USP30 Renal Disease Program

Pipeline

Disease Indication

AKI / CKD

One of Mission’s lead assets, MTX652, which is now in the clinic, is intended to address the important unmet need of treatment of acute kidney injury (AKI). AKI is important in itself, but also leads to chronic kidney disease (CKD) and end stage renal disease.

AKI occurs in about 13.3 million people globally per year and it is thought to contribute to about 1.7 million deaths every year (Mehta, Cerda et al. 2015). As a result of increased diagnostics and awareness, the severity of the burden of AKI has become undeniable. The attributable healthcare costs for AKI were estimated in 2017 to be around 1% of the total NHS budget in England and between US$5.4 – 24 billion in the US (Silver S.A., Chertow G.M. Nephron 2017;137:297–301).

AKI can result from a wide spectrum of physiological causes, with significant morbidity/mortality outcomes, substantial effect on quality of life and healthcare cost. AKI frequently results in permanent kidney damage (i.e., CKD) and may also cause damage to non-renal organs. AKI is therefore a significant public health concern, particularly when taking into account the absolute number of patients developing incident CKD, progressive CKD, and end-stage renal disease. There is therefore a clear unmet medical need, making the development of medicinal products for the prevention and/or treatment of AKI an urgent matter.

Acute Kidney Injury leading to Chronic Kidney Disease

AKI and CKD are increasingly viewed as a continuum on the same disease spectrum. The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines define AKI as an abrupt decrease in kidney function occurring over 7 days or less, whereas CKD is defined by the persistence of kidney disease for a period of >90 days.

Multiple risk factors influence outcome after renal injury, such as age, race, genetic factors, hypertension, diabetes mellitus, and metabolic syndrome. Disease modifiers include the severity of AKI, stage of CKD, number and duration of episodes and proteinuria. The attributable NHS costs in the UK for CKD were around £1.5 billion in 2009/10; while in the US the stage 2–stage 4 CKD costs to Medicare were estimated at about $49 billion each year (Honeycutt et al. JASN September 2013, 24 (9) 1478-1483).

Approximately 400,000 Americans have end-stage renal disease, and over 300,000 of these patients require maintenance dialysis. Mortality rates remain above 20 percent per year even with the use of dialysis. The annual direct medical costs for end-stage renal disease are nearly $23 billion. In the UK, the costs to the NHS (excluding costs in the community) are estimated to be between £434 million and £620 million per year (2013, NICE), which is more than the costs associated with breast cancer, or lung and skin cancer combined.

Proposed Mechanism Of Action

Mitochondria are considered to be the powerhouse of the cell, generating the energy used for essential cellular activities. If these mitochondria are damaged or unhealthy, they need to be eliminated to prevent damaging consequences. A major route for this elimination is called “mitophagy”.

USP30 is a mitochondrial-associated DUB and inhibits Parkin mediated mitophagy. Inhibition of USP30 therefore aids mitophagy, which results in increased degradation of impaired mitochondria, with the expectation that this will improve and preserve cellular health.

Therapeutic Rationale

The kidney is a site of high metabolic demand, with high mitophagy rates demonstrated in vivo (McWiliiams et al., 2018). Renal Proximal Tubule Epithelial Cells (PTECs), a cell type with significant energy requirement, are rich in mitochondria and therefore extremely vulnerable to injury if the mitochondria are not working properly. Mitochondrial dysfunction is strongly implicated in acute kidney injury (Agarwal et al. 2016), as well as in both AKI and CKD mechanisms, as evidenced through multiple preclinical AKI and CKD models and also through data demonstrating abnormal mitochondria in patient biopsies (Emma et al., 2016; Eirin et al., 2017).

Tang et al. (2018) demonstrated that renal injury was exacerbated following AKI due to reduced blood supply in PINK1 or PARK2 deficient mice, suggesting that ubiquitin-mediated mitophagy plays a protective role. In addition, ubiquitin-mediated mitophagy protects against cisplatin-induced kidney injury (Wang et al., 2018). Furthermore, chronic kidney fibrosis is exacerbated in Parkin knockout mice implying that there is a strong rationale for USP30 inhibition as a treatment both for acute injury and chronic fibrotic disease (Bhatia et al. JCI Insight. 2019;4(23)).