Drug-tolerant assay not needed for infliximab-treated IBD patients

Last Updated: 2017-05-10

By Marilynn Larkin

NEW YORK (Reuters Health) - In patients in stable remission from inflammatory bowel disease (IBD) on infliximab, a drug-tolerant assay yields no benefit over a less costly drug-sensitive assay even though the latter detects more anti-drug antibodies (ADAs), researchers in Belgium say.

ADAs are associated with infusion reactions and loss of response. “A number of assays for ADAs exist, but most of them underestimate the amount of ADAs due to their drug sensitivity,” Dr. Ann Gils of the University of Leuven explained by email. “This means that in the presence of drug, no ADAs can be detected.”

To see whether using a newly developed drug-tolerant ADA assay would make a difference, Dr. Gils and colleagues analyzed data from a subgroup of 76 patients (65% male, median age, 42) with Crohn’s disease or ulcerative colitis screened to participate in the TAXIT trial (http://bit.ly/1HO9vuR). All patients had infliximab concentrations <3 mcg/mL.

ADAs in 221 serum samples - taken at initial screening, after infliximab optimization and at the end of the one-year study - were reanalyzed using a drug-tolerant assay. Patients were grouped into quartiles based on ADA concentrations at screening.

As reported in Gut, online April 27, the immunogenicity detection rate at screening increased from 21% with the drug-sensitive assay to 63% with a drug-tolerant assay; from 0% to 51% after optimization and from 3% to 42% at the end of the trial.

Patients in the highest quartile required a higher cumulative infliximab dose (median, 2,390 mg) to achieve target trough concentrations, which resulted in a higher drug cost (median per patient, every four weeks, 10,712 euros) compared with ADA-negative patients (2,060 euros) and those in quartile 1 (2,060 euros) and quartile 2 (2,060).

However, all patients in quartile 4, except for one, were also ADA-positive with the drug-sensitive assay.

No difference was observed in clinical remission rates between ADA-positive and ADA-negative patients at screening (76% versus 70%, p=0.59), after optimization (95% versus 85%, p=0.20) or at one year after optimization (86% versus 81%, p=0.74).

“Once dose-optimized, patients have similar rates of clinical, biological and endoscopic remission after one year of treatment regardless of ADA status in a drug-tolerant assay,” the authors conclude, adding that “low concentrations of ADAs that are not detectable with a drug-sensitive assay are ‘clinically irrelevant.’”

Since it costs more to optimize patients in the highest quartile, Dr. Gils said, “it might be more cost efficient to switch these patients within class or out of class.”

“Within class is possible since it has been shown that antibodies towards infliximab do not cross react with adalimumab,” Dr. Gils continued. “However, it is not possible to switch these patients to a biosimilar of infliximab since several studies have shown that antibodies towards the originator infliximab do cross react with infliximab biosimilars.”

“Out of class is also an option,” she noted, “but new drugs like vedolizumab and ustekinumab come at a higher cost. Thus ADA determination using a drug-tolerant assay could indicate the treatment that is most cost-efficient.”

“To argue against the use of a drug-tolerant assay, which requires a more complicated protocol,” she added, “all but one patient belonging to quartile four were also positive in the drug-sensitive assay, making the additional cost and effort of a drug-tolerant assay hard to defend.”

“In conclusion,” Dr. Gils said, “this study demonstrates that patients can have antibodies in the presence of therapeutic drug concentrations and that, for patients in clinical remission, the use of a more costly drug tolerant antidrug antibody testing is not needed.”

Dr. Louis Cohen called the study “important,” noting “it is increasingly understood that optimization of infliximab dosing is critical to ensuring an appropriate response.”

“It has generally been believed that the presence of antibodies with detectable infliximab levels suggests these antibodies may not be clinically relevant,” he told Reuters Health by email, “but few studies have demonstrated this fact.”

“This study is well designed and presents an intriguing conclusion that supports the belief that the presence of antibodies in a patient sample is likely to be far more clinically meaningful when there is no infliximab present, as a potential surrogate for the neutralizing capability of the antibodies.”

“The study is widely applicable to a large number of physicians who may not have access to drug-tolerant assays,” Dr. Cohen concluded, “and also identifies important questions about the immune response to infliximab that warrant future study, including the need to assess the neutralizing capability of detected antibodies and to determine whether it is possible to overcome a meaningful antibody response.”

SOURCE: http://bit.ly/2qTervb

Gut 2017.