Treating Irritable Bowel Syndrome > A Tough Hill to Climb

Irritable bowel syndrome is not much fun – not that you didn’t know that already.  The disease is associated with daytime abdominal pain, bloating and discomfort, and altered bowel habits without progressive deterioration or detectable structural, mechanical, biochemical or overt inflammatory abnormalities. 

A lot of people take painkillers to decrease abdominal pain associated with IBS.  Unfortunately, many stronger painkillers are associated with constipation.  To reduce constipation, patients are given laxatives to stimulate the bowels, which then renews IBS symptoms – creating a viscous cycle of pain and discomfort for IBS patients. 

I was saddened to learn that IBS afflicts about 12% of all adults (this figure includes Chron’s disease and ulcerative colitis) in the United States.  Interestingly, the incidence of IBS in women is twice that of men and there is some evidence that symptom activity in women is correlated with menstruation.  The underlying cause of the disease is still unknown.

For a disease that afflicts 12% of the US population, there is an appalling lack of IBS drug development. The graph above shows the almost complete absence of prescriptions being filled for IBS patients.  

IBS presents a minefield of challenges for drug developers.

First, there is no real consensus about IBS clinical trial design. IBS is a cyclical condition characterized by periods of symptom activity alternating with relatively asymptomatic periods.  During disease flares, patients can have wildly different levels of response with regards to pain, diarrhea, and overall discomfort.  Those endpoints tend to be highly subjective (ex: some people have higher pain thresholds) which is not ideal for clinical trials.  Therefore, it is not so easy to design a trial that can smooth out disease flares (has to be sufficiently large) and can integrate multiple endpoints that are fairly subjective.  In general, pharma companies avoid IBS all together, and prefer to go after lower hanging inflammatory disorders like asthma or rheumatoid arthritis. 

Second, IBS trials are notorious for having incredibly high placebo rates.  In one study, the placebo rate was shown to be 42%!  In several trials, placebo response rates were shown to be strongly correlated with the number of times a patient visited a doctor and the longer the patient thought they were on treatment.  People thought they were getting better just by frequently visiting their doctor! 

Placebo response rates could be managed by running clinical trials that minimize patient / doctor interactions and shorten the length of treatment.  Another thought is to only recruit patients with severe IBS.  These patients have more consistent symptoms and are less likely to have a placebo effect.  The downside is that more diseased patients typically have all sorts of other issues going on that interfere with drug responses.

Lastly, current animal models do not provide ideal models to represent the human condition.  Current animal models rely on colon length (shortening of the colon is bad) and diarrhea frequency as endpoints.  Those end points are not bad per se, but they do not reflect the primary human symptom, which is abdominal discomfort.  Newer animal models need to account for the pain and discomfort associated with IBS if better drugs are to be created. 

The IBS market is too big for pharma companies to keep avoiding, and developing RA or asthma drugs and then using them off-label for IBS is not the solution.  Below are a couple of realistic fixes that could greatly improve IBS clinical trial design: 

•   Create a global assessment of a drug response rate: abdominal pain, stool changes, quality of life
•   Recruit patients with more severe disease states
•   Use a sufficiently long run-in period to remove placebo hyper-responders
•   Increase length of trials to account for cyclical nature of disease flares