Original article
Alimentary tract
A Phase 2 Study of Tofacitinib, an Oral Janus Kinase Inhibitor, in Patients With Crohn’s Disease

https://doi.org/10.1016/j.cgh.2014.01.029Get rights and content

Background & Aims

Tofacitinib, an orally administered Janus kinase inhibitor, blocks signaling through γ-chain–containing cytokines (interleukins 2, 4, 7, 9, 15, and 21). We performed a phase 2 trial to measure its efficacy in patients with moderate-to-severe active Crohn’s disease.

Methods

Patients (N = 139; age, ≥18 y) with moderate-to-severe active Crohn’s disease were assigned randomly to groups given 1 mg (n = 36), 5 mg (n = 34), or 15 mg (n = 35) tofacitinib or placebo (n = 34), twice daily for 4 weeks, at 48 centers in 12 countries. The primary end point was the proportion of clinical responders at week 4 (decrease from baseline in the Crohn’s Disease Activity Index score of ≥70 points [Response-70]). Secondary end points included clinical remission (Crohn’s Disease Activity Index score of <150 points) at week 4.

Results

A clinical response was observed in 36% (P = .467), 58% (P = .466), and 46% (P ≥ .999) of patients given the 1-, 5-, and 15-mg doses of tofacitinib, compared with 47% of patients given placebo. Clinical remission was observed in 31% (P = .417), 24% (P = .776), and 14% (P = .540) of patients given the 1-, 5-, and 15-mg doses of tofacitinib, compared with 21% of patients given placebo. The 15-mg dose of tofacitinib reduced levels of C-reactive protein and fecal calprotectin from baseline. Adverse and serious adverse events were similar among groups. Dose-dependent increases in low- and high-density lipoprotein cholesterol were observed in patients given the 5- or 15-mg doses of tofacitinib.

Conclusions

There were no significant differences in the percentage of patients with moderate-to-severe active Crohn’s disease who achieved clinical responses (Response-70) or clinical remission after 4 weeks' administration of tofacitinib (1, 5, or 15 mg) or placebo twice daily. However, a large percentage of patients given placebo achieved Response-70 or remission. Reductions in C-reactive protein and fecal calprotectin levels among patients given the 15-mg dose of tofacitinib indicate its biologic activity. ClinicalTrials.gov number: NCT00615199.

Section snippets

Methods

The study (A3921043, ClinicalTrials.gov NCT00615199) was conducted in compliance with the Declaration of Helsinki and Good Clinical Practice Guidelines established by the International Conference on Harmonisation. The protocol was approved by the Institutional Review Board at each center. All patients provided written informed consent. The study investigators were responsible for adhering to the study procedures described in the protocol. The study was patient-, investigator-, and

Patient Disposition and Demographics

In total, 236 patients were screened; 139 (58.9%) patients were randomized to receive tofacitinib 1 (n = 36), 5 (n = 34), or 15 mg twice daily (n = 35), or placebo twice daily (n = 34); 126 (90.6%) patients completed the study (Supplementary Figure 1). One patient with a baseline CDAI score of less than 150 from the 5-mg twice-daily group was excluded from all efficacy analyses. Baseline demographic characteristics were similar between groups (Table 1). Steroids (meprednisone, prednisone,

Discussion

In this 4-week, phase 2 trial in patients with moderate-to-severe active Crohn’s disease, a proportion of whom had failed conventional therapy, tofacitinib did not show efficacy in the induction of a clinical response, as measured by Response-70/-100 or clinical remission rates; however, placebo response and remission rates were greater than expected. Tofacitinib 15 mg twice daily reduced CRP and fecal calprotectin concentrations, and numeric improvements from baseline in IBDQ score were

Conclusions

In conclusion, patients with moderate-to-severe active Crohn’s disease treated with tofacitinib were not more likely to achieve clinical response or clinical remission vs those receiving placebo; however, the placebo response and remission rates were unexpectedly high. The reductions in CRP and fecal calprotectin values in the tofacitinib 15-mg twice-daily group suggest biologic activity. Further studies are needed to determine whether tofacitinib is effective for the treatment of Crohn’s

Acknowledgements

The authors would like to thank the patients who were involved in this study, and the A3921043 investigators and study team.

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Conflicts of interest The authors disclose the following: William Sandborn has received consulting fees from Abbott, ActoGeniX NV, AGI Therapeutics, Inc, Alba Therapeutics Corp, Albireo, Alfa Wasserman, Amgen, AM-Pharma BV, Anaphore, Astellas, Athersys, Inc, Atlantic Healthcare, Ltd, Aptalis, BioBalance Corp, Boehringer-Ingelheim, Bristol-Myers Squibb, Celgene, Celek Pharmaceuticals, Cellerix SL, Cerimon Pharmaceuticals, ChemoCentryx, CoMentis, Cosmo Technologies, Coronado Biosciences, Cytokine Pharmasciences, Eagle Pharmaceuticals, EnGene, Inc, Eli Lilly, Enteromedics, Exagen, Diagnostics, Inc, Ferring Pharmaceuticals, Flexio Therapeutics, Inc, Funxional Therapeutics, Ltd, Genzyme Corp, Gilead Sciences, Given Imaging, GlaxoSmithKline, Human Genome Sciences, Ironwood Pharmaceuticals, Janssen Pharmaceutical Research & Development, LLC, KaloBios Pharmaceuticals, Lexicon Pharmaceuticals, Lycera Corp, Meda Pharmaceuticals, Merck Research Laboratories, Merck Serono, Millennium Pharmaceuticals, Nisshin Kyorin Pharmaceuticals, Novo Nordisk, NPS Pharmaceuticals, Optimer Pharmaceuticals, Orexigen Therapeutics, Inc, PDL Biopharma, Pfizer Inc, Procter and Gamble, Prometheus Laboratories, ProtAb, Ltd, Purgenesis Technologies, Inc, Relypsa, Inc, Roche, Salient Pharmaceuticals, Salix Pharmaceuticals, Santarus, Schering Plough, Shire Pharmaceuticals, Sigmoid Pharma, Ltd, Sirtris Pharmaceuticals, SLA Pharma UK, Ltd, Targacept, Teva Pharmaceuticals, Therakos, Tilliotts Pharma AG, TxCell SA, UCB Pharma, Viamet Pharmaceuticals, Vascular Biogenics, Ltd, Warner Chilcott UK, Ltd, and Wyeth; has received research grants from Abbott, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Janssen Pharmaceutical Research & Development, LLC, Millennium Pharmaceuticals, Novartis, Pfizer Inc, Procter and Gamble, Shire Pharmaceuticals, and UCB Pharma; has received payments for lectures and speakers bureau fees from Abbott, Bristol-Myers Squibb, and Janssen Pharmaceutical Research & Development, LLC; and holds stock/stock options in Enteromedics. Subrata Ghosh has received consulting fees from Abbott, Pfizer Inc, Merck, Shire, Centocor, and BMS; has received research grants from Merck and Abbott; has received payment for lectures from Abbott, Merck, Shire, Millennium, Centocor, and Ferring; and has received payment for the development of an educational presentation from Abbott. Julian Panes has received speaker fees from AbbVie, MSD, Shire Pharmaceuticals, and UCB; has acted as a scientific consultant for AbbVie, Bristol-Myers Squibb, Ferring, MSD, Novartis, Pfizer Inc, Shire Pharmaceuticals, Tygenics, and UCB; and has received research grants from AbbVie and MSD. Ivana Vranic, Wenjin Wang, and Wojciech Niezychowski are employees of, and hold stock/stock options in, Pfizer Inc.

Funding This study was sponsored by Pfizer Inc. Editorial support was provided by Karen Irving at Complete Medical Communications, funded by Pfizer Inc.

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