A single arm pilot study of Brodalumab in the treatment of Primary Sclerosing Cholangitis

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 delivery Single 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 courses 12-30 months: screening of patients, commencement of treatment & analysis of data 30-36: dissemination of findings, write up and publication of PhD Anticipated impact and dissemination Results 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.