Wojciech Niezychowski

Tofacitinib, an Oral Janus Kinase Inhibitor, in Active Ulcerative Colitis

BACKGROUND Ulcerative colitis is a chronic inflammatory disease of the colon for which current treatments are not universally effective. One additional treatment may be tofacitinib (CP-690,550), an oral inhibitor of Janus kinases 1, 2, and 3 with in vitro functional specificity for kinases 1 and 3 over kinase 2, which is expected to block signaling involving gamma chain-containing cytokines including interleukins 2, 4, 7, 9, 15, and 21. These cytokines are integral to lymphocyte activation, function, and proliferation. METHODS In a double-blind, placebo-controlled, phase 2 trial, we evaluated the efficacy of tofacitinib in 194 adults with moderately to severely active ulcerative colitis. Patients were randomly assigned to receive tofacitinib at a dose of 0.5 mg, 3 mg, 10 mg, or 15 mg or placebo twice daily for 8 weeks. The primary outcome was a clinical response at 8 weeks, defined as an absolute decrease from baseline in the score on the Mayo scoring system for assessment of ulcerative colitis activity (possible score, 0 to 12, with higher scores indicating more severe disease) of 3 or more and a relative decrease from baseline of 30% or more with an accompanying decrease in the rectal bleeding subscore of 1 point or more or an absolute rectal bleeding subscore of 0 or 1. RESULTS The primary outcome, clinical response at 8 weeks, occurred in 32%, 48%, 61%, and 78% of patients receiving tofacitinib at a dose of 0.5 mg (P=0.39), 3 mg (P=0.55), 10 mg (P=0.10), and 15 mg (P<0.001), respectively, as compared with 42% of patients receiving placebo. Clinical remission (defined as a Mayo score ≤2, with no subscore >1) at 8 weeks occurred in 13%, 33%, 48%, and 41% of patients receiving tofacitinib at a dose of 0.5 mg (P=0.76), 3 mg (P=0.01), 10 mg (P<0.001), and 15 mg (P<0.001), respectively, as compared with 10% of patients receiving placebo. There was a dose-dependent increase in both low-density and high-density lipoprotein cholesterol. Three patients treated with tofacitinib had an absolute neutrophil count of less than 1500. CONCLUSIONS Patients with moderately to severely active ulcerative colitis treated with tofacitinib were more likely to have clinical response and remission than those receiving placebo. (Funded by Pfizer; ClinicalTrials.gov number, NCT00787202.).

The mucosal addressin cell adhesion molecule antibody PF-00547,659 in ulcerative colitis: a randomised study

Background and aims Leucocyte migration to gut mucosa, mediated by integrin binding to mucosal addressin cell adhesion molecule (MAdCAM), is a promising target for therapeutic intervention in inflammatory bowel disease. This first-in-human study of a monoclonal antibody to MAdCAM, PF-00547,659, aimed to explore the safety and preliminary efficacy of this gut-specific mechanism in ulcerative colitis. Methods In this randomised, double-blind placebo-controlled study, 80 patients with active ulcerative colitis received single or multiple (three doses, 4-week intervals) doses of PF-00547,659 0.03–10 mg/kg IV/SC, or placebo. Safety was assessed by adverse events, laboratory tests, and immunogenicity. Exploratory efficacy analyses were based on Mayo score and endoscopic responder rates at weeks 4 and 12. Faecal calprotectin was quantified as a measure of disease activity, and the number of α4β7+ lymphocytes was measured to demonstrate drug activity. Results No obvious drug-related side effects were observed in the PF-00547,659 group, while patient numbers, especially those fully exposed, were small. Overall responder/remission rates at 4 and 12 weeks were 52%/13% and 42%/22%, respectively with combined PF-00547,659 doses compared with 32%/11% and 21%/0%, respectively with placebo. Equivalent endoscopic responder rates were 50% and 42% versus 26% and 29%, respectively. Faecal calprotectin levels decreased to a greater extent with PF-00547,659 than placebo (week 4: 63% vs 18%). Despite variability, there was a trend for an increase in α4β7+ lymphocytes in patients receiving PF-00547,659. Conclusions The favourable short-term safety profile and preliminary efficacy findings for PF-00547,659 in this first-in-human study pave the way for further investigation in larger trials, to establish the role of PF-00547,659 in ulcerative colitis treatment. Trial Register No: NCT00928681.

Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis

BACKGROUND Tofacitinib, an oral, small‐molecule Janus kinase inhibitor, was shown to have potential efficacy as induction therapy for ulcerative colitis in a phase 2 trial. We further evaluated the efficacy of tofacitinib as induction and maintenance therapy. METHODS We conducted three phase 3, randomized, double‐blind, placebo‐controlled trials of tofacitinib therapy in adults with ulcerative colitis. In the OCTAVE Induction 1 and 2 trials, 598 and 541 patients, respectively, who had moderately to severely active ulcerative colitis despite previous conventional therapy or therapy with a tumor necrosis factor antagonist were randomly assigned to receive induction therapy with tofacitinib (10 mg twice daily) or placebo for 8 weeks. The primary end point was remission at 8 weeks. In the OCTAVE Sustain trial, 593 patients who had a clinical response to induction therapy were randomly assigned to receive maintenance therapy with tofacitinib (either 5 mg or 10 mg twice daily) or placebo for 52 weeks. The primary end point was remission at 52 weeks. RESULTS In the OCTAVE Induction 1 trial, remission at 8 weeks occurred in 18.5% of the patients in the tofacitinib group versus 8.2% in the placebo group (P=0.007); in the OCTAVE Induction 2 trial, remission occurred in 16.6% versus 3.6% (P<0.001). In the OCTAVE Sustain trial, remission at 52 weeks occurred in 34.3% of the patients in the 5‐mg tofacitinib group and 40.6% in the 10‐mg tofacitinib group versus 11.1% in the placebo group (P<0.001 for both comparisons with placebo). In the OCTAVE Induction 1 and 2 trials, the rates of overall infection and serious infection were higher with tofacitinib than with placebo. In the OCTAVE Sustain trial, the rate of serious infection was similar across the three treatment groups, and the rates of overall infection and herpes zoster infection were higher with tofacitinib than with placebo. Across all three trials, adjudicated nonmelanoma skin cancer occurred in five patients who received tofacitinib and in one who received placebo, and adjudicated cardiovascular events occurred in five who received tofacitinib and in none who received placebo; as compared with placebo, tofacitinib was associated with increased lipid levels. CONCLUSIONS In patients with moderately to severely active ulcerative colitis, tofacitinib was more effective as induction and maintenance therapy than placebo. (Funded by Pfizer; OCTAVE Induction 1, OCTAVE Induction 2, and OCTAVE Sustain ClinicalTrials.gov numbers, NCT01465763, NCT01458951, and NCT01458574, respectively.)

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

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 Crohns 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.

861 Safety and Efficacy of Pf-00547,659, a Fully Human Anti-MAdCAM Antibody, in Ulcerative Colitis. Results of a First in Human Study

INTRODUCTION: MAdCAM is predominantly expressed on high endothelial venules of intestinal lymphoid tissue and expression is increased at sites of gastrointestinal inflammation. MAdCAM binds a4b7 integrin on lymphocytes facilitating their migration to the inflamed intestinal tract. PF-00547,659, a fully human anti-MAdCAM IgG2 antibody blocksMAdCAM/ a4b7 dependent lymphocyte recruitment to the gut and is therefore anticipated to reduce gut inflammation and mucosal damage. AIM: To evaluate efficacy, safety and pharmacokinetics of PF-00547,659 in patients with active UC (Mayo score > 6). METHODS: In this doubleblind placebo-controlled study a total of 80 patients were included, of whom 30 in 6 singledose (SD) cohorts (doses from 0.03 to 10 mg/kg IV and 3 mg/kg SC or placebo) and 50 in 5 multiple-dose (MD) cohorts (doses from 0.1 to 3.0 mg/kg IV and 0.3 to 1 mg/kg SC or placebo every 4-weeks). Efficacy was measured at week 4 in SD cohorts and at week 4 and week 12 in MD cohorts. Safety information was collected during the double-blind treatment and the follow-up period. Patients were followed-up until the drug plasma levels were below the detection level. RESULTS: Safety: PF-547,659 was well tolerated with an adverse event (AE)profile similar to placebo. There were no safety concerns from laboratory tests, BP and ECG measurement. No anti-drug antibodies were detected. Efficacy: Results from an interim analysis performed after all patients completed Week 12 in the MD cohorts are presented. CONCLUSION: PF-00547,659 was well tolerated with AE profile similar to placebo. Within the limitations of a small sample size, the compound performed better than placebo in clinical as well as endoscopic endpoints and biomarker levels. No dose-response was observed.

Tu1109 Evaluation of the Relationship Between Fecal Calprotectin Concentrations and Clinical and Endoscopic Outcome Measures in a Phase 2 Study of Tofacitinib, an Oral Janus Kinase Inhibitor, in Active Ulcerative Colitis

and, therefore, people with inflammatory bowel disease (IBD) are at risk. Methods: To investigate how frequently health care professionals (HCPs) assess FI in a cohort of patients with IBD we performed a cross sectional survey of 380 adults attending a tertiary referral IBD clinic. Patient surveys were: the validated ICIQ-B questionnaire, detailing frequency and severity of bowel pattern, control and quality of life; and the non-validated Bowel Leakage Questionnaire, detailing any prior interventions by health care professionals. Demographics of age, gender, diagnosis, Montreal classification, St Mark’s Continence Score and disease activity were also recorded. Data was entered into a database and analysed using SPSS statistical package. Results: 229/380 (60%) had Crohn’s Disease (CD) and 180/380 (47%) were female. Median age was 38 years (IQR: 31 50) with a median disease duration of 8.7 years (3.4 15.1). 343/380 (90%) had experienced incontinence of flatus or faeces while 255/380 (67%) reported FI. Only 136/380 (36%) had been asked about FI during an encounter with a HCP. Of the people who had been asked about FI, the vast majority had been asked in IBD clinics (130/136, 96%). Fewer enquiries were made by HCPs in a primary care setting with 42/136 (31%) people having been asked by a family doctor and 12/136 (9%) by a practice nurse. A minority of patients spontaneously volunteered information about incontinence to a healthcare professional (146/380, 39%). Of the people who had discussed continence issues with a HCP, 55 (38%) were offered specific advice or referral for treatment. Those who volunteered information regarding continence had worse ICIQ-B control scores (9 [6 14] vs 3 [1 8], p < 0.0001) and quality of life scores (16 [11 20] vs 9 [6 14], p < 0.0001), reflecting greater burden of disease. Conclusions: Faecal incontinence is common in IBD. It is both under-reported by patients and under-recognised by healthcare professionals. Because symptoms and quality of life can be significantly improved with appropriate intervention, healthcare professionals should enquire about faecal incontinence as part of routine assessment.

Exposure–response characterization of tofacitinib efficacy in moderate to severe ulcerative colitis: Results from a dose‐ranging phase 2 trial

Tofacitinib is an oral, small molecule JAK inhibitor being investigated for ulcerative colitis (UC). In a phase 2 dose‐ranging study, tofacitinib demonstrated efficacy vs. placebo as UC induction therapy. In this posthoc analysis, we aimed to compare tofacitinib dose and plasma concentration as predictors of efficacy and identify covariates that determined efficacy in patients with UC.