Many 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, 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 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 Astellas 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

Let’s examine the steps that the translational science team at Astellas took to interrogate mitochondrial science and arrive at a new way to treat disease.

Prior to the acquisition of Mitobridge, Astellas studied cutting-edge scientific research examining kidney biopsies from patients with kidney disease. This research revealed links to how mitochondrial dysfunction can be a key driver in both acute and chronic kidney disease. The team at Astellas began pursuing the mitochondria as a therapeutic target for kidney diseases, specifically for acute kidney injury (AKI). 

After acquiring Mitobridge in 2018, Astellas has accelerated its efforts 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, the Astellas R&D team initiated a drug discovery program based on a target reported to activate a protein called PPARδ (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 – the main energy source for the kidney – that are metabolized by the mitochondria in kidney tubular cells. With this foundation of understanding, the team 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: Next, the team identified a potent and selective PPARδ modulator, ASP1128/ MA-0217, and embarked on preclinical studies that showed enhancing fatty acid oxidation with a PPARδ modulator restored mitochondrial function in the kidney.
• Advancing to the clinic: With this rapid progress, Astellas is 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. The success of translating mitochondrial science into an opportunity to pursue a potential treatment option for patients with AKI has energized the mitochondrial biology team at Astellas to pursue treatments for other diseases with high unmet need in patients.

Powering on

Within Astellas, the translational science team has recognized the significance of mitochondrial dysfunction and its ability to affect a broad range of disease areas. The team at Mitobridge has a rich history in the mitochondrial research and that experience allows them to pursue new opportunities and expanding on their expertise as part of the Astellas Biomedical innovation Hub. The commitment to this science and to the needs of patients is felt throughout the entire organization as Astellas looks forward to future discoveries and pipeline developments.

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