Fibrosis

Our research strategy in fibrosis builds on our drug discovery capability, exemplified by the in-house discovery of our selective ROCK2 inhibitor RXC007, currently in Phase 1 in healthy volunteers. Our research capability in fibrosis was further demonstrated when we signed a licensing agreement with AstraZeneca in 2020 to develop RXC006 in idiopathic pulmonary fibrosis (IPF). 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 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 discovery approach is based on three steps:

  1. Target: 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. Design: Design molecules with differentiated properties, leveraging our design frameworks and our strength and experience in medicinal chemistry and translational biology to optimize a novel differentiated molecule for the target.
  3. Deliver: Focus our differentiated, targeted small molecules towards commercially attractive markets in which we believe we can be successful.
Lead Fibrosis Research 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.

Our focus areas in Fibrosis

Idiopathic Pulmonary Fibrosis (IPF)

Idiopathic pulmonary fibrosis (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. Around 53,000 people are diagnosed each year with IPF (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.

Chronic Kidney Disease (CKD)

It is estimated that over 850 million people worldwide have some form of kidney disease. Diabetes and high blood pressure are the two leading causes, but rarer conditions such as membranous nephropathy and focal segmental glomerulosclerosis also contribute. Over time damage, remodelling and fibrosis of the kidneys impairs their function and a significant number of patients progress to end-stage renal disease, where the kidneys are no longer able to function, and the only treatment is dialysis and / or organ transplant.  There are no current treatments targeting fibrosis in this disease.

Associated programmes

Fibrostenosis associated with 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

Non-alcoholic Steatohepatitis (NASH)

NASH is an inflammatory and fibrotic disease of the liver caused by non-alcoholic fatty liver disease (NAFLD) – a condition where fatty deposits build-up in liver tissue. It is estimated that up to 30% of adults in the developed world may have fatty livers caused by obesity, poor diet and lack of exercise. Whilst lifestyle changes can reverse NAFLD in the early stages, once inflammation and fibrosis are established, disease progression is very challenging to reverse with changes in patient behaviours alone. Over time the fat accumulation leads to inflammation, tissue damage and eventual tissue remodelling and fibrosis. Fibrotic tissue build-up results in loss of metabolic function in the liver and reduced blood flow. NASH progresses through different stages, each with increasing severity. In the final stages, patients have a condition known as cirrhosis, a severely debilitating disease caused by a heavily scarred liver with minimal function remaining. Cirrhosis patients are also at high risk of developing hepatocellular carcinoma (HCC), the third leading cause of cancer deaths worldwide. There are currently no approved treatments for NAFLD or NASH and there is a need for new therapies to address these diseases.

Associated programmes