Many factors complicate search for targeted IBD therapies
Pharmacogenomics — the study of drug-gene interactions — offers the possibility of developing personalized drugs that have greater efficacy and safety. Although most research in this rapidly expanding field is in the early stages and presents significant challenges, a few applications are well established in clinical practice.
One is genotype or phenotype testing for thiopurine methyltransferase (TPMT), which metabolizes thiopurine compounds such as azathioprine, mercaptopurine and thioguanine. Testing helps identify patients at risk of toxicity from these drugs, explains Mayo Clinic gastroenterologist Edward V. Loftus Jr., M.D.
"About 89 percent of people have normal TPMT enzyme activity and respond well to normal doses of thiopurines. Ten percent have one copy of a variant allele, leading to moderately low levels of TPMT and an increased risk of drug toxicity. And 1 in every 300 people is severely deficient in TPMT, which can cause profound myelosuppression with thiopurine agents. So for the last 20 years or so, we have been measuring TPMT genotypes and thiopurine metabolites in patients to help reduce toxicity and improve therapeutic response."
Another example is anti-infliximab antibody testing, which seeks to identity a subset of patients who either fail induction therapy with tumor necrosis factor (TNF) inhibitors or lose response to them over time, an outcome linked to the production of antibodies that hasten the drug's clearance. Infliximab antibodies are also associated with infusion reactions and drug hypersensitivity.
Although studies have found as much as a 50 percent increase in infusion reactions in patients with anti-infliximab antibodies, findings related to clinical remission have been mixed.
"Many factors affect how patients metabolize anti-TNF drugs, including age, body mass index, sex and the use of other immunomodulators," Dr. Loftus points out. "All of these impact drug levels, so the interindividual variation is enormous. The hope is that in the near future we will come up with a predictive pharmacokinetic model where we would plug these various factors into an algorithm upfront."
Personalized IBD therapy
He expresses the same cautious optimism with respect to personalized IBD medications in general.
"There is more and more talk about a personalized approach to IBD therapy, but we are not to that point yet. Maybe five or 10 years from now," he says. "So far, there are about 300 single nucleotide polymorphisms — DNA sequence variations that occur when a single nucleotide in the genome is altered — and 160 genes associated with IBD. The average patient with IBD may have five or six mutations among those 160 genes. Furthermore, the penetrance of these genes is very low and looking at them in isolation isn't going to get us very far. IBD results from a combination of genetics plus an environmental trigger. Ultimately we may need a complete genetic profile to help us understand at diagnosis which patients are most likely to respond to any particular drug. That would not only take the guesswork out of finding the right agent but also reduce or even eliminate adverse reactions."
Also needed are anti-inflammatory drugs with overlapping mechanisms of action.
"If you have a fancy biotech drug that's only blocking one molecule, it is only going to work for a few people," Dr. Loftus says, noting that many novel agents currently under investigation address a wider variety of targets compared with older drugs.
Raising the complication quotient further is the role of the fecal microbiome in IBD. Even small abnormalities in a single gene may alter the microbiota enough to cause disease. The computational implications are staggering, Dr. Loftus says, "but if you have multiple groups of investigators looking at hundreds of thousands of specimens and the right computing power, you might be able to say with some certainty that a patient with a particular genetic risk profile and x bacteria is more likely to get IBD."
The feasibility of such investigations depends on having a robust biorepository of blood, feces and colonoscopy tissue. Mayo Clinic is in the process of creating an IBD biobank, in conjunction with a consortium of hospitals. "A well-considered genetic approach to IBD could help direct therapy over a patient's lifetime," Dr. Loftus says. The benefits for people diagnosed in their 20s or 30s may be enormous."