Chinyu Su

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.).

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.)

Randomized trial of tofacitinib in active ulcerative colitis: analysis of efficacy based on patient-reported outcomes.

BackgroundTofacitinib, a novel, oral Janus kinase inhibitor, demonstrated a dose-dependent efficacy for induction of clinical response and remission in patients with active ulcerative colitis (UC). The objective of the current study was to determine the effect of tofacitinib on patient-reported outcomes (PROs).MethodsEligible patients (≥18 years of age) with a diagnosis of active UC (total Mayo score of 6-12 points and moderately-to-severely active disease on sigmoidoscopy) were randomized in a 2:2:2:3:3 ratio to receive oral tofacitinib 0.5 mg, 3 mg, 10 mg, or 15 mg, or placebo twice daily (BID) for 8 weeks. PROs were assessed by the Inflammatory Bowel Disease Questionnaire (IBDQ) and the Inflammatory Bowel Disease Patient-Reported Treatment Impact (IBD PRTI) survey.ResultsAt Week 8, mean IBDQ total scores had improved relative to baseline across all five treatment groups (baseline range 123.2-134.5; Week 8 range 149.6-175.4). Improvement from baseline was significantly greater (P = 0.001) for tofacitinib 15 mg BID versus placebo. For tofacitinib 15 mg BID, most patients reported satisfaction or extreme satisfaction, definite preference for tofacitinib, and definite willingness to use tofacitinib again on the IBD PRTI at week 8. Patients achieving endoscopic remission (Mayo endoscopy score of 0) had significantly higher IBDQ scores and favorable PRTI scores than those not achieving endoscopic remission.ConclusionsShort-term treatment with tofacitinib BID was associated with dose-dependent improvement in health-related quality of life and patient preferences for tofacitinib. The results complement previously reported efficacy and safety data for the Phase II study. (NCT 00787202, November 6, 2008).

Tofacitinib in Patients with Ulcerative Colitis: Health-Related Quality of Life in Phase 3 Randomised Controlled Induction and Maintenance Studies

Abstract Background and Aims Tofacitinib is an oral, small molecule Janus kinase [JAK] inhibitor that is being investigated for ulcerative colitis [UC]. We evaluated health-related quality of life [HRQoL] in tofacitinib UC Phase 3 studies. Methods Patients ≥ 18 years old in OCTAVE Induction 1 [N = 598] and 2 [N = 541] with moderately to severely active UC were randomised [1:4] to placebo or tofacitinib 10 mg twice daily [BID] for 8 weeks. Subsequently, OCTAVE Sustain re-randomised [1:1:1] clinical responders [N = 593] from induction studies to placebo, tofacitinib 5 mg BID, or 10 mg BID, for 52 weeks. Inflammatory Bowel Disease Questionnaire [IBDQ] and SF-36v2® Health Survey [SF-36v2] assessed HRQoL. Results In OCTAVE Induction 1 and 2, mean changes from baseline IBDQ were greater with tofacitinib 10 mg BID at Week 8 [40.7 and 44.6] versus placebo [21.0 and 25.0; p < 0.0001]; mean changes from baseline SF-36v2 Physical and Mental Component Summaries [PCS/MCS] were also greater with 10 mg BID [PCS: 6.8 and 6.8; MCS: 6.8 and 7.6] versus placebo [PCS: 2.5 and 4.6; MCS: 3.5 and 4.4; p < 0.01]. In OCTAVE Sustain atWeek 52, changes in IBDQ were maintained with tofacitinib 5 mg [3.7] and 10 mg BID [4.8], and larger with placebo [-26.5; p < 0.0001]. Changes in SF-36v2 PCS/MCS were also maintained with 5 mg [PCS: 0.0; MCS: -1.0] and 10 mg BID [PCS: 0.3; MCS: 0.1] versus placebo [PCS: -5.2; MCS: -6.7; p < 0.0001] at Week 52 in OCTAVE Sustain. Conclusions Tofacitinib 10 mg BID induction therapy significantly improved HRQoL versus placebo at Week 8. Improvements were maintained through 52 weeks’ maintenance therapy with tofacitinib 5 mg and 10 mg BID. ClinicalTrials.gov registration numbers NCT01465763, NCT01458951 and NCT01458574

Herpes Zoster Infection in Patients With Ulcerative Colitis Receiving Tofacitinib

Abstract Background Tofacitinib is an oral, small molecule Janus kinase inhibitor that is being investigated for ulcerative colitis (UC). Tofacitinib is approved for rheumatoid arthritis and psoriatic arthritis, where it has been shown to increase herpes zoster (HZ) risk. We evaluated HZ risk among UC patients using tofacitinib. Methods HZ cases were identified in tofacitinib phase II/III/ongoing, open-label, long-term extension (OLE) UC trials. We calculated HZ incidence rates (IRs) per 100 patient-years of tofacitinib exposure within phase III maintenance (Maintenance Cohort) and phase II/III/OLE (Overall Cohort) studies, stratified by baseline demographics and other factors. HZ risk factors were evaluated in the Overall Cohort using Cox proportional hazard models. Results Overall, 65 (5.6%) patients developed HZ. Eleven patients had multidermatomal involvement (2 nonadjacent or 3–6 adjacent dermatomes), and 1 developed encephalitis (resolved upon standard treatment). Five (7.7%) events led to treatment discontinuation. HZ IR (95% confidence interval [CI]) in the Overall Cohort was 4.07 (3.14–5.19) over a mean (range) of 509.1 (1–1606) days, with no increased risk observed with increasing tofacitinib exposure. IRs (95% CI) were highest in patients age ≥65 years, 9.55 (4.77–17.08); Asian patients, 6.49 (3.55–10.89); patients with prior tumor necrosis factor inhibitor (TNFi) failure, 5.38 (3.86–7.29); and patients using tofacitinib 10 mg twice daily, 4.25 (3.18–5.56). Multivariate analysis identified older age and prior TNFi failure as independent risk factors. Conclusions In tofacitinib-treated UC patients, there was an elevated risk of HZ, although complicated HZ was infrequent. Increased HZ rates occurred in patients who were older, Asian, or had prior TNFi failure (NCT00787202, NCT01465763, NCT01458951, NCT01458574, NCT01470612).

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.

Ulcerative Colitis Treatment Patterns and Cost of Care

OBJECTIVES To examine treatment patterns, dosing, health care resource utilization, and cost of tumor necrosis factor inhibitors (TNFi), adalimumab (ADA) and infliximab (IFX), among patients enrolled in US Humana insurance plans who have been diagnosed with ulcerative colitis (UC). METHODS This retrospective cohort study identified the first pharmacy or medical claim for ADA or IFX (from January 1, 2007, to December 31, 2014) in patients with continuous enrollment for 6 months or more preindex and 12 months or more postindex, with one or more UC diagnosis claim 6 months pre- or postindex. TNFi discontinuation was defined as a therapy gap of 56 days or more for ADA and 112 days or more for IFX. TNFi switch was defined as nonindex TNFi initiation. Health care resource utilization and costs were characterized quarterly according to treatment patterns. RESULTS The study population comprised 295 patients: mean age 50.9 years, 50.5% females, and 61.7% in southern United States. At the index date, 17% of patients received ADA and 83% received IFX. Treatment discontinuation was observed in 52% of ADA and 45% of IFX users through 12 months postindex (mean time 19 and 22 weeks, respectively). Among discontinuers, 46% of ADA and 68% of IFX users did not restart/switch TNFi. ADA and IFX showed mean times to switch of 18 and 30 weeks, respectively. TNFi discontinuers had the lowest mean quarterly total health care cost (

PTU-001 Tofacitinib, an oral jak inhibitor, in the treatment of ulcerative colitis: open-label, long-term extension study

3,935) versus patients who initiated/switched TNFi (

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

15,004). Nevertheless, discontinuers had higher UC-related hospitalization versus patients receiving therapy. CONCLUSIONS Approximately half of ADA and IFX users discontinued, with approximately half of discontinuers not restarting/switching therapies. Further investigation of treatment patterns and outcomes after TNFi discontinuation is required.

DOP075 Tofacitinib in active ulcerative colitis: Analysis of efficacy based on patient-reported outcomes

Introduction Tofacitinib is an oral, small molecule JAK inhibitor that is being investigated for ulcerative colitis (UC). The efficacy and safety of tofacitinib was demonstrated as induction and maintenance therapy in 3 Phase 3, randomised, placebo-controlled studies (OCTAVE Induction 1, NCT01465763; OCTAVE Induction 2, NCT01458951; OCTAVE Sustain, NCT01458574) in patients (pts) with moderate to severe UC.1 Methods We present interim safety and efficacy data up to 3 years of treatment (as of 8 July 2016) from an ongoing Phase 3, multicentre, open-label, long-term extension study (OLE; NCT01470612) in pts who had completed or demonstrated treatment failure in OCTAVE Sustain, or who were non-responders after completing OCTAVE Induction 1 or 2. Pts in remission at Week 52 of OCTAVE Sustain received tofacitinib 5 mg twice daily (BID); all others received 10 mg BID. At Month 2, all pts underwent endoscopy, and non-responders from Induction were mandated to withdraw if no evidence of clinical response was shown. Remission was defined by a Mayo score ≤2 with no individual subscore >1, and rectal bleeding subscore of 0. Binary efficacy endpoints were derived from Mayo score, based on local-read endoscopic subscore. Results 914 pts (5 mg BID, n=156 [17.1%]; 10 mg BID, n=758 [82.9%]) received ≥1 dose of study drug; 381 pts (41.7%) discontinued. The most frequent AE leading to discontinuation was worsening of UC. The most frequent treatment-emergent AEs by system organ class (both doses) were ‘infections/infestations’ and ‘gastrointestinal disorders’, and by preferred term were ‘nasopharyngitis’ and ‘worsening of UC’. Serious infections AEs were reported in 4 (2.6%) and 14 (1.8%) pts with 5 and 10 mg BID, respectively. Malignancies excl. NMSC were reported in 9 (1.2%) pts in the 10 mg BID group (no clustering of malignancy type); none were reported in the 5 mg BID group. No new safety risks were identified. Data ‘as observed’ for remission and mucosal healing at Months 2, 12 and 24 are shown. Conclusions In pts with moderate to severe UC who remained in the OLE study, no new safety concerns emerged compared with those observed with tofacitinib in rheumatoid arthritis. Efficacy results from this OLE study support sustained efficacy with tofacitinib 5 and 10 mg BID. Funded by Pfizer Inc.Abstract PTU-001 Table 1 Summary of safety and efficacy is the OLE study Reference 1. Sandborn WJ, et al. N Engl J Med 2017;376:1723–36.