RXC007 (ROCK2 selective)

ROCK2 inhibitor for the treatment of fibrosis

Phase 1 preliminary data announced March 2022

Target/Product

Research

Preclinical

Phase 1

Phase 2

Phase 3

Upcoming Milestones

Fibrosis

ROCK2
Selective Inhibitor
(RXC007)

Idiopathic pulmonary fibrosis (IPF)

Initiate Phase 2a – 2022

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 where ROCK2 is upregulated. 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. There is also potential in other systemic fibrotic conditions.

Our ROCK2 inhibitor, RXC007, has demonstrated potential to be an attractive agent for the treatment of fibrotic indications.

RXC007 has been shown to be safe and well tolerated in a Phase 1 clinical study in healthy volunteers, and is now being progressed to patients with IPF being targeted as the first indication for clinical development.

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 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 has potential to 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 approved by the FDA for chronic Graft vs Host Disease (cGvHD) now being developed by  Sanofi following its acquisition of Kadmon in August 2021.

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

Diagram of ROCK2 pathway

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 idiopathic pulmonary fibrosis (IPF) model with therapeutic dosing.

Programme summary

RXC007 (ROCK2 selective)

Target

ROCK2 selective inhibitor (RXC007) for treatment of fibrosis

Status

Phase 1 Clinical development

Indications

Idiopathic Pulmonary Fibrosis (IPF)

Future development

2022

Phase 2 start