Regina Fritsche Danielson, Senior Vice President and Global Head, Research and Early Development, CVRM, AstraZeneca, shares insight with DDW’s Megan Thomas on the first precision medicine to treat APOL1-mediated kidney disease (AKMD).

MT: Can you provide an overview of the key findings from the study on APOL1-mediated kidney disease (AKMD)? 

RFD: AstraZeneca presented promising results from a Phase I study of AZD2373 for APOL1-mediated kidney disease (AMKD), a progressive kidney disease that disproportionally impacts patients of sub-Saharan West African ancestry. This study aimed to examine the safety, tolerability, pharmacokinetics, and pharmacodynamics of AZD2373 in healthy participants.  

In a Phase I multiple ascending dose (MAD) study of 24 healthy male volunteers aged 18-55, a 67% reduction from baseline in plasma APOL1 levels was observed for AZD2373 150 mg after six once weekly doses. AZD2373 demonstrated proof of mechanism in lowering APOL1 plasma protein levels and was shown to be well tolerated.     

MT: What specific genetic factors contribute to AKMD and how do they impact kidney function?  

RFD: AMKD is a kidney disease associated with the presence of two APOL1 risk variants, G1 and/or G2, which can be carried by the individual in any combination (G1/G1, G2/G2, G1/G2). These genetic variants originated in sub-Saharan West African populations where they protect individuals against African sleeping sickness. However, having these two risk variants alone is not enough to result in AMKD; an additional trigger, often referred to as a ‘second hit’, is necessary for the disease to manifest.    

The exact mechanism by which APOL1 risk variants lead to AMKD remains unclear, but studies suggest that these variants result in a harmful, dysregulated gain of function resulting in cellular damage in the kidney. AMKD is known for its early onset and rapid advancement into chronic kidney disease (CKD).  

MT: What makes this approach different from existing treatments for CKD?  

RFD: AZD2373 is an antisense oligonucleotide (ASO) that has been designed to target expression of the APOL1 protein and decrease its expression in patients with APOL1 variants associated with disease. AZD2373 is being developed as a precision medicine approach that could potentially act across the full range of mechanisms by which APOL-1 drives disease progression in AMKD.  

Based on the Phase I results, we are reassured about its potential to address the underlying genetic disease driver in AMKD. 

At present, no specific treatments exist for AMKD, so diagnosed patients are often provided with the standard of care for CKD, which is aimed at controlling blood pressure and the consequences of reduced kidney function. Unfortunately, the subset of CKD patients with AMKD who do not respond to the standard of care therefore remain at increased risk of rapid decline in kidney function, often advancing to end-stage kidney disease within a decade.   

The development of AZD2373 is being conducted in collaboration with Ionis Pharmaceuticals. 

MT: How soon might this treatment be available to patients if it continues to show promise? What regulatory hurdles do you anticipate in bringing this treatment to market? 

RFD: It is too early to comment on how quickly this potential treatment might be available to patients, but we continue to explore innovative solutions to accelerate our clinical programme development and navigation of regulatory submissions and our hope is that this process will continue to become more efficient. Given the promising Phase I results, AZD2373 is on track to enter Phase II in 2025.     

MT: What impact do you foresee this treatment having on the lives of patients, particularly those of African ancestry who are more at risk?  

RFD: We’re reassured in the potential of AZD2373 to address the genetic driver in AKMD, based on the promising Phase I results. Currently, no specific treatments for AKMD exist and diagnosed patients rely on the standard of care for CKD which does not work for a subset of patients. If approved, AZD2373 will be the first precision medicine for the treatment of the disease and address a critical unmet need in AKMD, for those who are at higher risk (approximately 13% of African Americans have two risk alleles, and approximately 20% of the double-risk allele group go on to develop CKD).  

MT: Are there potential applications of this research beyond AMKD?  

RFD: Targeting the genetic drivers of disease with nucleotide-based therapies, such as ASOs, provides a way to reduce the expression of genes associated with disease biology through a precision medicine approach. At AstraZeneca, we are exploring several nucleotide-based modalities from oligonucleotides and RNA-based therapies as therapeutic tools. In addition to AZD2373, we are also advancing a novel precision medicine approach in metabolic dysfunction-associated steatohepatitis (MASH) with AZD2693, an ASO targeting a disease-causing gene variant.   

 We believe that in the future, RNA-based therapies could offer new ways to target the genetic drivers of disease, alter the course of disease and enable long-lasting treatment.   

Biography  

Regina Fritsche-Danielson is Senior Vice President and Head of Research and Early Development for Cardiovascular, Renal, and Metabolism (CVRM) within the BioPharmaceuticals R&D division at AstraZeneca. During her 23 years at AstraZeneca, Fritsche-Danielson has led numerous clinical development projects from early target discovery through Phase II clinical development, in addition to line management and strategic responsibilities. She was instrumental in establishing the Cardiac Regeneration research area for heart failure, and led AstraZeneca’s first mRNA programme, VEGF-A, through to Phase II.