Translational research and efficacy of biologics in Crohn's disease: a cautionary tale

Abstract

In the last several years many biologic agents for Crohn's disease have been developed. Due to their unique molecular specificity biologics are de facto indicators of the ultimate significance of the molecule targeted by the biologic itself. Here, we have reviewed many clinical studies that have used biologics for Crohn's disease. Their results show that despite potentially sound theoretical mechanisms of action and some initially promising data, most biologics – with few notable exceptions - have failed. Pharmacologic, study design or patient-related issues might explain these findings in some studies. However in many cases clinical failure of biologics might highlight the complexity of in vivo events and the potential deficiencies of current experimental settings. Hence, these observations call for new and efficient ways of predicting drug efficacy in clinical trials based on bench research. Conceivably, computer-based pathogenetic models could be used to simulate and predict clinical studies results in vivo.

Keywords::

• biologic agents
• clinical trials
• computer-based disease models
• Crohn's disease
• Crohn's disease pathogenesis
• monoclonal antibodies
• translational research

Financial & competing interests disclosure

D Sorrentino has been a consultant for AbbVie, Janssen, Centocor, MSD, Hoffmann-LaRoche, Giuliani, Schering and Ferring. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Biologic agents for Crohn's disease (CD) are extremely specific medications that target individual molecules potentially playing a major role in inflammation in CD;

• Of all the molecules tested so far, only anti-TNF agents and to a lesser extent individual anti-IL-12/-23 and α4β7 integrin inhibitors have shown efficacy;

• The large majority of the other tested molecules have shown very little or no efficacy at all in clinical trials;

• This is puzzling because their development followed information gathered at the bench, indicating a major role of their targets in disease pathogenesis;

• It is possible that factors related to these agents pharmacology or to the design of the studies or to patients' features might explain the negative clinical results obtained with many biologics;

• However, it is also likely that the molecules targeted by these drugs might not play the postulated role in disease pathogenesis in vivo – which might be more complex than generally perceived;

• For the time being, only few alternative biologic agents are available for patients who do not respond to anti-TNF agents – hence optimization of existing therapy will be paramount in the short term;

• A thorough understanding of CD pathogenesis might require a combination of clinical and basic research as well as computer modeling and in silico simulation with further in vivo testing.

Notes