Deborah A Woodworth

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.)

Efficacy and safety of open-label etanercept on extended oligoarticular juvenile idiopathic arthritis, enthesitis-related arthritis and psoriatic arthritis: part 1 (week 12) of the CLIPPER study

Objective To investigate the efficacy and safety of etanercept (ETN) in paediatric subjects with extended oligoarticular juvenile idiopathic arthritis (eoJIA), enthesitis-related arthritis (ERA), or psoriatic arthritis (PsA). Methods CLIPPER is an ongoing, Phase 3b, open-label, multicentre study; the 12-week (Part 1) data are reported here. Subjects with eoJIA (2–17 years), ERA (12–17 years), or PsA (12–17 years) received ETN 0.8 mg/kg once weekly (maximum 50 mg). Primary endpoint was the percentage of subjects achieving JIA American College of Rheumatology (ACR) 30 criteria at week 12; secondary outcomes included JIA ACR 50/70/90 and inactive disease. Results 122/127 (96.1%) subjects completed the study (mean age 11.7 years). JIA ACR 30 (95% CI) was achieved by 88.6% (81.6% to 93.6%) of subjects overall; 89.7% (78.8% to 96.1%) with eoJIA, 83.3% (67.2% to 93.6%) with ERA and 93.1% (77.2% to 99.2%) with PsA. For eoJIA, ERA, or PsA categories, the ORs of ETN vs the historical placebo data were 26.2, 15.1 and 40.7, respectively. Overall JIA ACR 50, 70, 90 and inactive disease were achieved by 81.1, 61.5, 29.8 and 12.1%, respectively. Treatment-emergent adverse events (AEs), infections, and serious AEs, were reported in 45 (35.4%), 58 (45.7%), and 4 (3.1%), subjects, respectively. Serious AEs were one case each of abdominal pain, bronchopneumonia, gastroenteritis and pyelocystitis. One subject reported herpes zoster and another varicella. No differences in safety were observed across the JIA categories. Conclusions ETN treatment for 12 weeks was effective and well tolerated in paediatric subjects with eoJIA, ERA and PsA, with no unexpected safety findings.

Two-year Efficacy and Safety of Etanercept in Pediatric Patients with Extended Oligoarthritis, Enthesitis-related Arthritis, or Psoriatic Arthritis

Objective. The main objective was to determine the 2-year clinical benefit and safety of etanercept (ETN) in children with the juvenile idiopathic arthritis (JIA) categories of extended oligoarthritis (eoJIA), enthesitis-related arthritis (ERA), or psoriatic arthritis (PsA). Methods. CLIPPER was a 96-week, phase IIIb, open-label, multicenter study. Patients with eoJIA, ERA, or PsA received ETN 0.8 mg/kg once weekly (50 mg max) for up to 96 weeks. The proportions of patients reaching the JIA American College of Rheumatology (ACR) 30/50/70/90/100 and inactive disease responses at Week 96 were calculated. Adverse events (AE) were collected throughout the study (intention-to-treat sample). Results. There were 127 patients (eoJIA n = 60, ERA n = 38, PsA n = 29) who received ≥ 1 dose of ETN. The mean disease duration was 31.6 (eoJIA), 23.0 (ERA), and 21.8 (PsA) months. At Week 96, JIA ACR 30/50/70/90/100/inactive disease responses (95% CI) were achieved by 84.3% (76.7, 90.1), 83.5% (75.8, 89.5), 78.7% (70.6, 85.5), 55.1% (46.0, 63.9), 45.7% (36.8, 54.7), and 27.6% (20.0, 36.2) of patients, respectively. The most common AE (no. events, events per 100 patient-yrs) overall were headache (23, 10.7), pyrexia (12, 5.6), and diarrhea (10, 4.6). The most common infections were upper respiratory tract infection (83, 38.6), pharyngitis (50, 23.2), gastroenteritis (22, 10.2), bronchitis (19, 8.8), and rhinitis (17, 7.9). No cases of malignancy, active tuberculosis, demyelinating disorders, or death were reported. Conclusion. Over 96 weeks of therapy, ETN demonstrated sustained efficacy at treating the clinical symptoms of all 3 JIA categories, with no major safety issues.

FRI0326 Effectiveness and safety of etanercept in paediatric subjects with extended oligoarticular juvenile idiopathic arthritis, enthesitis-related arthritis, or psoriatic arthritis: The clipper study

Background Limited information is available on the effects of etanercept (ETN) on the juvenile idiopathic arthritis (JIA) subtypes, extended oligoarticular JIA (eoJIA), enthesitis-related arthritis (ERA), and psoriatic arthritis (PsA). Objectives To assess the efficacy and safety of ETN in paediatric subjects with eoJIA, ERA, and PsA. Methods CLIPPER is an ongoing, Phase 3b, open-label, multi-centre study; the primary analyses (12-week data) are reported here. Subjects with eoJIA (2–17 y old), ERA (12–17 y old), or PsA (12–17 y old) received ETN 0.8 mg/kg once weekly (max. dose 50 mg). Endpoints included the percentage of subjects achieving American College of Rheumatology (ACR) Paediatric 30 (primary endpoint) and 50/70/90/100 criteria at Week 12. Logistic regression analysis was used to compare the ACR Paediatric 30 data with historical placebo data from a meta-analysis of JIA studies [1] and a juvenile-onset spondyloarthropathy study [2]. Results 127 subjects (mean age 11.7 y) received ≥1 dose of ETN; 5 (3.9%) subjects discontinued the study. Concomitant disease-modifying anti-rheumatic drugs, corticosteroids, and non-steroidal anti-inflammatory drugs were received by 109 (85.8%), 16 (12.6%), and 74 (58.3%) subjects, respectively. ACR Paediatric 30/50/70/90/100 response rates (Tables 1 and 2) were similar across all JIA subtypes. Odds ratios for ACR Paediatric 30 showed a significant advantage of ETN over the historical placebo data. Table 1. ACR Paediatric 30 Responses, Week 12 JIA Subtype % Subjects (95% CI) ETN 0.8 mg/kg vs. Placebo Historical Data ETN 0.8 mg/kg Placebo Historical data Odds Ratio (95% CI) Overall, n=123 88.6 (81.6–93.6) 28.9 (24.0–34.2)a 23.5 (12.5–44.3) eoJIA, n=58 89.7 (78.8–96.1) 28.9 (24.0–34.2)a 26.2 (10.6–64.2) ERA, n=36 83.3 (67.2–93.6) 28.9 (24.0–34.2)a 15.1 (6.0–38.2) ERA, n=36 83.3 (67.2–93.6) 42.8 (16.9–68.8)b 6.7 (1.7–26.3) PsA, n=29 93.1 (77.2–99.2) 28.9 (24.0–34.2)a 40.7 (9.4–176.9) Modified intent-to-treat (mITT) population (observed cases). aMeta-analysis weighted estimate of placebo response rate in Ruperto et al. [1]. bPlacebo response rate in Burgos-Vargas et al. [2]. Table 2. ACR Paediatric 50/70/90/100 Responses, Week 12 ACR Paediatric 50 ACR Paediatric 70 ACR Paediatric 90 ACR Paediatric 100 n=122 n=122 n=121 n=122 Overall, % subjects (95% CI) 81.1 (73.1–87.7) 61.5 (52.2–70.1) 29.8 (21.8–38.7) 23.0 (15.8–31.4) mITT population (observed cases). Treatment-emergent adverse events (TEAEs), treatment-emergent infections, serious TEAEs, and malignancies were reported in 45 (35.4%), 58 (45.7%), 4 (3.1%), and 0 (0.0%) subjects, respectively. Serious TEAEs were 1 (0.8%) case each of abdominal pain, bronchopneumonia, gastroenteritis, and pyelocystitis. One (0.8%) subject reported an opportunistic infection of herpes zoster. No clinically meaningful differences in safety were observed across the JIA subtypes. Conclusions Etanercept treatment for 12 weeks was effective in treating subjects with the JIA subtypes, eoJIA, ERA, or PsA, with no unexpected safety findings. References Ruperto N, et al. Arthritis Rheum 2003;48(Suppl 9):S90. Burgos-Vargas R, et al. Ann Rheum Dis 2008;67(Suppl 2):69. Disclosure of Interest G. Horneff Grant/Research support from: Abbott, Pfizer Inc., Wyeth., N. Ruperto Grant/Research support from: Abbott, AstraZeneca, Bristol-Myers Squibb, Centocor Research and Development, Eli Lilly and Co., “Francesco Angelini” s.p.a., GlaxoSmithKline, Italfarmaco, Merck Serono, Novartis, Pfizer Inc., Regeneron, Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Wyeth, Xoma, Speakers Bureau: AstraZeneca, Bristol-Myers Squibb, Janssen Biologics B.V., Novartis, Roche, R. Burgos-Vargas Grant/Research support from: Abbott, Consultant for: Abbott, Bristol-Myers Squibb, Janssen, Pfizer Inc., Roche, Speakers Bureau: Abbott, Bristol-Myers Squibb, Janssen, MSD, Pfizer Inc., Roche, V. Panaviene: None Declared, D. Alvarez Employee of: Pfizer Inc., C. Zang Employee of: Pfizer Inc., J. Wajdula Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., D. Woodworth Employee of: Pfizer Inc., B. Vlahos Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., A. Martini Grant/Research support from: Abbott, AstraZeneca, Bristol-Myers Squibb, Centocor Research and Development, Eli Lilly and Co., “Francesco Angelini” s.p.a., GlaxoSmithKline, Italfarmaco, Merck Serono, Novartis, Pfizer Inc., Regeneron, Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Wyeth, Xoma, Speakers Bureau: AstraZeneca, Bristol-Myers Squibb, Janssen Biologics B.V., Novartis, Roche

Tofacitinib Induction Therapy Reduces Symptoms Within 3 Days for Patients With Ulcerative Colitis

BACKGROUND & AIMS: Tofacitinib is an oral, small molecule inhibitor of JAK for the treatment of ulcerative colitis (UC). We evaluated the onset of symptom improvement in post‐hoc analyses of data from 2 phase 3 trials of induction therapy with tofacitinib in patients with UC (OCTAVE Induction 1 and 2). METHODS: The studies comprised patients with moderate to severe active UC who were intolerant to, or failed by previous treatment with, corticosteroids, thiopurines, and/or tumor necrosis factor (TNF) antagonists. Patients received tofacitinib (10 mg twice daily, n = 905) or placebo (n = 234) for 8 weeks. Daily Mayo stool frequency and rectal bleeding subscores were calculated using diary data from the first 15 days of therapy. We analyzed data from subgroups including failure of prior anti‐TNF therapy, baseline corticosteroid use, and baseline serum levels of C‐reactive protein. RESULTS: Mean changes were significantly greater in patients given tofacitinib vs placebo in reductions from baseline stool frequency subscore (tofacitinib: –0.27 vs placebo: –0.11; P < .01), total number of daily bowel movements (–1.06 vs –0.27; P < .0001), and rectal bleeding subscore (–0.30 vs –0.14; P < .01) by day 3. Compared with placebo, more tofacitinib‐treated patients had reductions from baseline in stool frequency subscore (by ≥1 point for tofacitinib, 241/837, 28.8% vs placebo, 39/218, 17.9%) (P < .01) and rectal bleeding subscore (by ≥1 point for tofacitinib, 266/830, 32.0% vs placebo, 43/214, 20.1%) (P < .01) by day 3. A consistent effect of tofacitinib was observed in all subgroups. CONCLUSIONS: In a post‐hoc analysis of data from phase 3 trials of induction therapy with tofacitinib in patients with UC, we found significant improvements in symptoms among patients given tofacitinib compared with placebo within 3 days. These findings indicate the rapid onset of effect of this drug in patients with UC. ClinicalTrials.gov no: NCT01465763 and NCT01458951.