Adding value to early clinical drug development in chronic kidney disease

Chronic kidney disease (CKD) affects more than 10% of the world’s population which is a number only expected to increase. Until recently, the treatment landscape in kidney disease has been limited, with few or no disease-specific treatments available. Established biomarkers of kidney disease stage and progression are not able to tell the whole story of why the kidneys are failing (Figure 1). To guide the development of new drugs in this area, it is necessary to get a deeper understanding of the underlying pathophysiological processes and there is a need for sensitive and reliable non-invasive biomarkers that can support drug development in CKD. Advances in Magnetic Resonance Imaging (MRI) offer an avenue that could overcome the limitations of the existing biomarkers in the kidney. Antaros Medical has been developing and implementing kidney MRI markers in several clinical trials to facilitate decision-making and understand the mode of action of new treatments for CKD.

Developing kidney imaging capabilities with our kidney MRI method study (AM-01)

The advantages of MRI in CKD clinical trials are its sensitivity in providing non-invasive quantification of unique aspects of pathophysiology and drug mode of action, and its repeatability over several assessments.

To investigate the possibilities with kidney MRI, Antaros Medical set up a kidney imaging method study in 2015 in collaboration with AstraZeneca and Sahlgrenska University hospital. The study included diabetic kidney disease (DKD) patients and was designed to investigate the link between kidney MRI biomarkers and current established markers as well as their repeatability and how they change longitudinally with disease progression. MRI markers of kidney hemodynamics (e.g. renal blood flow), macrostructure (kidney volume), oxygenation and microstructure (for kidney damage potentially reflecting inflammation and fibrosis) were measured at baseline and after 2 years (Figure 2). The high-level results of this study showed that:

Not only did this study give additional support for the evidence of multiparametric MRI as a non-invasive tool for evaluating and predicting diabetic kidney disease and its progression, but it also allowed us to gain further expertise and capabilities to set up and run imaging in kidney clinical trials.

Other initiatives to understand MRI markers in chronic kidney disease

The promise for kidney MRI as a non-invasive biomarker for CKD is further underlined by the multiple large scientific consortia that have been formed around this topic. Antaros Medical is a proud partner of both renalMRI.org and BEAt-DKD addressing the need and feasibility for non-invasive biomarkers in kidney disease. Further, we are part of the The East and North London Diabetes Cohort (HEROIC) study designed to investigate the heterogeneity of DKD using kidney and cardiac imaging, lab biomarkers, and tissue biopsy. This study will give further insights on how kidney MRI can be used to better understand diabetic kidney disease and its pathophysiology as well as short- and long-term progression of DKD (3).

Antaros Medical is and has been involved in several interventional trials in the kidney space, looking at both treatment effects and mechanisms with imaging, providing support for advancing both disease understanding and novel treatments in the kidney (4, 5). To date, around 40 interventional studies in DKD utilising MRI endpoints have been reported, including treatment with e.g. loop diuretics, ACEis, ARBs, GLP-1 agonists, and SGLT-2 inhibition (6). These studies demonstrated that changes in kidney MRI biomarkers following an intervention may be seen with relatively few subjects and can therefore be included in early phase trials. There is also a growing body of evidence showing that kidney MRI can measure endpoints that reflect changes in the underlying pathophysiology following an intervention.

Antaros Medical has developed an expertise in kidney imaging in clinical studies. We have a portfolio of highly repeatable and sensitive kidney MRI biomarkers to look at drug effects and mode of action for kidney drug development. MRI markers provide additional information on pathophysiological processes in CKD including kidney hemodynamics, macrostructure, microstructure, and oxygenation, allowing potential investigation of the dynamic interplay of these processes in disease progression (6). Our portfolio of kidney MRI biomarkers adds value particularly early clinical trials to address questions to build confidence and minimize risk when moving forward to later stages of drug development.

In addition to our expertise in imaging, we are advancing image analysis tools to deliver high quality and timely data in clinical trials. Combining this with extensive experience from the pharma industry gives us unique capabilities to tailor and perform trials not only in CKD, but also in other related disease areas (Figure 3). With previous and ongoing experience from multiple clinical imaging trials we have generated insights to clinical questions related to both mode of action as well as drug efficacy of novel treatments to support early clinical development of new treatments for CKD.

(1)    Makvandi K, Hockings P D, Jensen G, Unnerstall T, Leonhardt H, Jarl L, Englund C, Francis S, Sundgren A K, Hulthe J, Baid-Agrawal S. Multiparametric Magnetic Resonance Imaging Allows Non-Invasive Functional and Structural Evaluation of Diabetic Kidney Disease. Clinical Kidney Journal, 2022
(2)    Makvandi K, Hockings P, Jensen G, Hulthe J, Haraldsson H, Baid-Agrawal S. Multiparametric Magnetic Resonance Imaging allows the prediction of diabetic kidney disease progression. American Society of Nephrology 2022 (Abstract)
(3)    Mccafferty K, Caplin B, Knight S, Hockings P, Wheeler D, Fan S L, Hulthe J, Kleta R, Ashman N, Papastefanou V, Mehta H, Salama A, Hadzovic S, Chowdhury T A, Jarl L, Unwin R, Challis B, Sundgren A K, Yaqoob M M. HEROIC: a 5-year observational cohort study aimed at identifying novel factors that drive diabetic kidney disease: rationale and study protocol. BMJ Open 2020
(4)    Bjornstad P, Cherney D, Lawson J, Møntegaard C, Pruijm M, Tuttle K, Vrhnjak B, Kretzler M. REMODEL: A mechanistic trial evaluating the effects of semaglutide on the kidneys in people with type 2 diabetes and chronic kidney disease. European Renal Association, ERA-EDTA 2022 (Abstract MO399)
(5)    van der Aart-van der Beek AB, Apperloo E, Jongs N, Rouw DB, Sjöström CD, Friedli I, Johansson L, van Raalte DH, Hoogenberg K, Heerspink HJL. Albuminuria lowering effect of dapagliflozin, exenatide and their combination in patients with type 2 diabetes: a randomised cross-over clinical study. Diabetes Obes Metab. 2023
(6)    Friedli I, Baid-Agrawal S, Unwin R, Morell A, Johansson L, Hockings P. Magnetic Resonance Imaging in Clinical Trials of Diabetic Kidney Disease. J. Clin. Med. 2023