The Problem
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a debilitating genetic disease affecting more than 600,000 Americans and 12 million people worldwide. Currently, only one FDA-approved drug (Tolvaptan) exists for ADPKD, but given its mechanism of action and side effects profile (liver toxicity, polyuria), the need for an improved therapy remains a priority.
The clinical course of kidney disease in ADPKD is typically marked by a long period of stable glomerular filtration rate (GFR) due to hyperfiltration despite the continuous expansion of height-adjusted total kidney volume (htTKV) due to the growth of cysts. Due to the observed stability or slow decrease of GFR even in the presence of ~5-fold change in kidney volume in many patients, clinical trial design in ADPKD is challenging, especially for earlier disease stages.
The Solution
There is a critical need for a biomarker that will assess disease progression at an earlier stage, when patients may be more likely to respond to new therapies, and before they have incurred serious, irreversible damage.
The initial goals of C-Path’s PKD Consortium were to develop CDISC (Clinical Data Interchange Standards Consortium) data standards for PKD and to use clinical data from ADPKD patients collected over many years in patient registries. Objectives included leveraging the mapped registry data to support the FDA and EMA qualification of an imaging biomarker, Total Kidney Volume (TKV), for use in drug development trials. Using the data collected, a disease model that evaluated the relationship between baseline TKV and progression of ADPKD was developed.
The Impact
The models, done in conjunction with the PKD Foundation, academic, industry and regulatory stakeholders, were used to support the regulatory qualification of baseline TKV (with or without age inclusion) as an enrichment prognostic biomarker for ADPKD, to predict a 30% decrease in eGFR.
PKDOC has successfully qualified Total Kidney Volume as a prognostic enrichment biomarker with both the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Furthermore, FDA designated TKV as a reasonably likely surrogate marker for disease progression in ADPKD. This marker could serve as an endpoint under an accelerated approval pathway followed by a post-marketing confirmation trial showing an effect on the loss of kidney function.
The current projects at PKDOC are focused on development of a clinical trial simulator (CTS) tool for ADPKD, identification and qualification of novel prognostic and drug response biomarkers, and development of COA/PRO tools. Attendees include biopharmaceutical companies, academic organizations, foundations, patient advocacy groups and regulatory agencies from around the world. Anyone who is interested may participate.
