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

This content is sampled from our coverage of ECCO last week and part of our UpdatesPlus service. UpdatesPlus-IBD is a regular report, and is part of our inflammation and dermatology collection. Reports are accompanied by ad hoc e-mail alerts providing near real time analysis of key breaking events.  For access to our full and in depth ECCO report or further information on UpdatesPlus please contact  jon.goldhill@leaddiscovery.co.uk - or access our UpdatesPlus product brochure

• 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

Further data presented at ECCO on MAdCAM mAb, PF-00547659 - efficacy demonstrated in ulcerative colitis

This content is sampled from our coverage of ECCO last week and part of our UpdatesPlus service. UpdatesPlus-IBD is a regular report, and is part of our inflammation and dermatology collection. Reports are accompanied by ad hoc e-mail alerts providing near real time analysis of key breaking events.  For access to our full and in depth ECCO report or further information on UpdatesPlus please contact  jon.goldhill@leaddiscovery.co.uk - or access our UpdatesPlus product brochure

• Pfizer provided an update on PF-00547659, its MAdCAM mAb, during the company’s JP Morgan presentation in Jan 2015.  Specifically, data were presented from the Phase 2b ulcerative colitis study, TURANDOT
  
• Approximately 60% patients were TNFi experienced.  12wk clinical remission rates were as high as 24%, but a loss of response at higher doses was observed possibly reflecting a block of protective T cells
• Further data were reported at ECCO (for full presentation please contact us)
• Particularly interesting was mucosal healing response which reflected the clinical remission response curve
• Despite the bell shaped endoscopic response, calprotectin levels fell at all doses
• MAdCAM levels, a biomarker of PF-00547659 fell at 7.5mg and reached 95% inhibition at 22mg

Comments: The new mucosal healing data presented at ECCO is impressive with a delta of 20% at 12wks (vs 16% at 6wks for Entyvio and 10% at 12wk for Humira in ULTRA 2).  Despite this, the dose response is a concern suggesting that at higher doses of PF-00547659, efficacy may be lost.  This is not such a problem if 22mg is a universally optimal dose however this may not be the case, with maximal effective dose potentially depending on the characteristics of the individual.  Moreover, it is possible that there is a balance between positive and negative impact across the entire dose response with an overall negative effect only becoming evident at high doses.  If this is the case more selective targeting, if possible, could further boost efficacy.  These issues deserve further investigation.  The apparent dissociation of calprotectin and mucosal healing is difficult to explain and also warrants further investigation

Promising Crohn disease data presented at ECCO for the IL-23 mAb, MEDI2070/AMG-139

This content is sampled from our coverage of ECCO last week and part of our UpdatesPlus service. UpdatesPlus-IBD is a regular report, and is part of our inflammation and dermatology collection. Reports are accompanied by ad hoc e-mail alerts providing near real time analysis of key breaking events.  For access to our full and in depth ECCO report or further information on UpdatesPlus please contact  jon.goldhill@leaddiscovery.co.uk - or access our UpdatesPlus product brochure

• A number of ECCO presenters commented on the promise of Stelara as a candidate treatment of Crohn disease (and even ulcerative colitis as well).  Phase 3 data are expected in approx 1yr
• Stelara (approved for RA and PsA)  targets p40, a common subunit of IL-12 and IL-23
• AstraZeneca and Amgen are co-developing a related mAb, MEDI2070/AMG-139 for Crohn disease  
• In contrast to Stelara, MEDI2070 targets the p19 subunit of IL-23, leaving the IL-12 pathway unimpeded.  This approach is being adopted for other indications such as PsO, with the suggestion that this may reduce the risk of infection.  To date this has been unproven
• Phase 2a Crohn disease data were presented at ECCO (for a copy of slides please contact us)
• 119 Crohn disease patients received 700mg iv MEDI2070 on days 1 and 29
• Clinical response (CDAI reduction of great than 100pt or CDAI less than 150pt) at 8wk was significantly improved vs placebo, even though 90% patients had previously received 1-2 TNFirs
• A composite endpoint combining symptom and biochemical improvement enhanced apparent efficacy
• TEAEs were unremarkable – in particular infection was unaffected

Comments: The challenge faced by AZ/Amgen will be to differentiate MEDI2070 and Stelara if both are approved. This is particularly so given the likely lead time that Janssen will gain.  Differentiation in terms of infection is questionable.  Possibly  more interesting are potential benefits drawn from psoriasis data.  Numerous IL-23 mAbs are being developed in this space and a consistent observation is the durability of response after treatment withdrawal.  This was particularly remarkable for BI 655066 (data reported last year), also in development for IBD.  Explanation of this phenomenon has yet to be offered although some are suggesting a resetting of the immune system.  Demonstration prolonged maintenance in Crohn disease following treatment tapering would be of obvious benefit and may be considered in Phase 3 designs