Tofacitinib for induction and maintenance therapy of Crohn's disease: results of two phase IIb randomised placebo-controlled trials

Abstract

Objective: Tofacitinib is an oral, small-molecule Janus kinase inhibitor that is being investigated for IBD. We evaluated the efficacy and safety of tofacitinib for induction and maintenance treatment in patients with moderate-to-severe Crohn's disease (CD).

Design: We conducted two randomised, double-blind, placebo-controlled, multicentre phase IIb studies. Adult patients with moderate-to-severe CD were randomised to receive induction treatment with placebo, tofacitinib 5 or 10 mg twice daily for 8 weeks. Those achieving clinical response-100 or remission were re-randomised to maintenance treatment with placebo, tofacitinib 5 or 10 mg twice daily for 26 weeks. Primary endpoints were clinical remission at the end of the induction study, and clinical response-100 or remission at the end of the maintenance study.

Results: 180/280 patients randomised in the induction study were enrolled in the maintenance study. At week 8 of induction, the proportion of patients with clinical remission was 43.5% and 43.0% with 5 and 10 mg twice daily, respectively, compared with 36.7% in the placebo group (p=0.325 and 0.392 for 5 and 10 mg twice daily vs placebo). At week 26 of maintenance, the proportion of patients with clinical response-100 or remission was 55.8% with tofacitinib 10 mg twice daily compared with 39.5% with tofacitinib 5 mg twice daily and 38.1% with placebo (p=0.130 for 10 mg twice daily vs placebo). Compared with placebo, the change in C-reactive protein from baseline was statistically significant (p<0.0001) with 10 mg twice daily after both induction and maintenance treatments.

Conclusions: Primary efficacy endpoints were not significantly different from placebo, although there was evidence of a minor treatment effect. No new safety signals were observed for tofacitinib.

Trial registration numbers: NCT01393626 and NCT01393899.

Keywords: CLINICAL TRIALS; CROHN'S DISEASE; IMMUNOLOGY.

Conflict of interest statement

Competing interests: JP: received consulting fees from AbbVie, Boehringer Ingelheim, Galapagos, GlaxoSmithKline, Janssen, MSD, Pfizer, Second Genome, Takeda, TiGenics and Topivert Pharma; received lectures and/or speaker bureau fees from AbbVie, Janssen, MSD, Pfizer and Takeda. WJS: received grant support from Receptos, Exact Sciences, Amgen, the American College of Gastroenterology and the Broad Foundation; received grant support and personal fees from Prometheus Laboratories, AbbVie, Boehringer Ingelheim, Takeda, Atlantic Pharmaceuticals, Janssen, Bristol-Myers Squibb, Genentech, Pfizer and Nutrition Science Partners; and personal fees from Kyowa Hakko Kirin, Millennium Pharmaceuticals, Celgene Cellular Therapeutics, Santarus, Salix Pharmaceuticals, Catabasis Pharmaceuticals, Vertex Pharmaceuticals, Warner Chilcott, Gilead Sciences, Cosmo Pharmaceuticals, Ferring Pharmaceuticals, Sigmoid Biotechnologies, Tillotts Pharma, Am Pharma BV, Dr. August Wolff, Avaxia Biologics, Zyngenia, Ironwood Pharmaceuticals, Index Pharmaceuticals, Nestle, Lexicon Pharmaceuticals, UCB Pharma, Orexigen, Luitpold Pharmaceuticals, Baxter Healthcare, Ferring Research Institute, Amgen, Novo Nordisk, Mesoblast, Shire, Ardelyx, Actavis, Seattle Genetics, MedImmune (AstraZeneca), Actogenix NV, Lipid Therapeutics GmbH, Eisai, Qu Biologics, Toray Industries, Teva Pharmaceuticals, Eli Lilly, Chiasma, TiGenix, Adherion Therapeutics, Immune Pharmaceuticals, Celgene, Arena Pharmaceuticals, Ambrx, Akros Pharma, Vascular Biogenics, Theradiag, Forward Pharma, Regeneron, Galapagos, Seres Health, Ritter Pharmaceuticals, Theravance, Palatin, Biogen and the University of Western Ontario (owner of Robarts Clinical Trials). SS: received consulting fees from Ferring, AbbVie, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Janssen, Galapagos, MedImmune, MSD, Pfizer/Hospira, Shire, Takeda and UCB; received lectures and/or speaker bureau fees from Ferring, AbbVie, MSD, Takeda, UCB and Falk. BES: received consulting fees from AbbVie, Akros Pharma, Amgen, AstraZeneca, Boehringer Ingelheim, Celgene, Forest Research Institute, Lilly, MedImmune, Puretech Ventures, LLC, Receptos, Salix, Shire, Takeda, Topivert Pharma, Vedanta Biosciences, Bristol-Myers Squibb, Janssen R&D, Luitpold Pharmaceuticals, Pfizer, Prometheus Laboratories, Synergy Pharmaceuticals, Takeda, Theravance Biopharma and Tigenix; received research grants from AbbVie, Celgene, GlaxoSmithKline, Janssen R&D, Pfizer, Prometheus Laboratories and Takeda. SV: received consulting fees from Takeda, Roche/Genentech, Merck, Centocor, AbbVie, UCB, Pfizer, Ferring, Second Genome and Galapagos; received research grants from Centocor, AbbVie, Takeda and Merck; received lectures and/or speaker bureau fees from Merck, AbbVie, Takeda, Pfizer, Ferring, Falk and Centocor. GD: received consulting fees from AbbVie, Ablynx, Amakem, AM Pharma, Avaxia, Biogen, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Celltrion, Cosmo, Covidien/Medtronics, Ferring, DrFALK Pharma, Engene, Galapagos, Gilead, GlaxoSmithKline, Hospira, Immunic, Johnson and Johnson, Lycera, Medimetrics, Millennium/Takeda, Mitsubishi Pharma, MSD, Mundipharma, Novo Nordisk, Pfizer, Prometheus laboratories/Nestle, Receptos, Robarts Clinical Trials, Salix, Sandoz, Setpoint, Shire, Teva, Tigenix, Tillotts, Topivert, Versant and Vifor; received research grants from MSD, AbbVie, Takeda, Mundipharma, Ferring and Falk; received lectures and/or speaker bureau fees from AbbVie, Ferring, Johnson and Johnson, MSD, Mundipharma, Norgine, Pfizer, Shire, Millennium/Takeda, Tillotts and Vifor. RP: received consulting fees from AbbVie, Amgen, Aptalis, AstraZeneca, Baxter, Biogen, Bristol-Myers Squibb, Celgene, Cubist, Eisai, Ferring, Gilead, Janssen, Merck, Robarts Clinical Trials, Salix, Samsung Bioepis, Shire, Centocor, Elan, GlaxoSmithKline, UCB, Pfizer and Takeda; received research grants from AbbVie, Ferring, Janssen and Takeda; received lectures and/or speaker bureau fees from AbbVie, Aptalis, AstraZeneca, Ferring, Janssen, Merck, Prometheus, Shire and Takeda; received advisory board fees from AbbVie, Abbott, Amgen, Aptalis, AstraZeneca, Baxter, Eisai, Ferring, Genentech, Jansen, Merck, Schering-Plough, Shire, Centocor, Elan, GlaxoSmithKline, UCB, Pfizer, Bristol-Myers Squibb, Takeda, Cubist, Celgene and Salix. PDRH: received consulting fees from AbbVie, Amgen, Genentech, JBR Pharma and Lycera. J-FC: received consulting fees from Abbott Laboratories, ActoGeniX, Albireo Pharma, Amgen, AstraZeneca, Bayer AG, Biogen Idec, Boehringer Ingelheim, Bristol-Myers Squibb, Cellerix, Centocor, Chemocentryx, Cosmo Technologies, Danone Research, Elan Pharmaceuticals, Genentech, Giuliani SpA, Given Imaging, GlaxoSmithKline, Hutchison MediPharma, MSD, Millennium Pharmaceuticals (now Takeda), Neovacs, Ocera Therapeutics, Pfizer, Shire Pharmaceuticals, Schering-Plough, Prometheus Laboratories, Sanofi-Aventis, Synta Pharmaceuticals Corp, Teva, Therakos, UCB Pharma and Wyeth; received research grants from AstraZeneca, Ferring, Schering-Plough and UCB Pharma; received lectures and/or speaker bureau fees from Abbott Laboratories, Centocor, Elan Pharmaceuticals, Given Imaging, Otsuka America Pharmaceutical, MSD, Schering-Plough, Shire Pharmaceuticals, Tillotts Pharma and UCB Pharma; received advisory board fees from Abbott Laboratories, Centocor, Danone, Elan, MSD, Millennium Pharmaceuticals (now Takeda), Schering-Plough and UCB Pharma. BGF: received consulting fees from Abbott/AbbVie, Actogenix, Akros, Albireo Pharma, Amgen, AstraZeneca, Avaxia Biologics, Avir Pharma, Axcan, Baxter Healthcare Corp., Biogen Idec, Boehringer Ingelheim, Bristol-Myers Squibb, Calypso Biotech, Celgene, Elan/Biogen, EnGene, Ferring Pharma, Roche/Genentech, GiCare Pharma, Gilead, Given Imaging, GSK, Ironwood Pharma, Janssen Biotech (Centocor), JnJ/Janssen, Kyowa Kakko Kirin Co Ltd., Lexicon, Lilly, Lycera BioTech, Merck, Mesoblast Pharma, Millennium, Nektar, Nestle, Novo Nordisk, Pfizer, Prometheus Therapeutics and Diagnostics, Protagonist, Receptos, Salix Pharma, Serono, Shire, Sigmoid Pharma, Synergy Pharma, Takeda, Teva Pharma, TiGenix, Tillotts, UCB Pharma, Vertex Pharma, VHsquared Ltd., Warner-Chilcott, Wyeth, Zealand, Zyngenia; received research grants from Abbott/AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Janssen Biotech (Centocor), JnJ/Janssen, Roche/Genentech, Millennium, Pfizer, Receptos, Santarus, Sanofi, Tillotts and UCB Pharma; received lectures and/or speaker bureau fees from Abbott/AbbVie, JnJ/Janssen, Takeda, Warner-Chilcott and UCB Pharma; received advisory board fees from Abbott/AbbVie, Amgen, AstraZeneca, Avaxia Biologics, Bristol-Myers Squibb, Celgene, Centocor, Elan/Biogen, Ferring, JnJ/Janssen, Merck, Nestle, Novartis, Novo Nordisk, Pfizer, Prometheus Laboratories, Protagonist, Salix Pharma, Takeda, Teva, TiGenix, Tillotts Pharma AG, UCB Pharma; is a board of directors member of Robarts Clinical Trials. GC, MM, WW, WN, AM, PH and EM are all employees and stockholders of Pfizer Inc.

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Figures

Figure 1

Study design. Patients who completed the 8-week induction study and achieved clinical response-100 (decrease in Crohn's disease activity index (CDAI) score at week 8 of at least 100 points from baseline) and/or clinical remission (CDAI

Figure 2

Flow diagram.