RXC007 (ROCK2 selective)

ROCK2 inhibitor for the treatment of fibrosis

Expected to enter clinic H1 2021

Target/ Product

Indication(s)

Research

Preclinical Development

Clinical Phase 1/2

Expected Milestones

ROCK2 Selective Inhibitor
(RXC007)

Lung fibrosis (IPF)
Liver fibrosis (NASH)

Entering clinic – H1 2021

RXC007 is an orally available, highly selective small molecule inhibitor that targets Rho Associated Coiled-Coil Containing Protein Kinase 2 (ROCK2) which sits at a nodal point in a cell signalling pathway, believed to be central to fibrosis. ROCK2 is therefore an important emerging drug target and RXC007 has the potential to treat several fibrotic diseases. These include the orphan disease, idiopathic pulmonary fibrosis (IPF), a severe and life-threatening chronic lung condition with very poor prognosis and limited treatment options; non-alcoholic steatohepatitis (NASH), an inflammatory and fibrotic disease of the liver; and other systemic fibrotic conditions.

Our ROCK2 inhibitor, RXC007 has demonstrated robust anti-fibrotic effects in a range of industry-standard in vivo preclinical models and after successful candidate nomination in H1 2020, RXC007 is expected to enter phase 1 clinical study in 2021, whilst evaluating clinical development pathways in IPF, NASH and systemic fibrotic conditions.

What is Fibrosis?

Fibrosis is an internal scarring process, which can occur in response to injury, where excess connective tissue is deposited in an organ or tissue – thereby impairing its function. Most chronic inflammatory diseases will result in fibrosis, with progressive injury resulting in organ failure. Fibrotic disease can occur in nearly any tissue in the body and contributes to 45% of deaths in the developed world. Solid organ (such as lung, liver or kidney) fibrosis can occur as a result of many different diseases and underlying health issues, including obesity or diabetes. Current therapeutic options are limited for these chronic and often life-threatening diseases.

Why target ROCK2 (Rho-associated protein kinase 2) for fibrotic diseases?

ROCK2 is an intracellular kinase with multiple cellular functions. ROCK2 signalling plays a key role in both the inflammatory component and the tissue re-modelling that drives disease progression in many fibrotic conditions. ROCK2 expression and activity have been shown to be upregulated in acute inflammatory injury and in chronic diseases such as diabetes, metabolic syndrome and idiopathic pulmonary fibrosis (IPF). Furthermore, ROCK2 activity is also upregulated in liver, lung and kidney models of fibrosis. ROCK2 has been shown to modulate activation of the hepatic stellate cells (central drivers of fibrosis in the liver) and mesangial cells (important drivers of fibrosis in the kidney). ROCK2 has also been shown to play important roles in the pro-fibrotic response of lung epithelial cells in IPF. Selective inhibition of ROCK2 will also prevent the hypotensive side effects typically associated with systemic pan-ROCK inhibitors (where both ROCK1 and ROCK2 are inhibited). Targeting ROCK2 has been clinically validated by other compounds currently in development, including KD025, a ROCK2 inhibitor recently submitted to the FDA as a New Drug Application for use in chronic Graft vs Host Disease (cGvHD) in September 2020.

ROCK2 sits at a nodal point in a cell signalling pathway, believed to be central to fibrosis

Figure 1: The ROCK signalling pathway

RXC007 demonstrates compelling efficacy in well-validated preclinical model of lung fibrosis

Figure 2: Therapeutic Bleomycin-induced Lung Mouse Model

RXC007 reduces fibrosis and collagen deposition in the lung and bronchoalveolar lavage fluid (BALF) in murine bleomycin-induced IPF model with therapeutic dosing.

Programme summary

RXC007 (ROCK2 selective)

Target

ROCK2 selective inhibitor (RXC007) for treatment of Fibrosis

Status

Preclinical development

Indications

Fibrotic conditions e.g IPF
NASH, other systemic fibrotic conditions

Future development

2021 H1

Phase 1 start

Future development

2022 H2

Phase 2 start