Assessment of radiographic progression in patients with rheumatoid arthritis treated with tofacitinib in long-term studies

OBJECTIVES: Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA. We evaluated radiographic progression in tofacitinib-treated patients with RA for up to 3 years in two pooled long-term extension (LTE) studies (ORAL Sequel; A3921041) (primary analysis), and for up to 5 years using data integrated from one phase (P)2 (A3921068), two P3 (ORAL Start; ORAL Scan) and two LTE studies (exploratory analysis). METHODS: In LTE studies, patients received tofacitinib 5 mg twice daily (BID) or 10 mg BID as monotherapy or with conventional synthetic (cs)DMARDs. Radiographic outcomes up to 3 years: least squares mean (LSM) change from baseline in van der Heijde modified Total Sharp Score (ΔmTSS), erosion score (ΔES) and joint space narrowing (ΔJSN) score; proportion of patients with no radiographic progression (ΔmTSS ≤0.5); proportion of patients with no new erosions (ΔES ≤0.5). ΔmTSS was evaluated for up to 5 years in an exploratory analysis. RESULTS: For all tofacitinib-treated patients with radiographic data available at LTE month 36 (n = 414), LSM ΔmTSS was 1.14, LSM ΔES was 0.66, LSM ΔJSN was 0.74, and 74.3% and 86.2% of patients showed no radiographic progression and no new erosions, respectively. Similar values were observed regardless of tofacitinib dose, or whether patients received tofacitinib as monotherapy or with csDMARDs. In an exploratory analysis of integrated P2/P3/LTE studies, LSM ΔmTSS was 3.34 at month 60 (n = 269). CONCLUSION: Limited progression of structural damage was observed in tofacitinib-treated patients up to 5 years, with similar results for tofacitinib used as monotherapy or combination therapy up to 3 years. TRIAL REGISTRATION: ClinicalTrials.gov (http://clinicaltrials.gov): NCT01164579; NCT01039688; NCT00847613; NCT00413699; NCT00661661

Efficacy and safety of abrocitinib in patients with moderate-to-severe atopic dermatitis: Results from the open-label run-in period of JADE REGIMEN

Abrocitinib, an oral once-daily Janus kinase 1 selective inhibitor, administered as monotherapy at doses of 200 mg and 100 mg, was well tolerated and more effective than placebo in patients with moderate-to-severe atopic dermatitis (AD) after 12 weeks of treatment in two phase III clinical trials [JADE MONO-1 (NCT03349060) and JADE MONO-2 (NCT03575871)] and one phase IIb (NCT02780167) clinical trial. The efficacy and safety of abrocitinib in an induction maintenance paradigm has not been investigated. The objective of this study was to assess the short-term efficacy and safety of abrocitinib monotherapy in the open-label runin period of the JADE REGIMEN study (NCT03627767). In JADE REGIMEN, patients aged ≥ 12 years with moderate-tosevere AD received abrocitinib monotherapy 200 mg for 12 weeks as part of an open-label run-in period before being randomly assigned 1 : 1 : 1 to receive abrocitinib 200 mg, abrocitinib 100 mg or placebo in a 40-week double-blind maintenance period. The analysis of efficacy in the run-in period was evaluated by measuring the proportion of patients who achieved an Investigator\u27s Global Assessment (IGA) response of \u27clear\u27 (0) or \u27almost clear\u27 (1) with ≥ 2- grade improvement, ≥ 75% improvement in Eczema Area and Severity Index (EASI 75 response) and Peak Pruritus Numerical Rating Scale (PP-NRS) (used with permission of Regeneron Pharmaceuticals, Inc. and Sanofi) response with ≥ 4-point improvement (PP-NRS4) at week 12. Patients who achieved IGA and EASI 75 responses during the 12-week run-in period (responders) were randomly assigned 1 : 1 : 1 to receive abrocitinib 200 mg, abrocitinib 100 mg or placebo during the 40-week maintenance period of the study; patients who did not reach this response threshold were considered nonresponders and completed the study at week 12. During the maintenance period, randomly assigned patients who experienced flares of AD (loss of ≥ 50% of EASI response achieved at week 12 with an IGA score ≥ 2) entered a 12-week open-label rescue period. As part of the open-label period, 1233 patients [mean age 31.6 years; 20.0% (n = 246) aged \u3c 18 years; male 55.5%; white 75.5%; moderate AD per IGA 59.1%; severe AD per IGA 40.9%; median EASI score 27.9; median Dermatology Quality of Life Index (DLQI) score 16.0; median Children\u27s DLQI score 12.0] were treated with abrocitinib 200 mg once daily. A total of 120 patients (9.7%) discontinued before week 12, mostly because of adverse events [49 patients (4.0%)] and patient/parent/guardian withdrawal [42 patients (3.4%)]. At week 12, 65.9% [95% confidence interval (CI) 63.3-68.6], 75.6% (95% CI 73.1-78.0) and 68.3% (95% CI 65.3-71.3) achieved IGA, EASI 75 and PP-NRS responses, respectively; 65.2% (95% CI 62.5-67.9) achieved both IGA and EASI 75 responses. In adolescents and adults, the week 12 response rates were 59.8% (95% CI 53.6-65.9) and 67.5% (95% CI 64.6-70.4) for IGA, 71.5% (95% CI 65.9- 77.2) and 76.6% (95% CI 73.9-79.2) for EASI 75, and 57.5% (95% CI 50.0-65.0) and 70.6% (95% CI 67.4-73.8) for PP-NRS4. During the run-in period, 820 patients (66.5%) reported AEs; 20 (1.6%) reported serious AEs, and 38 (3.1%) reported severe AEs. Overall, 798 patients (64.7%) were randomly assigned to the maintenance period at week 12. Abrocitinib monotherapy 200 mg was effective and well tolerated in adolescents and adults with moderateto- severe AD during the 12-week run-in open-label period of JADE REGIMEN. These results support the efficacy and safety observed in the phase III JADE MONO-1 and JADE MONO-2 abrocitinib monotherapy clinical trials

Safety and efficacy of tofacitinib for up to 9.5 years in the treatment of rheumatoid arthritis: final results of a global, open-label, long-term extension study

Abstract Background Final data are presented for the ORAL Sequel long-term extension (LTE) study evaluating the safety and efficacy of tofacitinib 5 mg and 10 mg twice daily (BID) for up to 9.5 years in patients with rheumatoid arthritis (RA). Methods Eligible patients had previously completed a phase 1, 2, or 3 qualifying index study of tofacitinib and received open-label tofacitinib 5 mg or 10 mg BID. Stable background therapy, including csDMARDs, was continued; adjustments to tofacitinib or background therapy were permitted at investigators’ discretion. Assignment to dose groups (5 mg or 10 mg BID) was based on patients’ average total daily dose. The primary objective was to determine the long-term safety and tolerability of tofacitinib 5 mg and 10 mg BID; the key secondary objective was to evaluate the long-term persistence of efficacy. Results Between February 5, 2007, and November 30, 2016, 4481 patients were enrolled. Total tofacitinib exposure was 16,291 patient-years. Safety data are reported up to month 114 for all tofacitinib; efficacy data are reported up to month 96 for tofacitinib 5 mg BID and month 72 for 10 mg BID (with low patient numbers limiting interpretation beyond these time points). Overall, 52% of patients discontinued (24% due to adverse events [AEs] and 4% due to insufficient clinical response); the safety profile remained consistent with that observed in prior phase 1, 2, 3, or LTE studies. The incidence rate (IR; number of patients with events per 100 patient-years) for AEs leading to discontinuation was 6.8. For all-cause AEs of special interest, IRs were 3.4 for herpes zoster, 2.4 for serious infections, 0.8 for malignancies excluding non-melanoma skin cancer, 0.4 for major adverse cardiovascular events, and 0.3 for all-cause mortality. Clinically meaningful improvements in the signs and symptoms of RA and physical functioning, which were observed in the index studies, were maintained. Conclusions Tofacitinib 5 mg and 10 mg BID demonstrated a consistent safety profile (as monotherapy or combination therapy) and sustained efficacy in this open-label LTE study of patients with RA. Safety data are reported up to 9.5 years, and efficacy data up to 8 years, based on adequate patient numbers to support conclusions. Trial registration NCT00413699, funded by Pfizer Inc (date of trial registration: December 20, 2006