Title: A single arm pilot study of Brodalumab in the treatment of Primary Sclerosing Cholangitis
Funder: Department of Health and Social Care

Abstract: Background Primary sclerosing cholangitis (PSC) is a NIHR rare immune-mediated liver disease, associated with a unique type of inflammatory bowel disease. The disease is characterised by chronic inflammation and stricturing fibrosis of the intra and extrahepatic biliary tree driven by oligoclonal autoreactive T and B cells. PSC is thought to arise due to an interaction of the genome and environment (with over 23 genetic loci statistically associated with PSC). With no recognised treatments to date, PSC patients may progress to: liver failure, liver transplant, colectomy or the development of a mucosal based cancer (cholangiocarcinoma, gallbladder, colorectal). The estimated prevalence of PSC in the UK is 5.58/100,000 with PSC representing approximately 10% of the UK indications for liver transplantation. Whilst the critical pathogenic mechanism underlying PSC is yet to be conclusively elucidated, it is widely accepted that abnormal T and B cells leads to the activation and progression of a fibro-obliterative cholangiopathy. Furthermore, an abundant IL-17 predominant lymphocytic infiltrate has been observed in the liver in human and animal models of PSC.Research question IL-17 inhibition has shown promise in several other autoimmune diseases. However, its potential benefit in PSC patients requires clarification. This pilot study will assess if Brodalumab (an IL-17 inhibitor) could represent a new safe, tolerable, practicable and acceptable treatment in PSC.Aims and objectives To date no clinical trials targeting IL-17 pathways in PSC are ongoing. Primary aims of this small pilot study (single arm pilot study of n=20) are to examine 1) patients' willingness to participate in studies of new biologics in PSC 2) Determine how many patients meet inclusion and exclusion criteria across 4 large treatment centres 3) Examine if there are any potential concerning safety signals with respect to the liver function, cholangitis, pruritis and inflammatory bowel disease following the administration of Brodalumab.Secondary aims will examine if there are any signals of potential drug efficacy using recognised surrogate markers of disease progression (liver function tests, serum fibrosis markers (ELF) and imaging markers of inflammation and biliary tree volume.Methods and timeline for deliverySingle arm pilot study conducted across 4 UK sites (Norwich Oxford, Birmingham, Cambridge), administering Brodalumab to 20 adults with early-stage PSC, and co-existing IBD who meet predefined inclusion and exclusion criteria.The study includes a screening period, 12-week treatment period and 12-week follow-up period, starting at week 12 or the last dose of the study drug for early withdrawal subjects. Administration schedule of Brodalumab as follows: week 0, 1, 2, 4, 6, 8, 10, 12. Regular research visits will be conducted coinciding with drug administration. Delivery timeline:0-12 months: Ethics and MHRA approval, recruitment of patients, and undertaking relevant training courses12-30 months: screening of patients, commencement of treatment & analysis of data30-36: dissemination of findings, write up and publication of PhD Anticipated impact and disseminationResults will be disseminated via PSC Support, oral presentation at conferences, and published in high quality peer reviewed publications. This study, if successful, will inform the design of a future randomised control trial.

Lay abstract: Primary sclerosing cholangitis (PSC) is a rare liver disease where the body attacks itself, causing inflammation and scarring of the bile ducts and liver. This causes bile to stop flowing properly and in turn leads to repeated infections, liver failure, and in some cases cancer. In more than 70% of people with PSC, the body also attacks the bowel, which can lead to development of a unique type of inflammatory bowel disease called PSC-IBD. People with PSC-IBD have an increased risk of bowel cancer compared to those with inflammatory bowel disease alone and therefore must have an annual colonoscopy to check for early cancer signs. Sadly, there is no recognised PSC medication that has been shown to improve survival. For some, liver transplantation is the only lifesaving option.Recent research (from both animal and human studies) shows that the immune system is responsible for bile duct damage in PSC. The parts of the immune system that drive this damage are called T cells and B cells. Research has shown us that in people with PSC, these T cells release a chemical called Interleukin 17 (IL-17). Interestingly, this same process is important in other autoimmune diseases, such psoriasis (a skin condition) and certain types of inflammatory arthritis. Importantly, powerful drugs called biologics that target the specific parts of the immune system have already been developed to treat these diseases. One such biologic is Brodalumab. It is used for psoriasis and reduces the effects of IL-17.Therefore, given the potential importance of IL-17 in PSC, we will study the effect of Brodalumab in people with PSC. The main aims of this pilot study are to understand:1) patients' willingness to take part in small pilot studies of new biologics in PSC.2) how many PSC patients are suitable to take part in the study.3) the impact of Brodalumab on the liver and bowel in people with PSC. We would also like to understand if Brodalumab reduces or slows the damage caused by PSC by measuring known markers of disease progression and liver damage with blood tests and scans.20 volunteers with PSC from four large PSC centres (Norwich, Oxford, Cambridge and Birmingham) will take part. They will all be given Brodalumab for 12 weeks (once a week for three weeks, then every other week). Brodalumab will be given using an injection pen and participants will be able to do this themselves at home after training. We will monitor participants with blood tests, liver scans, a colonoscopy and questionnaires. A group of 10 PSC patients from across the UK helped us improve the design of our study and highlight patients' needs and concerns. For example, the group felt that two colonoscopies might put people off, as they already need to have one annually. Therefore, we will use the results of participants' most recent colonoscopy so that only one additional colonoscopy is needed to take part. If our study is successful, we then propose to build on our findings and replicate them in a larger study (randomised control trial).For the duration of this study, we will continue working closely with the PSC community. Patient experts from the patient organisation, PSC Support, will join our Trial Steering Group, and a group of PSC patients, led by PSC Support and the Primary Investigator, will meet virtually at key milestones to help develop patient facing materials and give vital feedback. Our study findings will be shared in high quality scientific journals, presentations and posters at national and international liver and gut research meetings, and through PSC Support social media, newsletters and meetings.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM