AstraZeneca at ERA 2024: Regina Fritsche-Danielson in an Illuminating Dialogue Exchange with PharmaShots

Shots:

Associated with early onset and rapid progression of chronic kidney disease (CKD), APOL1 Mediated Kidney Disease dramatically affects people of African descent

AstraZeneca is developing AZD2373, the first potential precision treatment option for the treatment of AMKD with Ionis Pharmaceuticals. Recently, AZ shared promising data from the early P-I data from the MAD study

Today at PharmaShots, we have Regina Fritsche-Danielson from AstraZeneca shedding light on AZD2373 and MAD trial

Saurabh: We've been following the alarming rise of AMKD, especially among people of African descent. Can you tell us more about this disease and why it's so aggressive in a specific population and is there any more demographic analysis that you can share with us? 

Regina: AMKD is a type of kidney disease that occurs in individuals who carry two APOL1 risk variants (G1 and/or G2) in any combination (G1/G1, G2/G2, G1/G2). These variants originated in populations of sub-Saharan West Africa where they provide protection against African sleeping sickness. Not all individuals with two risk alleles develop AMKD, with a ‘second hit’ necessary for disease initiation.

There is currently no consensus on the exact mechanism through which APOL1 risk variants lead to AMKD, but studies have suggested a dysregulated gain of function leading to cellular damage in the kidney. AMKD is associated with early onset and rapid progression of chronic kidney disease (CKD).

Approximately 13% of African Americans have 2 risk alleles, and approximately 20% of the double-risk allele group go on to develop CKD. AMKD may contribute to the disparities in prevalence and progression of kidney disease between black and white patients.

Saurabh: The current treatments for chronic kidney disease seem powerless against AMKD. But AZD2373 seems to be a potential weapon. Can you explain how this drug works and why it might be a game-changer?  

Regina: If approved, AZD2373 will be the first precision medicine for the treatment of the disease. AZD2373 is an antisense oligonucleotide (ASO), a class of drugs that comprises synthetic nucleotide strands designed to suppress translation, and therefore, expression of specific proteins.

Evidence suggests that AMKD is a result of a dysregulated gain of function mechanism in APOL1-mediated pathways leading to cellular damage in the kidney. AZD2373 is designed to decrease the expression of the APOL1 protein in patients with APOL1 variants and could potentially act across the full range of mechanisms by which APOL-1 drives disease progression in AMKD.

AZD2373 is being developed in collaboration with Ionis Pharmaceuticals. It was found to be well tolerated in Phase I trials. 

Saurabh: While the study reported mild to moderate injection site reactions, can you elaborate on what steps might be taken to minimize discomfort in future trials? 

Regina: There are no major safety concerns at high doses of AZD2373 after the Phase I multiple ascending dose (MAD) study. The most common adverse events were injection site reactions that were dose dependent and mild to moderate in severity. They did not lead to treatment discontinuation in any case.

Saurabh: Considering the potential benefits of AZD2373, how can researchers and drug developers ensure this treatment becomes affordable and accessible to those who need it most? 

Regina: It is too early to comment on potential cost of AZD2373, but we anticipate competitive pricing relative to other therapies in this space and are planning for broad patient access that is not unduly restricted by price. 

Saurabh: The Phase 1 results are encouraging! what are the next stages of development for AZD2373’s progress to Phase II studies in 2025?  

Regina: Given the promising Phase I results, AZD2373 is on track to enter Phase II studies in 2025. 

Saurabh: How optimistic are you about the impact of AZD2373 on the future of AMKD treatment to address this critical unmet medical need? 

Regina: AZD2373 is being developed as a precision medicine approach, and based on the phase I results, we are reassured about its potential in addressing the underlying genetic driver in AMKD.

Currently, no specific treatments exist for AMKD, so diagnosed patients are often provided with the standard of care for CKD, which is aimed at controlling symptoms. 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 progressing to end-stage kidney disease within a decade. 

 AstraZeneca is committed to closing this gap and addressing the needs of patients with AMKD.

Image Source: Canva

About the Author:

Regina Fritsche-Danielson

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. In this role, she leads a group of more than 340 employees in the development journey from target discovery through clinical proof of concept across small and large molecules.

Regina is an expert in cardiovascular physiology and pharmacology including regenerative medicine, atherosclerosis and Heart failure with deep insights into disease mechanisms, unmet needs, and novel target discovery. She has authored more than 60 scientific research articles, along with several review articles and book chapters in the field. 

During her 23 years at AstraZeneca, Regina has led numerous clinical development projects from early target discovery through Phase 2 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 program, VEGF-A, through to Phase 2.

Regina earned her PhD in cardiovascular physiology/pharmacology from the University of Gothenburg in 1993. Following a distinguished eight-year tenure in academia, she joined AstraZeneca in September 2001.