Lee, Jennifer

Background and objectives Tolvaptan slows kidney function decline in patients with autosomal dominant polycystic kidney disease (ADPKD) at risk of rapid progression. In the 3-year Tolvaptan Efficacy and Safety in Management of ADPKD and Its Outcomes (TEMPO) 3:4, 2-year extension to TEMPO 3:4 (TEMPO 4:4), and 1-year Replicating Evidence of Preserved Renal Function: An Investigation of Tolvaptan Safety and Efficacy in ADPKD (REPRISE) trials, aquaretic adverse events were common. Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevations occurred in all three studies. Three patients met Hy Law criteria (ALT or AST more than three times and total bilirubin more than two times the upper limit of normal) for severe drug-induced liver injury (two in TEMPO 3:4 and one in TEMPO 4:4). In REPRISE, liver enzyme monitoring frequency was increased to monthly, with no Hy Law cases. A long-term, phase 3 safety study has further characterized tolvaptan safety. Design, setting, participants, & measurements Subjects who completed TEMPO 4:4, REPRISE, or other tolvaptan trials could enroll in this prospective, multinational, open-label safety study. Assessments included monthly liver enzyme testing during the first 18 months of tolvaptan exposure and every 3 months thereafter. Results Among 1803 subjects, median tolvaptan exposure during the extension was 651 days (interquartile range, 538–924), and cumulative exposure (extension and previous trials) was ≤11 years. Subjects entering from REPRISE placebo experienced more aquaretic adverse events compared with subjects from TEMPO 4:4 or REPRISE tolvaptan ( i.e ., patients with prior long-term tolvaptan exposure). Liver enzyme elevations also occurred more frequently in subjects from REPRISE placebo. Percentages experiencing ALT ≥3/≥5/ ≥10/≥20 times the upper limit of normal were 3.2%/2.1%/0.9%/0.7%, respectively, in subjects from REPRISE placebo and 0.6%–1.1%/0.0%–0.1%/0%/0%, respectively, in those from REPRISE tolvaptan and TEMPO 4:4. Percentages experiencing AST ≥3/ ≥5/≥10/≥20 times the upper limit of normal were 6.9%/3.8%/2.3%/0.8%, respectively, in subjects from REPRISE placebo and 0.9%–2.0%/0.0%–1.0%/0%/0%, respectively, in those from REPRISE tolvaptan and TEMPO 4:4. No Hy Law cases occurred. Conclusions No new safety signals emerged during this long-term extension. Monthly liver function testing for the first 18 months of treatment appeared to enable effective detection and management of transaminase elevations. Clinical Trial registry name and registration number: Open Label Extension of TEMPO 3:4, NCT02251275

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, placebo-controlled 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.