A Tool to Model Disease Progression in Patients With ADPKD

While there have been regulatory advances in autosomal dominant polycystic kidney disease (ADPKD), including the qualification of total kidney volume (TKV) as a prognostic enrichment biomarker and the US Food and Drug Administration’s designation of TKV as a “reasonably likely surrogate end point,” clinical development models for PKD remain challenging, according to Varun Aggarwal and colleagues.

During a poster session at the American Society of Nephrology Kidney Week 2023, the researchers reported on a clinical trial enrichment tool for AKPKD. The poster was titled Development of a Clinical Trial Enrichment (CTE) Tool for Autosomal Dominant Polycystic Kidney Disease.

The researchers utilized data from registries (Mayo, Emory, Colorado), CRISP, and HALT, a randomized control trial. The data were curated and mapped to Clinical Data Interchange Standards Consortium Study Data Tabulation Model standards. Using estimated glomerular filtration rate (eGFR) decline and total kidney volume (TKV) as longitudinal markers, model-informed drug development approaches to predict time to end-stage renal disease were developed. Data were divided, with 80% for training and 20% for validation.

Of two base models that captured the overall trend of TKV and eGFR, the researchers opted to use the one with a lower Akaike information criteria (AIC) score. Continuous covariates were age of diagnosis, baseline age, baseline eGFR, and baseline log (TKV); categorical covariates were race, sex, and presence of hypertension at baseline. For the TKV longitudinal model, covariates were age at diagnosis, baseline age, baseline TKV, and sex. For the eGFR longitudinal model, covariates were baseline age, baseline eGFR, race, and baseline TKV.

The Weibull distribution was selected for the time-to-event model based on the lowest AIC before incorporating longitudinal markers. Virtual simulations of disease progression were created using a graphical user interface for the CTE tool.

The tool models different trial durations, population sizes, and hypothetical magnitude of drug effects on progression of TKV and eGFR and predicts their effect on ESRD.

“A quantitative tool can be utilized to model disease progression trajectories in defined ADPKD subpopulations and potentially simulate impact on ESRD based on theoretical drug effects on TKV/eGFR progression,” the authors said. “The tool may be beneficial in clinical trial design to ultimately benefit ADPKD patients.”

Source: Aggarwal V, Zaph S, Leiser RJ, et al. Development of a clinical trial enrichment (CTE) tool for autosomal dominant polycystic kidney disease. TH-PO415. Abstract of a poster presented at the American Society of Nephrology Kidney Week 2023; November 2, 2023; Philadelphia, Pennsylvania.