A Drug Development Tool for Trial Enrichment in Patients With Autosomal Dominant Polycystic Kidney Disease

Abstract

IntroductionTotal kidney volume (TKV) is a promising imaging biomarker for tracking and predicting the natural history of patients with autosomal dominant polycystic kidney disease.MethodsA drug development tool was developed by linking longitudinal TKV measurements to the probability of a 30% decline of estimated glomerular filtration rate (eGFR) or end-stage renal disease. Drug development tools were developed based on observational data collected over multiple decades for an eGFR decline and end-stage renal disease in 641 and 866 patients with autosomal dominant polycystic kidney disease, respectively.ResultsThe statistical association between predicted TKV at the time of a 30% decline of eGFR and that at the time of end-stage renal disease were both highly significant (P < 0.0001). The drug development tool was applied to demonstrate the utility of trial enrichment according to prespecified baseline TKV, age, and eGFR as enrollment criteria in hypothetical clinical trials. Patients with larger TKV (≥1000 ml) displayed steeper slopes of hazard, which translated into a higher risk of a 30% decline of eGFR within each baseline age (< or ≥40 years) or baseline eGFR (< or ≥50 ml/min per 1.73 m2) subgroups.DiscussionThese results suggest that, when eGFR is preserved, patients with larger TKV are more likely to progress to a 30% decline of eGFR within the course of a clinical trial, whereas eGFR and age displayed limited predictive value of disease progression in early disease. Pharmaceutical sponsors and academic investigators are encouraged to prospectively employ the above drug development tool to optimize trial designs in patients with autosomal dominant polycystic kidney disease.

Total Kidney Volume Is a Prognostic Biomarker of Renal Function Decline and Progression to End-Stage Renal Disease in Patients With Autosomal Dominant Polycystic Kidney Disease

“…Indeed, based on these analyses and those in the accompanying manuscript, 27 TKV was qualified as a prognostic biomarker for the selection of patients in clinical trials for new therapies for the treatment of ADPKD by the FDA in the form of a draft guidance and by the EMA in the form of a qualification opinion. 28 , 29…”

Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease

“…The selection of participants mainly on the basis of the estimated GFR was justified by the fact that the estimated GFR is an excellent predictor of disease progression when the rate is already declining. 33,34 Nevertheless, it remains possible that additional selection criteria regarding genotype or age-adjusted total kidney volume could have further enriched the trial population for patients who would have rapid disease progression. 30,31 We did not study whether the effect of tolvaptan on the estimated GFR was mediated or paralleled by an effect on kidney volume; renal hemodynamic or other mechanisms could have also played a role.…”

Application of a Dynamic Map for Learning, Communicating, Navigating, and Improving Therapeutic Development

“…In order to pool data, first a Clinical Data Interchange Standards Consortium data standard was developed for ADPKD and then subject matter experts resolved methodologic differences between studies [data repository; data standards] . Analysis of the pooled data revealed that baseline TKV, in combination with patient age and baseline estimated glomerular filtration rate, can accurately predict the risk and cadence of disease progression in patients with ADPKD [prognostic and predictive biomarker] . The US Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) recently qualified TKV as a prognostic biomarker that can be used by drug developers in submissions of investigational new drug (IND) applications, new drug applications (NDAs), and biologics license applications without the relevant CDER review group reconsidering and reconfirming the suitability of the biomarker [biomarker qualification]…”

“…7 Analysis of the pooled data revealed that baseline TKV, in combination with patient age and baseline estimated glomerular filtration rate, can accurately predict the risk and cadence of disease progression in patients with ADPKD [prognostic and predictive biomarker]. 8,9 The US Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) recently qualified TKV as a prognostic biomarker that can be used by drug developers in submissions of investigational new drug (IND) applications, new drug applications (NDAs), and biologics license applications without the relevant CDER review group reconsidering and reconfirming the suitability of the biomarker [biomarker qualification]. 10 Now the next phase can begin, in which companies conducting clinical trials of potential therapeutics can carry out TKV measurements during enrollment and conduct of the trial.…”