How Mice Can Help Treat Crohn's Disease

News of a new clinical trial
By A Member Of The Natalizumab Investigating Team

The humble mouse is now playing an important and direct role in the treatment of Crohn's disease. How, you might ask?

A major goal in treating Crohn's disease is to stop the inflammation that is occurring in the bowel. This inflammation is purposeless and injures the bowel. Traditional therapies, such as steroids (like prednisolone), suppress the inflammation by working on many parts of the inflammatory process. While this broad spectrum of action can work reasonably well, it is associated with many unwanted effects, as anyone who has taken such treatment will attest.

What we really need is something that will suppress or remove only factors involved in inflammation that are critically important to maximise the effectiveness of the treatment and minimise side effects.

Enter the Mouse

Research has now identified several factors that are critically important in the progression of the complex process of inflammation. Many of these factors are proteins, and designing drugs that can remove and/or neutralise those proteins is difficult. Here is where the mouse comes in.

Human proteins, when injected into mice, lead to the production of antibodies. Antibodies are proteins themselves that can neutralise what they bind to. In general, one antibody will only bind to one specific protein. You can't make antibodies in humans to our own proteins. So why not make antibodies in mice to the protein you want to neutralise, inject them into humans, and, hey presto, that protein is eliminated and nothing else is affected!

This in fact does happen, but injecting a mouse protein, like an antibody, into a human leads to an immune response which in turn leads to fever, chills, aches and pains. This can be worse than the disease being treated! The way around this is to take the small part of the mouse antibody that binds to the protein and to hook it into a human antibody that will not cause sickness when injected into a person.

The result is called a "chimeric" or "humanised" antibody. This nifty way of generating a safe antibody (i.e the human antibody) to one that specifically binds to the human protein we want to neutralise can actually be done by modern technology.

Is this all science fiction? The answer is clearly NO! A range of such agents is already in use for different conditions, including one for the treatment of Crohn's disease (infliximab or Remicade), which is a chimeric antibody to a human protein TNF (tumour necrosis factor).

A New Antibody on the Block

A new humanised antibody, made to a protein completely different to TNF, is currently undergoing clinical trial in Australia. This is called natalizumab (or Antegren, which is less of a mouthful to say). Natalizumab binds a protein that enables white blood cells to move from within the blood vessels into the tissues. Therefore, when natalizumab binds this protein, white blood cells find it very hard to get into the tissues.

White blood cells are very big players in causing the injury associated with inflammation. If they are prevented from entering the tissue, inflammation is markedly reduced!

Trials of natalizumab in over 200 patients have shown that is can be very effective in many patients with Crohn's disease with only a small chance of what have been relatively minor side effects.

A major clinical trial (phase III study) examining the effectiveness of natalizumab in Crohn's disease has just commenced across Australia. The study aims to recruit 845 people with active Crohn's disease worldwide. Treatment is with natalizumab or placebo (dummy drug). There is a one in five chance that anyone entering the study will get placebo. The treatment is given by a drip into the vein over 60 minutes. The treatment is repeated after four and eight weeks.

Clinical Trial: Natalizumab in Active Crohn's Disease

Where is the trial being run?

In 17 countries worldwide, including approximately 10 major hospitals throughout Australia located in ACT, Melbourne, New South Wales, Queensland (Brisbane), South Australia and Western Australia.

Who is eligible?

• Aged 18 years or older with Crohn's disease
• Active disease (that is, lots of symptoms), but fistulas not allowed
• Can be taking other Crohn's medications (conditions apply)
• Women must not be breastfeeding or pregnant, and must not become pregnant during the study
• Participation is voluntary; no payments are made to participants
• All patients receive/sign an informed consent and plain language statement prior to participation

What is involved?

• Treatment is either natalizumab or placebo (dummy drug). There is a 1 in 5 chance of getting placebo.
• Treatment comprises infusions of the study medication into the vein over 60 minutes every 4 weeks for three doses
• 9 visits to the clinic are required over 20 weeks
• Study medication and tests involved are provided free to participants

How is the response to treatment assessed?

Diary cards of symptoms, blood tests and questionnaires

What happens at the end of the study?

If the participant has benefited from the treatment, there is an opportunity to enter a long-term treatment study.