A clinical trial, which is to begin shortly, will look at a new way of delivering drugs to patients with ulcerative colitis, writes CLAIRE O'CONNELL
CAN YOU teach an old drug new tricks? That’s what an innovative Irish-led clinical trial plans to do over coming months. By delivering a well-known immune-suppressing drug straight to where it needs to act in the gut, the approach could potentially offer a new way of treating ulcerative colitis.
The trial, which is scheduled to start shortly, will use an oral drug formulation developed by Irish company Sigmoid Pharma that releases the drug ciclosporin directly into the large bowel, rather than the medicine being absorbed or injected into the bloodstream to get to its site of action.
Ulcerative colitis is a chronic, inflammatory condition of the large bowel, explains Prof Diarmuid O’Donoghue, a consultant gastroenterologist at St Vincent’s University Hospital and a clinician involved in the trial.
“It’s a lifelong condition and it varies from being very mild and easily treated with long periods of remission to being extremely severe and acute, and there are all grades in between,” he says, noting that the incidence here is about 20 cases per 100,000 people per year. “It classically affects young people in their late teens and 20s.”
Current drug treatments dampen down the immune system, which is thought to play a role in the condition, explains O’Donoghue. “Although we don’t know the cause of ulcerative colitis, we know that in some way our immune system is attacking the colon, so if we dampen down the immune system we can get good remission.”
Treatment for more severe cases can include steroids or biologic agents that block inflammation, but they can have side effects if used long term, and if the colitis continues some patients may have to undergo surgery to remove the bowel.
However, some people with severe ulcerative colitis who face surgery may respond well to a ‘rescue’ therapy of high doses of ciclosporin, an immune-suppressing drug that has been in use for over two decades and first came into its own in transplant medicine.
“If you give ciclosporin intravenously or on high dose orally to people who have severe ulcerative colitis that are looking like they are going to need surgery, about 50-60 per cent of people respond very well and they avoid surgery in the short term,” says O’Donoghue.
“But the problem with ciclosporin is that measuring the levels is not always very easy and people are worried about the side effects, the major ones being a peripheral neuritis, [kidney] problems and hypertension.
“It’s a good drug, but not used very often because of that.”
The new trial, which aims to recruit 100 patients with mild to moderate ulcerative colitis, will test an oral version of ciclosporin that gets released in the large bowel where it needs to work, rather than needing to enter the bloodstream to make its way there, explains Dr Ivan Coulter, chief executive of Sigmoid Pharma based at Dublin City University’s Invent centre.
“We are avoiding the drug being released while it is going through the intestine, and then it starts to be released in the bowel.”
The trial will see outpatients taking a relatively low dose of the new ciclosporin formulation by mouth over the course of four weeks, he explains.
“There are three main advantages – one is convenience, it’s given orally, once a day. Secondly, the drug is very effective and thirdly, because it doesn’t get absorbed into the body there are fewer concerns about side effects.”
Lab studies have already shown that Sigmoid’s drug formulation targets the bowel effectively, and the trial – which involves centres in Dublin, Cork, Galway and Limerick as well as sites in the UK – will provide information on how well the newly formulated ciclosporin can treat ulcerative colitis, according to O’Donoghue.
“We are fairly confident that this trial will show the drug is safe. What we don’t know, and this is why we have to do the trial, whether it is effective at the dose we will use,” he says. “It has theoretical advantages, we just have to prove its efficacy, and we would hope to find that it is much more efficacious than a placebo and that there are no side effects.
“If that is the case then the other great advantage is that we can use it long term. That would be the ideal.”
