Our research strategy in fibrosis builds on our drug discovery capability, exemplified by the in-house discovery of our next-generation selective ROCK2 inhibitor zelasudil, currently in a Phase 2 clinical programme for patients with idiopathic pulmonary fibrosis (IPF).

Our research capability in fibrosis was further demonstrated by the advancement of our GI-targeted pan-ROCK inhibitor, RXC008, through preclinical studies and into a Phase 1 healthy volunteer clinical trial. Furthermore, work on a novel fibrosis target, DDR, has resulted in a development compound RXC009 which is progressing through IND-enabling work as a potential treatment for chronic kidney disease, specifically Alport’s syndrome.

Our experienced team of scientists has considerable expertise in understanding the molecular mechanisms underlying fibrosis and druggable targets to focus on. We are developing small molecule therapies that aim to stop and ultimately reverse the formation of fibrotic tissue. By targeting pathways involved in the progression of these devastating diseases, we believe these drugs have potential to be disease-modifying rather than simply providing symptomatic relief.

Our distinctive approach consistently enables us to generate, potential best-in-class drug candidates and is built around three steps:

  1. Smart Target Selection: With the goal of de-risking our programs, we select biologically or clinically validated targets where we believe there is an opportunity to successfully apply our drug discovery capabilities in diseases of high unmet medical need.
  2. Differentiated Molecule Design: Create molecules with differentiated properties, leveraging our design frameworks and our strength and experience in medicinal chemistry, computational design and translational biology to optimise a novel differentiated molecule for the target.
  3. Translate: Focus our differentiated, targeted small molecules towards commercially attractive markets in which we believe we can be successful.
Preclinical Programme – RXC008 (GI-targeted ROCK)

About 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.

What is the role of fibrosis in cancer?

Fibrosis is increasingly recognised to have an important role in the progression of many tumours, and to regulate key cellular interactions within the tumour microenvironment. The effects on the tumour induced by cancer associated fibroblasts (CAFs; the main cells responsible for the scarring process) range from reduced access of chemotherapy/drugs to the tumour to impairment of the body’s anti-tumour immunity. Unsurprisingly, the more severe the fibrosis, the more aggressively the tumour will behave, and the worse the prognosis.

Clearly, therefore, therapeutic interventions which can reduce fibrotic damage not only have the potential to directly improve prognosis, but also to enhance the efficacy of other treatment modalities, for example, chemotherapy and immunotherapy.

Our focus areas in Fibrosis

Idiopathic Pulmonary Fibrosis (IPF)

IPF is a debilitating disease of the lungs which progressively causes scarring and a reduction in lung function. Occurring primarily in older adults (>50 years old), it involves irreversible and variable scarring, stiffening, and thickening of the lung tissues, leading to patients experiencing shortness of breath and lack of oxygen absorption. Over 170,000 patients suffer with IPF* and around a further 53,000 people are diagnosed each year (US, 5 EU, Japan). Patients diagnosed with IPF have an estimated life expectancy of 3 to 5 years**. There is no known cure and current treatment only slows progression of the disease.

* Patient numbers (diagnosed prevalence) & market size forecast data sourced from Global Data (US, EU5, Japan)
** Clinical Estimates from Hyun 2015, Ley 2012, Raghu 2006

Interstitial Lung Disease (ILD)

ILD is an umbrella term used for a group of diseases that cause fibrosis of the lungs* and IPF accounts for around one third of patients who have a significant lung pathology. Progressive fibrosing interstitial lung disease (PF-ILD) is a subset of ILD characterised by progressive, intractable lung fibrosis. Systemic sclerosis- ILD is a rare connective tissue disease which has a similar prognosis to IPF and is estimated to be the next largest individual ILD market segment. Other PF-ILDs include mixed connective tissue disease-ILD and rheumatoid arthritis- ILD.

**Kaul 2002Clinical Estimates from Hyun 2015, Ley 2012, Raghu 20061

Fibrostenotic Crohn’s Disease

Crohn’s disease (CD) is a chronic inflammatory condition of the colon and small intestine. It is one of the three main subgroups of inflammatory bowel disease (IBD), which also includes ulcerative colitis (UC), and IBD unclassified (IBDU). As inflammation persists, tissue damage occurs resulting in tissue remodelling and fibrosis in the intestine. In the USA, 30-40% of patients with IBD will develop fibrosis within 10 years of diagnosis. Fibrotic tissue can cause stricture formation and life-threatening obstruction of the intestine often requiring invasive and debilitating surgical intervention to restore bowel function. Fibrosis commonly recurs in these patients, necessitating further surgery that ultimately results in short bowel syndrome, a severe condition resulting in malnutrition and major quality of life issues for the patient. Anti-inflammatory medication is unable to inhibit fibrosis and there are currently no approved anti-fibrotic treatments for IBD.

Associated programmes