, Groningen, Netherlands

Ron T. Gansevoort,

• Perrone, Ronald D., Tufts Medical Center, Boston, Massachusetts, United States

Ronald D. Perrone,

• Koch, Gary G, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States

Gary G Koch,

• Ouyang, John, Otsuka Pharm. Dev. & Comm., Rockville, Maryland, United States

John Ouyang,

• Mcquade, Robert D., Otsuka Pharmaceutical Development and Commercialization Inc, Rockville, Maryland, United States

Robert D. Mcquade,

• Blais, Jaime, Otsuka Pharmaceutical Development and Commercialization, Princeton, New Jersey, United States

Jaime Blais,

• Czerwiec, Frank S., Otsuka Pharma. Devel. & Comm., Inc., Rockville, Maryland, United States

Frank S. Czerwiec,

• Sergeyeva, Olga, Otsuka Pharmaceuticals, Princeton, New Jersey, United States

Olga Sergeyeva,

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 – Otsuka Pharmaceuticals