Judging by Celgene’s business development activities the company is determined to make a splash in the increasingly competitive area of inflammatory bowel diseases, though it seems to want investors to take evidence of clinical efficacy on trust.
Keenly awaited endoscopy data for mongersen, its phase III asset for Crohn’s disease, have been a long time coming, finally released in dribs and drabs at this week’s United European Gastroenterology Week meeting. Celgene’s 1% climb on a flat day for biotech yesterday suggests that the market is impressed, even if enthusiasm for mongersen has been reined in considerably.
Still, it would have taken knockout data for mongersen, a Smad7-targeting antisense oligonucleotide, to live up to the promise suggested by its purchase by Celgene from Nogra Pharma for $710m. Phase II results looked impressive, but doubts soon set in over the relatively mild Crohn’s patients recruited, and the use of subjective disease severity scoring.
While disease scores remain a useful measure, a shift towards the use of endoscopy is under way. Celgene has long hinted that these data were forthcoming for mongersen, but it was only this week that they dribbled out, first in a release of topline phase I results and then a presentation at the gastroenterology meeting.
Patients in the CD-001 trial had moderate to severe Crohn’s, Celgene stressed, and 37% of the 52 evaluable for endoscopy had 25% or greater reduction in SES-CD score (simple endoscopic score for Crohn's disease) at 12 weeks across three doses. Most analysts agreed that the data were broadly positive, though Leerink cautioned that they were “hardly transformative”.
The sellside was pleased that activity was best in the most ill patients: in the 16 with high SES-CD at baseline, 63% had scores cut by 25% or more, and 31% by 50% or more. However, one worry is that endoscopic improvement above 50%, across all patients, was just 15%.
Across-trial comparisons can be unsound, but in the Fitzroy trial presented at the same meeting Galapagos/Gilead’s filgotinib showed 25% of patients improving SES-CD scores by 50% at 10 weeks. Fitzroy had a placebo arm, and >50% SES-CD improvement in these control patients was nearly 14%, casting major doubts about what Celgene was seeing in its uncontrolled study.
Celgene had been expected to provide endoscopy data a month ago, but ended up merely revealing an endoscopic improvement “in a proportion of patients” (Event – Celgene takes a deeper look in Crohn’s, September 7, 2016).
Probably the most important thing about mongersen is that it is an oral agent so, even if its activity does not blow biologicals like Remicade and Humira out of the water, it comes with increased convenience and the potential to be used in Humira failures. There do not appear to be any other projects targeting Smad7 in development for Crohn’s.
But some analysts already questioned mongersen’s importance when Celgene subsequently bought Receptos for $7.2bn. With Receptos came the oral S1P1 modulator ozanimod, which, like mongersen, is in development for Crohn’s as well as ulcerative colitis.
The two inflammatory diseases share some characteristics, but while Crohn’s can occur in any part of the gastrointestinal tract, and across its entire wall, ulcerative colitis is limited to the colorectal region’s mucosa and superficial submucosa.
Yesterday Celgene said an extension of ozanimod’s phase II Touchstone trial in ulcerative colitis – in 131 of the original 197 patients – showed a 9.4% serious adverse event rate, with no notable cardiac treatment-emergent effects. This is important since ozanimod needs to differentiate itself in the chronic setting from Gilenya – a marketed multiple sclerosis drug with the same S1P1 mechanism, whose use is limited by bradycardia.
Ozanimod and mongersen are both in pivotal programmes, and mongersen’s will measure SES-CD improvement at 52 weeks. On a call today Celgene stressed the continuing importance of clinical remission in Crohn’s, and said endoscopic improvement usually needs follow-up beyond 12 weeks to become evident.
But doubts are slowly growing around mongersen, suggesting that Celgene was correct to be reluctant to release detailed data.