MISSION 2030

The last few years have seen major advances in PSC research. These include

• Better understanding of how the gut influences the development of liver disease
• Improved knowledge of what is associated with a good (compared to not-so-good) prognosis
• An evidence base to guide cancer surveillance
• A wealth of clinical trial activity, with more (potential) PSC treatments being tested than ever before.

The Gut and PSC

Approximately 70-80% of people with PSC will also have (or develop) inflammatory bowel disease (IBD) at some point. The IBD in PSC has been found to behave a little differently to IBD without PSC, and it has been shown that this may be due to differences in the gut microbiome (bacteria, viruses and fungi) that live in the bowel. Perhaps most exciting, is the fact that there are now several different ways the gut microbiome can be ‘manipulated’ in order to treat gut inflammation. Early studies of certain antibiotics and stool transplantation have shown promise in improving quality of life and blood tests. We are now eagerly awaiting results of larger studies to see whether and how these technologies can slow or stop progression of PSC liver disease.

In addition, there is emerging data to show how certain types of bowel operations maybe more beneficial than others if you have PSC and had a liver transplant. Surgery to remove the colon (large bowel) before a transplant has been shown to lower the risk of PSC recurrence in the new liver (see Colectomy type and PSC transplant). Importantly, the beneficial effects are seen mostly in people who choose to keep a stoma bag (ileostomy) compared to people to who choose to be joined up again afterwards. This observation has now led doctors to study whether bowel surgery very early on in ‘course’ of PSC, particularly with an ileostomy, is associated with a lower risk of needing a liver transplant in the first place, a lower risk of bile duct cancer, and overall improved quality of life.

Determining prognosis (how and/or when the disease will develop)

One of the most unsettling things to contend with is the ‘uncertainty’ of what a PSC diagnosis brings. For instance, what is the probability or likelihood of developing a complication, needing a liver transplant or bowel surgery in later life. For many years, it was only possible to answer these questions very late in the course of disease (i.e., immediately before an intervention was required). However, doctors can now use combinations of MRI scans, liver stiffness scans (fibroscans) and blood test scoring systems to provide patients with a more accurate estimate of prognosis long-term. These tools also allow doctors to identify people who are most in need of new medicine, and if appropriate, refer them for participation in a PSC clinical trial.

Additionally. colleagues in Spain and Germany are developing very sophisticated biomarkers to tell the difference between PSC alone and PSC with bile duct cancer. Although at an early stage, these promising tools have the potential to revolutionise cancer screening, and reduce the need for multiple invasive tests.

Cancer screening

Data from the UK and North America has shown that people who undergo regular scans (1-2 yearly) of the liver and bile ducts survive longer in the event a cancer is diagnosed in this area, compared to people who do not undergo regular scans. However, it is still uncertain as to which type of scan is most effective at picking up cancers, or pre-cancerous changes that can be treated early and effectively. Extensive research is ongoing in this area. In a similar vein, work from the Netherlands show that people undergoing yearly colonoscopies are less likely to die from bowel cancer compared to people who have bowel cancers diagnosed incidentally. Further research is needed to know if different lengths of time between colonoscopies can be applied (e.g. 2-3 yearly, 3-5 yearly), particularly for people without symptoms and those with well-controlled colitis associated with their PSC.

New potential treatments

At present, there are no medical treatments proven to cure PSC, or slow the rate at which liver and bile duct damage is occurring. However, the horizon for new therapies is encouraging, with a very active clinical trials’ arena.

Each potential new agent (treatment) undergoes a rigorous process of testing and evaluation, initially in healthy volunteers and later in small groups of people who actually have PSC. Usually, these early ‘phase 0 to I trials’ are of short duration (days to weeks), conducted in around 5-10 people, don’t test whether an agent has any effect on disease behaviour. However, these early phase studies are very important to see how a medicine behaves in the body, how long it stays in the body, and to refine a dose range that is likely to be safe and effective in larger trials. There are several early phase trials of this nature at the moment; for instance, using mesenchymal stromal cells (previously called stem cells).

The next step (phase II trials) involves larger groups of people who have the disease (usually more than 10 people, and up to a few hundred), can last anywhere between a few weeks to more than a year long, and tests if a medicine has benefit in a particular biomarker of disease. A biomarker can be in a particular symptom, blood test or scan result. Most PSC trials are currently at this stage, with medicines looking to

• Improve bile flow and reduce damage to the bile duct lining (e.g., berberine ursodeoxycholate),
• Lower / reduce the amount of scar tissue that builds up in the liver. This can be either intravenously (as in the SPRING study) or with tablets (as in the INTEGRIS trial),
• Change the gut microbiome using antibiotics (like in the PSC vancomycin study), using faecal transplantation (the FARGO trial) or by reducing the absorption of certain toxins from the gut (the CATCH trial).
• Reduce autoimmune attack in the gut and liver by dampening the immune system (e.g., the SABR-PSC study)

Often (but not always), phase II trials include people who receive an inactive version of the medicine under study called a placebo. This is so that researchers can compare differences between what is an active compound or medicine, to something that is inactive and does nothing.

Importantly, there are now trials that have been successful in all prior steps, and which have now progressed to phase III. A phase III trial involves many hundreds of patients from around the world, lasts many years, and is the step before a new medicine can be licensed as a treatment. The front-runner at the moment is a compound developed in Europe called NorUrsodeoxycholic acid. This is similar to ursodeoxycholic acid in structure, but lacks one particular part of the molecule. This means that the active portion of the drug circulates between the liver and bile ducts (unlike ursodeoxycholic acid, which also circulates around the bowel). Studies in animals have shown that NorUrsodeoxycholic acid reduces the amount of scarring in the liver and bile ducts. Additionally, there is some animal data to suggest that changes of sclerosing cholangitis may actually be reversible on treatment. Early data from the NorUrsodeoxycholic studies show improvement in liver blood tests and the PSC world eagerly await results of the phase III study to see if this medicine was also able to improve (or reverse) tissue damage in a large group of PSC patients.