Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 18th United European Gastroenterology Week

Barcelona, Spain / October 23-27, 2010

The evidence of differences between TNF-a inhibitors was explored in multiple sessions at the UEGW. Although biologics have been instrumental in reducing the complications of advanced Crohn’s disease (CD), prudent use is encouraged by many national and international guidelines because of the expense of these medications and the small increase in risk they pose for adverse events. In patients already obtaining a good response from infliximab, many physicians are reluctant to switch therapies, but adalimumab is emerging as an interesting first-line choice because of the reduced need for dose escalation.

“The loss of response to infliximab in CD is observed in up to 50% of patients and is generally considered to be the consequence of low or undetectable drug concentrations,” according to Dr. Severine Vermeire, gastroenterology department, University Hospitals, Leuven, Belgium. “Loss of response is managed clinically by shortening the interval between infusions or increasing the dose or switching anti-TNFs. Yet despite those adjustments, the median drop-out rate from therapy with infliximab is approximately 10% per year.

It is unclear if low and undetectable drug concentrations are responsible for the presence of neutralizing antibodies or a result of the presence of antibody. In either case undetectable drug levels are clearly associated with a loss of response to infliximab. Adalimumab has been associated with a lower propensity for both having patients with undetectable drug levels and for generating neutralizing antibodies. Standard doses of adalimumab have been shown to provide sustained clinical efficacy for periods extending to three years, judging from results of the ADHERE (Additional Long-Term Dosing With Humira/Adalimumab to Evaluate Sustained Remission and Efficacy in CD) trial, which was a three-year extension of the phase III efficacy trial. Although adalimumab and infliximab have not been compared in blinded studies for long-term efficacy, the authors of the National Institute for Health and Clinical Excellence (NICE) guidelines calculated a lower incremental cost efficacy ratio (ICER) for adalimumab relative to infliximab for routine therapy.

In the data presented by Dr. Vermeire, 90 patients with CD on maintenance infliximab every eight weeks were evaluated. All of these patients had lost response clinically after a mean of 52 weeks with a range of 35 to 85 weeks. In 51 patients, the intervals between doses were reduced. In the other 39, the dose was increased by 10 mg per kg body weight. Dose adjustments were considered successful when symptoms were controlled and infusions could be continued without further dose adjustments.

Dose adjustments were clinically successful in 56.7% of patients, but Dr. Vermeire reported that there was a large inter-individual variability of infliximab trough levels over time. For example, 13 patients in this cohort had undetectable trough levels at all time points, and only one of those had a positive effect from the dose adjustment. Moreover, she reported that 88% of patients with undetectable trough levels had high levels of antibodies to infliximab although antibodies are only measurable in patients with undetectable trough levels.

Similar findings regarding loss of patient response with infliximab were reported by Dr. Edward V. Loftus, Mayo Clinic, Rochester, Minnesota. In his examination of the occurrence of events that may indicate the need for treatment adjustment, which includes switching to another biologic agent, he defined a potential treatment adjustment event (PTAE) as the occurrence of dosage escalation, CD-related emergency department visit or hospitalization, CD-related surgery, new fistula or initiation of a new biologic therapy.

In this observational study with a sample of 388 CD patients who met the criteria for initial response to infliximab maintenance therapy, the 3-year cumulative probability of any PTAE was 78%, according to Dr. Loftus. He reported that the most common PTAE, accounting for 43% of the total, was a CD-related hospital or emergency department visit. He reported that predictors of a PTAE included corticosteroid use. His data suggesting very high rates of dose adjustment with long-term infliximab therapy may contribute to the cost premium elucidated in the NICE guidelines.

Dr. Loftus reported, that in the real-world setting, most patients with Crohn's disease and who initially responded to infliximab required subsequent treatment adjustment and that these findings may be important for monitoring patients on long-term infliximab.

However, the relative differences regarding the need for dose adjustments with adalimumab relative to infliximab are difficult to quantify in the absence of direct comparisons. This was acknowledged in the discussion in the NICE guidelines, which observed that adalimumab does not appear to be free of the need for dose adjustments even if dose adjustments are required less frequently. These relative differences are important for cost analyses. Although drug prices vary in different regions, the greatest potential for defining one agent as more cost-effective is the relative freedom from dose escalation. This difference is reflected in the recent CADTH guidelines, which addressed the use of biologics in rheumatoid arthritis but have relevance to the same type of discussion in inflammatory bowel disease (IBD). CADTH stands for Canadian Agency for Drugs and Technologies in Health. It is a national body that provides Canada’s federal, provincial and territorial health care decision makers with credible, impartial advice and evidence-based information about the effectiveness and efficiency of drugs and other health technologies. The analyses was designed to guide physicians to the most cost effective biologic, which included certolizumab, etanercept, and golimumab as well as adalimumab and infliximab. The authors of CADTH supported these large potential differences in long-term management costs by noting that “in clinical practice dose escalation is most often observed with infliximab.” CADTH also reported that dose escalation was not anticipated for other biologics.

One of the concerns of dose escalation is that higher doses will produce a greater risk of adverse events. The data demonstrating a correlation between dose escalations and side effects remain limited, but the theoretical risk is significant. In addition, if dose escalation is based on increased frequency of infusions, this can impact adversely on patient quality of life. Studies are needed to compare the impact of both of these variables on patient well-being.

Adalimumab And Deep Remission

Another area of interest for relative efficacy of these and other treatment strategies is the concept of deep remission. Commonly defined as Crohn’s Disease Activity Index (CDAI) score <150 plus mucosal healing, deep remission may provide a better measure of true disease remission than less strict measures of disease control. In an analysis of data generated by the EXTEND study, Dr. Jean-Frédéric Colombel, University Hospital Centre, Lille, France reported that deep remission was more common in patients on the active treatment, adalimumab, than placebo and that this deep remission was observed more frequently in patients with a disease duration less than five years, with the best results seen in patients with a disease duration of less than 2 years.

Perhaps this reflected the greater likelihood that patients with longer duration had received more courses of biologics or other treatments previously? This data is consistent with concerns about the potential for diminishing efficacy of TNF-a inhibitors over time and the need to optimize the sequence of agents at initiation to maximize long-term benefit. Most importantly it may suggest that the initiation of biologics should not be delayed to maximize the benefits of the drugs.

Summary

Large multicenter trials have demonstrated that both infliximab and adalimumab are highly effective in the control of advanced IBD. The long-term data, however, suggests that the persistence of benefit without dose escalation (to counter loss of efficacy) differs. These differences have been noted by several guidelines attempting to define the most cost-effective and rational approach to drug selection. While the focus of these guidelines has been on cost, the risks of dose escalation and outcomes also deserve further study in order to sequence available treatments appropriately.