Lay Summary
Proposal No. IBD-0245
Principal Investigator: Miles Patrick Sparrow, MBBS
Applicant Organization: Alfred Health (Melbourne, Australia)
Project Title: Use of adjunctive allopurinol in azathioprine/6-mercaptopurine non-responders to optimize 6-thioguanine nucleotide production and improve clinical outcomes
Period of Award: April 1, 2010 - August 31, 2012
The inflammatory bowel diseases (IBD), Crohn’s disease and ulcerative colitis, are potentially debilitating illnesses affecting young people that can be associated with a markedly reduced quality of life if poorly controlled. These autoimmune conditions involve an inappropriately overactive immune response from the body’s white blood cells that is directed against the intestines, causing inflammation and the characteristic symptoms of diarrhea, abdominal pain and weight loss. Treatments for IBD can broadly be thought of in two categories: anti-inflammatories that aim to control the intestinal inflammation and immune modifying drugs (immunomodulators) that attempt to dampen down the overactive white blood cells that are the cause of the inflammation. A very important class of immune modifying agents is the thiopurine immunomodulators azathioprine (AZA) and 6-mercaptopurine (6-MP), which are chemically effectively identical. About 50-60% of patients respond to these drugs. AZA and 6-MP have been shown to get patients well (induce remission), and keep patients well (maintain remission). Importantly, they also minimize the need for cortisone-based medicines such as prednisone that are otherwise used and are associated with unacceptable side effects and no long-term benefits.
It is now understood that the body breaks down (metabolizes) AZA/6-MP to produce two chemical end-products (metabolites) that are responsible for the benefits and also side-effects of these drugs. These chemicals are known as 6-thioguanine (6-TGN) and 6-methylmercaptopurine (6-MMP). 6-TGN appears to be the active chemical that makes these drugs work, while 6-MMP instead can cause side-effects, especially inflammation of the liver. Therefore it is desirable to have adequate levels of 6-TGN and minimal levels of 6-MMP. How an individual patient breaks down these drugs is genetically determined and about 15-30% of patients make 6-MMP instead of 6-TGN and therefore these drugs don’t work. Now that we understand the metabolism of these drugs, the next question to ask is whether this can be deliberately manipulated to increase their effectiveness?
Our research group has shown in two small studies that by adding another drug, allopurinol, patients who otherwise made 6-MMP immediately switched to instead produce 6-TGN, thereby increasing their response to these drugs. These promising initial results need to be confirmed and expanded upon in a clinical trial such that the relative risks and benefits of this metabolic manipulation can be more accurately ascertained. Our proposal is for a multi-center randomized six month clinical trial comparing two doses of allopurinol in the subgroup of 15-30% of IBD patients that otherwise do not respond to these agents due to their genetically pre-determined ineffective metabolic profile.
This therapeutic maneuver is novel, practical, simple, inexpensive and potentially applicable to clinical practice immediately should our initial results be reproduced. The best possible outcome is that this combination therapy would allow 15-30% more IBD patients to tolerate and benefit from AZA/ 6-MP. This would represent a significant step towards improving the quality of life of patients suffering from IBD.