Data presented for the first time at ECCO from OPERA – - Efficacy of MAdCAM mAb PF-00547659 in Crohn's disease remains unclear

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• As well as presenting Phase 2b ulcerative colitis data from TURANDOT at ECCO, Pfizer also presented Crohn's disease data at ECCO for MAdCAM mAb, ‘PF-00547659
• OPERA evaluated 22.5, 75 and 225mg ‘PF-00547659 sc (note that 7.5mg was only studied TURNADOT)
  
• Patients were TNFi experienced (25% and 55% primary and secondary non-responders respectively; 20% TNFi intolerant)
• Although ‘PF-00547659 produced a dose dependent increase in CDAI-70 at 8wk [contact us for full slide deck], response was flat by 12wks and not different to the very high placebo response (48% at 8wks vs 25% in TNF experienced patients at 4wks in pivotal Humira studies)
• CDAI-100, a key secondary response was 50-57% vs 41% for placebo.  Again, this was not significant and the placebo response was close to double that in Entyvio studies
• alpha4beta7+ central memory T cell count (employed as a biomarker) rose following  ‘PF-00547659 but not placebo
• Of interest ‘PF-00547659 efficacy vs placebo was suggested in patients with lower baseline CRP levels particularly at earlier time points
• Safety was good with the possible exception of increased GI infection (10% vs 2%).  Severity was not reported 
  

Comments: The high placebo response is the key issue in OPERA; its impact is blunted when remission rather than response is evaluated, particularly in patients with higher CRP levels and at earlier time-points.  Of note, baseline CDAI values appear balanced across groups.  While there appears to be a signal, the challenge will avoiding placebo responses jeopardizing Phase 3 studies; it remains to be seen if placebo response was homogenous across sites.  Of note endoscopy was not built into the study.  This should be considered moving forward