Modelling the long-term benefits of tolvaptan therapy on renal function decline in autosomal dominant polycystic kidney disease: an exploratory analysis using the ADPKD outcomes model

Abstract

Background: The short-term efficacy of tolvaptan in patients with autosomal dominant polycystic kidney disease (ADPKD) has been demonstrated across several phase 3 trials, while the ADPKD Outcomes Model (ADPKD-OM) represents a validated approach to predict natural disease progression over a lifetime horizon. This study describes the implementation of a tolvaptan treatment effect within the ADPKD-OM and explores the potential long-term benefits of tolvaptan therapy in ADPKD.

Methods: The effect of tolvaptan on ADPKD progression was modelled by applying a constant treatment effect to the rate of renal function decline, consistent with that observed in the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes trial (TEMPO 3:4; ClinicalTrials.gov identifier NCT00428948 ). Predictions generated by the ADPKD-OM were compared against aggregated data from a subsequent extension trial (TEMPO 4:4; ClinicalTrials.gov identifier NCT01214421 ) and the Replicating Evidence of Preserved Renal Function an Investigation of Tolvaptan Safety Efficacy in ADPKD trial (REPRISE; ClinicalTrials.gov identifier NCT02160145 ). Following validation, an application of the ADPKD-OM sought to estimate the benefit of tolvaptan therapy on time to end-stage renal disease (ESRD), in a range of ADPKD populations.

Results: Model validation against TEMPO 4:4 and REPRISE demonstrated the accuracy and generalisability of the tolvaptan treatment effect applied within the ADPKD-OM. In simulated patients matched to the overall TEMPO 3:4 trial population at baseline, tolvaptan therapy was predicted to delay the mean age of ESRD onset by five years, compared to natural disease progression (57 years versus 52 years, respectively). In subgroup and sensitivity analyses, the estimated delay to ESRD was greatest among patients with CKD stage 1 at baseline (6.6 years), compared to CKD 2 and 3 subgroups (4.7 and 2.7 years, respectively); and ADPKD patients in Mayo subclasses 1C-1E.

Conclusions: This study demonstrated the potential for tolvaptan therapy to delay time to ESRD, particularly among patients with early-stage CKD and evidence of rapidly progressing disease. Data arising from this study highlight the value to be gained by early intervention and long-term treatment with tolvaptan, which may alleviate the economic and societal costs of providing care to patients who progress to ESRD.

Keywords: Autosomal dominant polycystic kidney disease; Disease modelling; End-stage renal disease; Renal function decline; Tolvaptan.

Conflict of interest statement

Ethics approval and consent to participate

This article is based on previously conducted research and does not involve any new studies of human or animal subjects performed by any of the authors, as such ethics approval and consent to participate were not required.

Consent for publication

Not applicable.

Competing interests

HBW, PM and KH have served as consultants to and received research funding from Otsuka Pharmaceutical Europe Ltd. in relation to this study. KO is an employee of Otsuka Pharmaceutical Europe Ltd.

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Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1

Flow diagram of health states modelled in the ADPKD Outcomes Model. Following the initiation RRT (grey box), patients were modelled across conservative care, dialysis and transplant health states

Fig. 2

Validation of tolvaptan treatment effect applied in the ADPKD Outcomes Model. a Least squares mean eGFR change as observed in the early-treated cohort of TEMPO 4:4, assuming an average washout period of 3 months between TEMPO 3:4 and TEMPO 4:4 (unfilled triangles), compared against ADPKD-OM predictions (black filled squares joined by line). b Effect of tolvaptan on one-year eGFR change, as observed in REPRISE (grey filled bars) and predicted by the ADPKD-OM (unfilled bars). c Annualised eGFR slopes for tolvaptan and placebo arms, as observed in REPRISE (grey filled bars) and predicted by the ADPKD-OM (unfilled bars). Error bars indicate 95% confidence intervals; eGFR was estimated using the CKD-Epi equation

Fig. 3

Predicted trajectory of CKD progression in modelled ADPKD patients treated with tolvaptan (black filled points), compared to natural history (white filled points). Labelled points indicate mean values; shaded regions indicate 95% confidence intervals; eGFR was estimated using the reciprocal of serum creatinine level

Fig. 4

Kaplan-Meier plot of predicted survival to ESRD in modelled ADPKD patients treated with tolvaptan (solid line), compared to natural history (dashed line)

Fig. 5

Influence of modelled scenarios on predicted time to ESRD, relative to the base case analysis in which the treatment effect measured by reciprocal of serum creatinine was applied to the overall TEMPO 3:4 population, without discontinuation. White bars indicate model predictions under natural history; grey bars indicate the incremental effect of tolvaptan on predicted time to ESRD