OGG1 enzyme has a major role in DNA repair in conditions of oxidative stress and also in regulation of gene transcription involved in immune responses and development of fibrotic scars in tissue. Genetic knock-out of OGG1 or treatment with OGG1 inhibitors have shown to protect from inflammation and fibrosis in several disease models.
Helleday laboratory, Karolinska Institute has developed first-in-class small molecule OGG1 inhibitors and demonstrated proof of concept in established disease model of pulmonary fibrosis. A handful of inhibitors were evaluated for pharmacokinetic properties and efficacy in pharmacodynamic acute disease model. One of the OGG1 inhibitors was selected and administered orally in three weeks chronic disease model. Treatment with selected compound was well tolerated and protected the model from lung tissue damage and inflammation, development of fibrotic scars and production of excessive extracellular matrix proteins associated with fibrotic tissue as well as infiltration of inflammatory cells in lungs. Results were confirmed in vitro using primary human lung fibroblasts where treatment with selected OGG1 inhibitor inhibited activation of fibroblasts and production of fibrotic markers.
The selected compound is now in preclinical development and will be evaluated in regulatory safety assessment program during 2022/2023. The plan is to enter phase 1 clinical trial for the first indication Idiopathic Pulmonary Fibrosis (IPF) in 2024.
Fibrosis in response to tissue damage or persistent inflammation is a pathological hallmark of many chronic degenerative diseases where IPF is one of the most severe diseases. IPF is a debilitating condition with significant morbidity and poor survival. Evidence indicates that IPF has considerable impact on Health Related Quality of Life (HRQoL), relative to the general population levels. Annual per capita cost of patients with IPF in North America was estimated around US$20,000, 2.5–3.5 times higher than the national healthcare expenditure. This confirms IPF as a growing threat for public health worldwide, with considerable impact to the patients and healthcare providers.
Thus there is a large unmet medical need for a safe drug with significant therapeutic effect that can be used alone or in combination with current drugs on the market.
