USP30 Heart Failure Disease Program

Disease Indication

Heart Failure

Heart Failure with preserved ejection fraction (HFpEF) represents at least half of all heart failure cases and is a complex clinical syndrome characterized by left ventricular diastolic dysfunction, causing raised filling/pulmonary pressures and associated dyspnoea and impaired
cardio/respiratory function. Left ventricular ejection fraction is above 40-50% reflecting relative stiffening of heart muscle with maintained systolic function. Co-morbidities are numerous, including arterial hypertension, coronary artery disease, obesity, and type 2 diabetes (T2D). A mainstay of treatment for HFpEF has included diuretics to reduce volume overload and targeting underlying comorbidities such as hypertension with ACE inhibitors, ARB and calcium channel blockers. Recently, the T2D drug class of SGLT2 inhibitors, including dapagliflozin and empagliflozin, have shown moderate clinical benefit and are now first line treatments for HFpEF regardless of comorbidity. Clinical benefits have also been shown with GLP1 receptor agonists (GLP1RA), although no marketed GLP1RAs are currently indicated specifically for HFpEF treatment.

However, an unmet need remains for drugs which specifically target direct cardio-protection and inflammation through a direct effect on the heart itself. Mitochondrial dysfunction is an early pathogenic event in HF. This leads to poor bioenergetic function and cardiac muscle weakness. Additional disease mechanisms driven by mitochondrial dysfunction include calcium dysregulation, inflammation, and ER stress, leading to cardiomyopathy. Mitophagy, the process of dysfunctional mitochondria elimination, is defective in HFpEF patient tissue and animal models of cardiomyopathy. Skeletal muscle energetics and function may also be improved by clearing dysfunctional mitochondria.

MTX652 is a USP30 inhibitor which promotes mitochondrial quality through mitophagy, leading to improved mitochondrial bioenergetics and functional outcomes, cardio-protection through reduced oxidative stress/inflammation, leading to reduced fibrosis. Pre-clinical efficacy of MTX652 has been observed in the experimental transverse aortic constriction (TAC) mouse model of pressure overload-induced cardiac hypertrophy & heart failure demonstrating positive effects on cardiac remodelling, left ventricle dilation & improved systolic cardiac function. MTX652 IP protection continues into the 2040s.

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