research into drug treatments

At our family information day in London late last year, Tom MacDonald - Professor of Immunology at Barts and the London School of Medicine and Dentistry, Queen Mary, University of London - spoke about the latest research into treatments for IBD. This is what he said...

I'm an immunologist, and the reason I work in IBD is because the cause of IBD is inflammation, and inflammation is caused by excessive activity of immune cells. The gut is a very interesting organ, because when it’s healthy it is packed with immune cells, but these are controlled and do not cause disease.  Because the gut is one of the main sites where infections can occur, the gut is richly endowed with immune cells and tissues. In fact, 70% of the body’s immune cells are in the gut.

As I said, the healthy gut is full of immune cells without disease. This is called physiological inflammation, and there's no damage done. But something happens in IBD that flips the immune system into a hyperactive state. I'll be honest - we don't know what causes this. Once you get gut damage, it keeps on going because inflammation is essentially white blood cells leaving the blood and moving into the tissues. In fact this is the basis for many of the diseases of the world in many different organs and tissues.

Inflammation is very important in terms of new therapies for IBD.

I would say that probably 99% of the effort involved in developing new therapies for IBD involve controlling inflammation. It's an exciting time because there are so many therapies coming through.

Recent studies have worked out a lot of the immune mechanisms that cause tissue damage. We know by studying samples from patients that inflammation is complex, but if we can identify those cells and molecules that are important, we can then find ways to combat their damaging activities.

The main way to combat inflammation up to now has been with antibodies. But things have moved on, and instead of using just antibodies like infliximab, there are now pills that look as though they are quite effective. And of course, taking a pill is much easier than having an injection under the skin or an intravenous infusion.

So what is driving all this research? Well, it is industry – it is big pharma.

A recent report showed that the size of the IBD market worldwide is enormous and increasing, as incidence of IBD also increases in developing economies. The biggest selling drug in the world is an anti-TNF antibody that is used in IBD, psoriasis, and rheumatoid arthritis. It has $20 billion of sales a year.

I spend a lot of time traveling around talking to pharma companies about new therapies. I was in San Antonio, Texas, three weeks ago talking to a company that has a new drug they think might work in IBD. We were discussing the ways in which we might do some studies to justify the huge investment they need to get that drug into IBD patients. Making drugs is very expensive. It costs $1 billion to get a drug on the market. Because the market is so big and there is potential to make money, lots of very big and small pharmaceutical companies have IBD research programmes.

There are literally hundreds of small pharmaceutical companies that are targeting IBD for new therapies with really creative and revolutionary drugs and better delivery systems (ie, pills instead of injections).

There is also quite a lot of activity in the UK. Recently Crohn’s and Colitis UK announced a £5million grant for a unique IBD research hub because we are now generating so much data from patients with IBD. We have their genetic profiles. We have the genes IBD patients have in common. We have their microbiome. We have the therapies to which they responded. We have their disease course and clinical history. Nowadays we have tens of millions of pieces of data on patients with IBD. This hub will gather all the data together and use artificial intelligence to identify new targets. We also have the Wellcome Trust IBD Case Consortium here in the UK and they are very active in research on IBD mechanisms and also on clinical trials.

However, it's very unlikely that we'll be able to find an inflammatory pathway that's common in all patients.

That's just not going to happen because Crohn's disease is a very diverse disease, probably more so than ulcerative colitis. The immune system is incredibly resourceful. It has been developed to protect against cancer and infections. If one pathway doesn't get rid of the infection, the immune system develops another pathway and another pathway and another pathway.  Someone who is given a very successful anti-TNF, such as infliximab, may find that it will stop working after two years. Why is that? It's because the treatment is changing the inflammation. What we need to try and figure out is the best treatments for individual patients.

In 1997, we discovered that infliximab was highly effective in IBD. Something that CICRA can be proud of because it funded the research in my lab that showed that TNF was a key factor in driving gut inflammation. Then there was no new drug licensed until 2012. Since 2012 however, we’ve had a whole range of things coming along such as more anti-TNFs and antibodies to IL-12 which are useful in patients who do not respond to anti-TNFs. I work with a company that is giving an oral anti-TNF - a pill. There's been a clinical trial, a Phase 2a study, at St Thomas' Hospital, that showed that this drug induced mucosal healing in colitis patients.

We've also got a new class of drugs called kinase inhibitors. These are drugs that target the molecules inside cells that drive inflammation. We’ve got Tofacitinib, Filgotinib and Persitinnib. These drugs can be delivered via a pill, but there have been some problems with side effects – for example the dose of Tofacitinib had to be dropped.

There's another whole new class of antibodies ready to be patented. These are called the cell migration inhibitors.

These work on the very simple idea that inflammation is when white blood cells leave the blood and go into tissues. If you can stop them leaving the blood, you don't get inflammation. The one that everyone uses now is Vedolizumab. There is another drug in development, an anti-MAdCAM which stops cells moving into the gut. A drug which should be licensed this summer is called Ozanimod, which is a pill that also stops cells from moving into tissues. The latest activity in this area is in what are called anti-IL12/23 inhibitors.

A potentially exciting area is to make antibodies which neutralise a cytokine called IL-23. There are five different antibodies being made by 5 different companies and clinical trials are starting to appear which show they have some efficacy in IBD.

However, one of the issues gastroenterologists face now is which one do you use?

That's a big question, and the answer is, at the moment nobody knows. The challenges ahead are very patient-oriented. Essentially, the question we want to ask at diagnosis is - which patients will have mild disease versus severe disease? How can we identify people who won't respond to anti-TNFs? At the moment, we give an anti-TNF to 100 people and only 50 will respond. So what's going on with these patients? The answer is we don't really know.

Finally, with a lot of new therapies around, can we determine the best therapy for each patient ie, can we use personalized medicine? In other words, can we say that the signature of this individual's Crohn's disease is such that an anti-TNF wouldn't work, but maybe vedolizumab might do it?

Something else people are thinking about; Is combination therapy better than monotherapy? One drug company wants to do a study with two of their antibodies. They want to use infliximab (an anti-TNF) and combine it with an anti-IL 23.

So, this is a very, very active area worldwide.

There are literally billions going into developing new treatments for IBD. We've got all these choices now.

Instead of having one option, soon we will have twenty different drugs for IBD. I believe the situation is very bright. I'm an optimist. I think that human beings are unbelievably clever and we can do all sorts of things. We can put a man on the moon without modern computing. We can cure IBD.