The lack of a validated prognostic biomarker impedes developing new treatments for rare diseases. Certara Strategic Consulting worked with the Critical Path Institute (C-Path) Polycystic Kidney Disease (PKD) Outcomes Consortium to identify a prognostic biomarker for a debilitating genetic rare disease, autosomal dominant polycystic kidney disease (ADPKD). Having a validated biomarker will help spur new research and clinical trials to find a treatment for ADPKD.
What is Autosomal Dominant Polycystic Kidney Disease?
Normal kidneys are fist-sized and weigh about a third of a pound. ADPKD patients develop cysts that cause the kidneys to enlarge over the course of decades. Renal enlargement leads to severe pain, increasing abdominal girth, hypertension, hematuria, kidney stones, and kidney infection. Many ADPKD patients develop end stage kidney disease (ESRD), which then requires either renal transplantation or dialysis. No medications can slow or stop the progression of ADPKD. Current treatments manage symptoms.
Developing a disease progression model for ADPKD
The lack of understanding of disease progression has hindered developing ADPKD treatments. Common renal function endpoints change late in the course of the disease. Thus, assessing the effectiveness of investigational drugs using these endpoints is difficult. Validating a biomarker that could predict disease progression earlier when patients are more likely to respond to medication was critical to enabling the development of treatments.
Certara Strategic Consulting won a bid to work with the C-Path Institute’s Polycystic Kidney Disease Outcomes Consortium to develop ADPKD disease progression models. The Consortium is a collaboration between C-Path, the PKD Foundation, Clinical Data Interchange Standards Consortium (CDISC), four academic medical centers, and three pharmaceutical companies. The consortium investigated Total Kidney Volume (TKV) as a prognostic biomarker for worsening kidney function and response to therapy in ADPKD patients.
Qualification of this novel biomarker involved multiple steps. First, data from patient registries and observational clinical trial data needed harmonization. To do this, C-Path worked with CDISC to create a data standard for ADPKD. Next, the data standard was used to remap the data into a single database. Then, Certara and the C-Path data management team curated the database for modeling. Finally, the data analysis and modeling strategies were discussed with the FDA pharmacometrics and biostats teams as well as clinicians to elucidate the role of age and glomerular filtration rate (eGFR) on the trajectory of TKV.
Model building and validation
Briefly, a key clinical outcome such as ESRD needed to be linked to the trajectory of TKV. Two additional endpoints were chosen— 30% and 57% worsening of renal function— since they occur in a shorter timeframe and predict the longer term outcome, ESRD. To identify potential confounding effects between the various predictors, Multivariate Cox models were used. Then, a simultaneous joint modeling framework of TKV and the time-to-event outcome was leveraged to account for TKV. A parametric survival submodel was used to simulate the probability of avoiding the clinical outcome according to a given baseline eGFR, TKV, and age. The final model was validated using a standard 5‑fold cross validation strategy.
The model will support ADPKD drug development in several ways. For example, it can simulate clinical trials to determine feasible trial durations. Likewise, the analysis results showed that longitudinal TKV, eGFR and age could predict the likelihood of developing the clinical outcome.
This complex project posed numerous challenges. For example, the database was continually updated. Thus, data analysis was an iterative process where outputs were generated as the dataset matured. Another challenge was finding a technology that facilitated working with busy clinicians. To obtain their critical input, they viewed project results via mobile devices that could be checked in the clinic. Certara’s technological infrastructure was indispensable to completing the project in record time.
Gaining regulatory support for a novel biomarker for ADPKD
In early 2015, the FDA issued a Biomarker Letter of Support for TKV. This biomarker will inform ADPKD clinical trial designs. Optimizing patient selection for clinical trials is an ethical imperative. It also increases the likelihood of the drug program’s success. Likewise, sponsors can use this biomarker to support regulatory decision making for drug development programs. The identification and validation of a prognostic biomarker for ADPKD should support developing new treatments that improve the lives of patients suffering from this devastating disease.
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