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OP015 Results of ANDANTE, a randomised clinical study with an anti-IL6 antibody (PF-04236921) in subjects with Crohns disease who are anti-tumour necrosis factor inadequate responders

S. Danese*1, S. Vermeire2, P. Hellstern3, R. Panaccione4, G. Rogler5, G. Fraser6, A. Kohn7, P. Desreumaux8, R.W. Leong9, G.M. Comer10, F. Cataldi10, A. Banerjee10, M.K. Maguire11, C. Li10, N. Rath11, J. Beebe10, S. Schreiber12

1Humanitas University Clinical and Research Hospital, Rozzano, Milan, Italy, 2University Hospitals Leuven, Leuven, Belgium, 3Nature Coast Clinical Research, Inverness, Florida, United States, 4University of Calgary, Calgary, Canada, 5University of Zürich, Zürich, Switzerland, 6Rabin Medical Centre and University of Tel-Aviv, Petah Tikva, Israel, 7AO San Camillo Forlanini, Rome, Italy, 8University of Lille, Inserm U995, Lille, France, 9Concord Hospital, Sydney, New South Wales, Australia, 10Pfizer Inc, Cambridge, Massachusetts, United States, 11Pfizer Inc, Collegeville, Pennsylvania, United States, 12Christian-Albrechts University, Kiel, Germany

Background

IL 6 plays a key role in intestinal inflammation in Crohn’s disease (CD). Increased production of IL 6 and soluble IL-6 receptor from CD4+ T-cells and macrophages is associated with CD activity and elevated C-reactive protein (CRP). We report the results of a Phase 2, randomised, multicentre, parallel, double-blind, placebo (PBO)-controlled, dose-ranging study of a fully human IgG2 monoclonal antibody that binds to human IL-6, PF-04236921(PF), in subjects with refractory CD (NCT01287897).

Methods

Adults aged 18–75, with active moderate-severe CD (CDAI of 220–450), history of failure or intolerance to anti-tumour necrosis factor (TNF), a CRP ≥ 5.0 mg/L and ulcers on colonoscopy were eligible. Subjects were randomised to PBO, or PF 10, 50, or 200 mg surveillance colonoscopy (SC) and dosed on day 1 and 28. The primary objective was to demonstrate clinical activity of PF using CDAI-70 response at week 8 or 12. Secondary end points were remission (CDAI < 150), CDAI-100, and safety. Dosing in 200 mg arm was terminated early because of safety concerns with 200 mg in the PF Lupus programme.

Results

In the study, 247 subjects were randomised and dosed. Baseline characteristics were comparable across groups. PF 50 mg met primary endpoint CDAI-70 at both week 8 and 12 with a delta of 18.8% over PBO at week 12 (p-value = 0.04). Clinical remission at week 12 was significant for PF 50 mg dose, as well. CRP levels were continually suppressed in active treatment groups, and reduction increased monotonically with increase in dose. Percent of change from baseline in CRP (geometric mean) at week 12 was +7.6, -64.9, and -86.3% in PBO, 10 and 50 mg groups, respectively.

There was 1 death of postoperative respiratory failure in the 50 mg group. There were 2 subjects with GI perforations (colon [50mg]; intestinal, unspecified [200 mg]) and 4 with serious GI abscesses (intestinal [10mg]; anal [1–10 mg; 2–50 mg]) during treatment (week 0–12). An additional 3 subjects had serious GI abscesses (perirectal [50mg]; retroperitoneal [50mg]; unspecified [PBO]) during follow-up (> week 12). Adverse events were generally balanced across all treatment groups; the percentage of subjects with serious adverse events and serious infections was highest in the 200 mg group.

Conclusion

Clinical response (CDAI-70) and clinical remission were statistically significant for the 50 mg dose in this refractory CD patient population. A dose-response relationship was observed for week-8 and -12 clinical endpoints for 10 and 50 mg. The overall safety profile appeared acceptable for this refractory CD patient population.