Fibrosis is defined as an excessive deposition of connective tissue components, considered as the endpoint of pathological remodeling. It contributes to the pathogenesis of several chronic diseases and aging related organ damage including that of – skin, lungs, heart, liver, kidney etc. Fibrotic tissue remodeling often leads to organ malfunction and is commonly associated with high morbidity and mortality. It is the result of chronic inflammatory reactions and chronic aberrant wound-healing response.

The key cellular mediator of fibrosis is the myofibroblast, which when activated serves as the primary collagen-producing cell. Myofibroblasts are activated by a variety of mechanisms, and targeting these factors is an ideal strategy for drug development.

Due to the unmet medical needs for fibrotic diseases, Insilico Medicine capitalized on PandaOmics to discover TNIK – a novel target for fibrosis. Then Insilico Medicine leveraged Chemistry42 to generate inhibitor candidates based on their high potency, and good development profile.

Idiopathic pulmonary fibrosis (IPF) is a type of chronic scarring lung disease characterized by a progressive and irreversible decline in lung function affecting around 5 million people globally. IPF carries a poor prognosis with a median survival of 3 to 4 years and represents a significant unmet medical need. Nintedanib and Pirfenidone are two drugs approved for treatment. However, their efficacy is moderate, and they do not halt or reverse the disease. Moreover, the side effects are frequent and include nausea, diarrhea, and liver damage risk leading to high discontinuation rate.

Kidney fibrosis is due to failure in wound healing of the kidney tissue, and the progressive disease is characterized by glomerulosclerosis, and tubulointerstitial fibrosis. Following kidney injury, progressive fibrosis leads to a detrimental effect on the kidney function and ultimately results in end-stage renal failure. The degree of renal fibrosis correlates with kidney function and Chronic Kidney Disease (CKD) stages. Currently, no targeted therapy exists to slow the kidney fibrosis.

Similar studies have also identified the involvement of TNIK in skin fibrosis (hypertrophic scarring) and liver fibrosis.

Rentosertib is a potent and selective small molecule inhibitor of TNIK with high affinity for the treatment of IPF. Preclinical data support the activity of Rentosertib and its combination use with Nintedanib & Pirfenidone in lung fibrosis models.

The results of the Phase I clinical trial in New Zealand demonstrated good safety, tolerability and pharmacokinetics data of Rentosertib in healthy participants. The interim results of a Phase I clinical trial in China also demonstrated similar encouraging safety and tolerability of Rentosertib in healthy participants.

In a 12-week Phase IIa study in Idiopathic Pulmonary Fibrosis (IPF) patients, Rentosertib met its primary endpoint of safety and tolerability across all dose levels. Positive results were also reported for the secondary efficacy endpoint, wherein a dose-dependent forced vital capacity (FVC) improvement was observed.