Total kidney volume (TKV) and beyond to understand treatment effects in ADPKD
Autosomal dominant polycystic kidney disease (ADPKD) is characterised by the formation and progressive expansion of fluid-filled cysts which compress and obstruct adjacent nephrons and lead to injury in the normal parenchyma. Disease progression manifests in the gradual enlargement of the kidneys, despite renal function remaining normal, or near-normal, for decades before leading to end-stage renal disease (ESRD) [1]. To this end, total kidney volume (TKV) emerged as a way of monitoring disease progression, and by extension, as a way of evaluating the efficacy of potential ADPKD therapeutics.
TKV is currently qualified as a reasonably likely surrogate endpoint for disease progression by the US Food & Drug Administration (FDA) [2] and a prognostic biomarker by the European Medicines Agency (EMA) [3]. Ultrasound (US), computed tomography (CT) and magnetic resonance imaging (MRI) can all be used for measuring TKV, with MRI generally considered the ‘gold standard’ in terms of reproducibility and precision. Notably, there are several different MRI-based methods for calculating TKV with varying sensitivity [4]. At Antaros Medical, we have developed our own method to measure TKV and combined with our worldwide imaging site network of 450+ active sites, are well-equipped for late-stage ADPKD trials that necessitate large numbers of imaging sites to reach desired patient numbers.
Figure 1: Macrostructural changes, hemodynamic alterations and imaging assessments in ADPKD
Imaging biomarkers for early-stage ADPKD drug development
However, TKV is challenging in the context of early phase (Phase 1 or 2) ADPKD drug development. This is because the average rate of increase for TKV is between 5-6% per year, which can be reduced to approximately 3% per year on treatment [5]. Detecting this change within the timeframe of a phase I trial (~3 months) is challenging. Therefore, it can be valuable to include other biomarkers to complement TKV and enable evaluation of efficacy and insights into mechanism of action. For example, MRI biomarkers like renal blood flow, cyst volume or number, and functional (parenchymal) kidney volume can be measured. Adding diffusion weighted imaging (DWI) also adds opportunities for better understanding treatment effects on cystogenesis.
Adding these biomarkers to an early-stage ADPKD trial can give an early indication of efficacy and mechanism of action.
References
[1] Grantham JJ et al. CJASN (2006). doi: 10.2215/CJN.00330705
[2] FDA . Table of Surrogate Endpoints That Were the Basis of Drug Approval or Licensure. (2018). Available online at: https://www.fda.gov/drugs/development-resources/table-surrogate-endpoints-were-basis-drug-approval-or-licensure
[3] EMA. Qualification opinion: Total Kidney Volume (TKV) as a prognostic biomarker for use in clinical trials
evaluating patients with Autosomal Dominant Polycystic Kidney Disease
(ADPKD) (2015). Available online at https://www.ema.europa.eu/en/human-regulatory-overview/research-development/scientific-advice-protocol-assistance/opinions-letters-support-qualification-novel-methodologies-medicine-development
[4] Sharma K et al. PLOS ONE (2017). doi: 10.1371/journal.pone.0178488
[5] Torres VE et al. N Engl J Med (2012) doi: 10.1056/NEJMoa1205511