P0680A POST-HOC ANALYSIS OF EFFICACY AND SAFETY OF TOLVAPTAN (TOL) IN DECREASING RATE OF RENAL FUNCTION DECLINE IN PATIENTS WITH VERY LATE-STAGE AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD)

Abstract

Background and Aims: ADPKD is a progressive inherited disease that causes end‐stage renal disease (ESRD) in∼50% of the affected individuals by 60 years of age. TOL, a selective vasopressin V2‐receptor antagonist, has been shown in randomized, placebocontrolled trials 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 ADPKD (eGFR of <30 mL/min/ 1.73m2). Method: This is a retrospective analysis of a subgroup of ADPKD subjects who enrolled in the TOL long‐term 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 with <25 (Subgroup 2). The variables evaluated included: 1) demographics, 2) adverse event (AE) profile, 3) intra‐subject comparison of change in annualized eGFR decline during the open‐label study (treatment period) to that during placebo use in the REPRISE trial (control period). 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 the 1,803 subjects enrolled, 159 (8.8%) subjects (76 in Subgroup 1 and 83 in Subgroup 2) met the selection criteria for analysis. Annualized eGFR change slopes for all subjects (n=148) were ‐5.28 (SE 0.27) in the control period and ‐3.16 (SE 0.30) in the treatment period with a treatment effect of 2.11 mL/min/1.73m2/year (95% CI 1.56, 2.66), p<0.0001). Demographic information, baseline eGFR, treatment duration and effects in the 2 subgroups are shown in the Table below. Treatment‐emergent AEs were observed in 95% and 90% of the subjects in the 2 subgroups, respectively. Discontinuation due to AEs occurred in 15% and 17% of the 2 subgroups, respectively. The 5 most common AEs for all subjects 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, hemodialysis and death (unrelated to TOL) was observed in Subgroup 2, but not in Subgroup 1. 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.