The Astellas Way Blog

Powering on with the Mitochondria: Kidney Disease & Beyond

By Effie Tozzo, PhD, Senior Vice President, Translational Sciences, Mitobridge, An Astellas Company

Nov 8, 2019

Many of us know mitochondria as the energy suppliers of our cells. Given the myriad roles that mitochondria play in cellular homeostasis, it is no surprise that defects in mitochondrial function can lead to a broad spectrum of diseases. Yet, it has only been relatively recently that meaningful discoveries have emerged about mitochondrial biology and their role in human disease.

Working with scientific leaders in the field, our team at Astellas has focused on developing mitochondria-directed medicines as an axis for new therapeutic approaches to treat various diseases with high unmet medical needs.  Emerging research has established the premise that mitochondrial dysfunction is the main culprit in a variety of human diseases affecting many organs, including muscle, kidney, brain, eyes, and liver. This has opened the door for drug developers, like us, to take a deep look at mitochondrial biology to gain insight into the disease pathways and mechanisms where mitochondria play a critical and complex role.

Creating mitochondria-targeted medicines

As an example, let me share how we interrogated mitochondrial science to arrive at a new way to treat disease.

In 2016, prior to the acquisition of Mitobridge by Astellas in 2018, our team picked up on new scientific reports examining kidney biopsies from patients with kidney disease that revealed links to how mitochondrial dysfunction can be a key driver in both acute and chronic kidney disease. We began pursuing the mitochondria as a therapeutic target for kidney diseases, specifically for acute kidney injury (AKI). 

Since then, we have continued on our path to develop a mitochondria-targeted medicine with the following steps:

  • Identifying a central target:Based on the new insights about the role of the mitochondria in AKI, our R&D team initiated a drug discovery program based on a target reported to activate a protein called PPARd (peroxisome proliferator-activated receptor delta.) PPARδ is a master regulator of metabolism that can increase or decrease gene transcription that controls a range of fundamental cellular functions. One of these PPARδ-regulated functions is the oxidation of fatty acids, which are the main energy source for the kidney and they are metabolized by the mitochondria in kidney tubular cells. With this foundation of understanding, we generated a library of targeted PPARδ modulators that activate the gene cascade for fatty acid oxidation and, therefore, improve mitochondrial function.

  • Modulating a pathway in AKI:We developed a potent and selective PPARδ modulator, ASP1128/ MA-0217, and embarked on preclinical studies that showed enhancing fatty acid oxidation with a PPARδ modulator restores mitochondrial function in the kidney

  • Advancing to the clinic:  With our rapid progress, we have now arrived at initiating a Phase 2 proof-of-concept clinical trial with ASP1128 in patients at high risk for AKI undergoing cardiac surgery; more information is available at Clinical Trials.gov.  This program was recently granted Fast Track designation by U.S. FDA. We are energized by this example of translating mitochondrial science into an opportunity to pursue a potential treatment option for patients with AKI, a disease with high unmet need.

Powering on

Within Astellas, our team has recognized the significance of mitochondrial dysfunction and its ability to affect a broad range of disease areas. The R&D team at Mitobridge has a rich history in the mitochondrial research area and our opportunities are expanding as we continue building our expertise as part of the innovation hub within Astellas. The commitment to this science and to the needs of patients is felt throughout our entire organization as we look forward to future discoveries and pipeline developments.

It’s been an exciting and rapid journey from our original hypothesis around a mitochondrial target to the initiation of a Phase 2 trial for a Fast Track-designated drug candidate for AKI. We hope to cultivate many more mitochondria-targeted medicines for other diseases to hopefully create and deliver value for patients.