tofacitinib and Opportunistic-Infections

To evaluate the risk of opportunistic infections (OIs) in patients with rheumatoid arthritis (RA) treated with tofacitinib.. Phase II, III and long-term extension clinical trial data (April 2013 data-cut) from the tofacitinib RA programme were reviewed. OIs defined a priori included mycobacterial and fungal infections, multidermatomal herpes zoster and other viral infections associated with immunosuppression. For OIs, we calculated crude incidence rates (IRs; per 100 patient-years (95% CI)); for tuberculosis (TB) specifically, we calculated rates stratified by patient enrolment region according to background TB IR (per 100 patient-years): low (≤0.01), medium (>0.01 to ≤0.05) and high (>0.05).. We identified 60 OIs among 5671 subjects; all occurred among tofacitinib-treated patients. TB (crude IR 0.21, 95% CI of (0.14 to 0.30)) was the most common OI (n=26); median time between drug start and diagnosis was 64 weeks (range 15-161 weeks). Twenty-one cases (81%) occurred in countries with high background TB IR, and the rate varied with regional background TB IR: low 0.02 (0.003 to 0.15), medium 0.08 (0.03 to 0.21) and high 0.75 (0.49 to 1.15). In Phase III studies, 263 patients diagnosed with latent TB infection were treated with isoniazid and tofacitinib concurrently; none developed TB. For OIs other than TB, 34 events were reported (crude IR 0.25 (95% CI 0.18 to 0.36)).. Within the global tofacitinib RA development programme, TB was the most common OI reported but was rare in regions of low and medium TB incidence. Patients who screen positive for latent TB can be treated with isoniazid during tofacitinib therapy.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Clinical Trials as Topic; Humans; Immunocompromised Host; Immunosuppressive Agents; Incidence; Janus Kinase 3; Opportunistic Infections; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Risk Assessment; Tuberculosis

Janus kinase (JAK) inhibitors have emerged as a novel orally administered small-molecule therapy for the treatment of ulcerative colitis and possibly Crohn disease. These molecules are designed to selectively target the activity of specific JAKs and to offer a targeted mechanism of action without risk of immunogenicity. Based on data from clinical trials in rheumatoid arthritis and phase 2 studies in inflammatory bowel disease, tofacitinib and other JAK inhibitors are likely to become a new form of medical therapy for the treatment of inflammatory bowel disease.

Topics: Animals; Dyslipidemias; Humans; Inflammatory Bowel Diseases; Janus Kinases; Opportunistic Infections; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Signal Transduction

Tofacitinib is an oral small molecule Janus kinase [JAK] inhibitor for the treatment of ulcerative colitis. We report an integrated summary of tofacitinib safety [exposure: ≤7.8 years] from the global clinical programme.. Patients receiving tofacitinib 5 or 10 mg twice daily [BID] from completed phase [P]2/3 placebo-controlled studies, an open-label, long-term extension study [final data cut-off: August 24, 2020], and interim analysis of a P3b/4 study (interim data cut-off: February 20, 2020; Overall plus P3b/4 [2020] Cohort) were included. Proportions with adverse events [AEs] and serious AEs, and incidence rates [IRs; unique patients with events/100 patient-years] for deaths and AEs of special interest [AESI] were evaluated. Opportunistic infections, malignancies, major adverse cardiovascular events [MACE] and gastrointestinal perforations were adjudicated.. In total, 1157 patients received one or more dose of tofacitinib (mean duration: 946.9 days); 955/1157 [83%] received a predominant dose of 10 mg BID; 412/1157 [35.6%] received tofacitinib for >4 years; 992/1157 [85.7%] had AEs, 244/1157 [21.1%] had serious AEs and 134/1157 (11.6%) discontinued use due to AEs. IRs [95% confidence intervals] for all tofacitinib doses were: deaths, 0.23 [0.09-0.46]; serious infections, 1.69 [1.26-2.21]; herpes zoster [non-serious and serious], 3.30 [2.67-4.04]; opportunistic infections, 1.03 [0.70-1.46]; malignancies (excluding non-melanoma skin cancer [NMSC]), 0.84 [0.55-1.24]; NMSC, 0.73 [0.45-1.10]; MACE, 0.29 [0.13-0.55]; deep vein thrombosis, 0.03 [0.00-0.18]; pulmonary embolism, 0.19 [0.07-0.42]; gastrointestinal perforations, 0.10 [0.02-0.28].. AESI IRs were stable to 7.8 years and generally <2.0 in the Overall plus P3b/4 [2020] Cohort, with the exception of herpes zoster [a known risk of tofacitinib treatment]. ClinicalTrials.gov:NCT00787202;NCT01465763;NCT01458951;NCT01458574;NCT01470612;NCT03281304JCC Topic/keyword selection: 3. Clinical trials.

Topics: Colitis, Ulcerative; Herpes Zoster; Humans; Janus Kinase Inhibitors; Opportunistic Infections; Protein Kinase Inhibitors; Pyrroles; Skin Neoplasms; Treatment Outcome

Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis. We report integrated analyses of infections in the Phase [P]2 and P3 OCTAVE programmes.. Three cohorts were analysed: Induction [P2/3 induction studies]; Maintenance [P3 maintenance study]; and Overall [all tofacitinib-treated patients in induction, maintenance, or ongoing, open-label, long-term extension studies; as of May 2019]. Proportions and incidence rates [IRs; unique patients with events/100 patient-years] of serious infections [SIs], herpes zoster [HZ] [non-serious and serious], and opportunistic infections [OIs] are reported [censored at time of event].. In the Induction Cohort [N = 1220], no patients receiving placebo and eight [0.9%] receiving tofacitinib 10 mg twice daily [BID] developed SIs. Maintenance Cohort [N = 592] SI IRs (95% confidence interval [CI]) were 1.94 [0.23-7.00] for placebo and 1.35 [0.16-4.87] and 0.64 [0.02-3.54] for tofacitinib 5 and 10 mg BID, respectively; HZ IRs were 0.97 [0.02-5.42], 2.05 [0.42-6.00], and 6.64 [3.19-12.22], respectively. In the Overall Cohort [N = 1157; 82.9% predominantly received tofacitinib 10 mg BID], SI, HZ, and non-HZ OI IRs were 1.70 [1.24-2.27], 3.48 [2.79-4.30], and 0.15 [0.04-0.38], respectively. No SIs resulted in death.. During induction, SIs were more frequent with tofacitinib versus placebo. SIs were generally infrequent in the Maintenance and Overall Cohorts, with rates comparable between treatment groups. Maintenance Cohort HZ IR was numerically higher with tofacitinib 10 mg BID versus 5 mg BID. Overall Cohort HZ IRs remained stable over time. Non-HZ OIs and viral infections were rare.

Topics: Adult; Colitis, Ulcerative; Dose-Response Relationship, Drug; Female; Herpes Zoster; Humans; Immunocompromised Host; Incidence; Infections; Janus Kinase Inhibitors; Male; Medication Therapy Management; Opportunistic Infections; Piperidines; Pyrimidines; Risk Assessment; Severity of Illness Index

Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We aimed to estimate the overall incidence of safety events in patients with UC in a real-life population cohort for comparison with the tofacitinib UC clinical trial program.. Clinical trial-like criteria were applied to an IBM MarketScan® claims database population-based cohort (n = 22,967) of patients with UC (October 2010 to September 2015) to identify a UC trial-like cohort treated with tumor necrosis factor inhibitors (TNFi; n = 6366) to compare with the tofacitinib UC clinical trial cohort (n = 1157).. Incidence rates (events per 100 patient-years; [95% confidence interval]) in the UC trial-like cohort were as follows: serious infections, 3.33 (2.73-4.02); opportunistic infections (OIs; excluding herpes zoster [HZ]), 1.45 (1.06-1.93); HZ, 1.77 (1.34-2.29); malignancies (excluding nonmelanoma skin cancer [NMSC]), 0.63 (0.43-0.90); NMSC, 1.69 (1.35-2.10); major adverse cardiovascular events (MACE), 0.51 (0.31-0.79); pulmonary embolism (PE), 0.54 (0.30-0.89); deep vein thrombosis (DVT), 1.41 (1.00-1.93); and gastrointestinal perforations, 0.31 (0.16-0.54). Compared with the UC trial-like cohort, tofacitinib-treated patients had numerically lower incidence rates for serious infections (1.75 [1.27-2.36]), OIs (excluding HZ; 0.16 [0.04-0.42]), NMSC (0.78 [0.47-1.22]), PE (0.16 [0.04-0.41]), and DVT (0.04 [0.00-0.23]), and a higher rate for HZ (3.57 [2.84-4.43]); rates for malignancies (excluding NMSC), MACE, and gastrointestinal perforations were similar.. When acknowledging limitations of comparing claims data with controlled clinical trial data, incidence rates for HZ among TNFi-treated patients in the UC trial-like cohort were lower than in the tofacitinib UC clinical trial cohort; rates for serious infections, OIs, NMSC, PE, and DVT were numerically higher.. NCT00787202, NCT01465763, NCT01458951, NCT01458574, NCT01470612.

Topics: Colitis, Ulcerative; Humans; Neoplasms; Opportunistic Infections; Piperidines; Product Surveillance, Postmarketing; Pyrimidines; Randomized Controlled Trials as Topic

Topics: Adrenal Cortex Hormones; Colitis, Ulcerative; Herpesvirus 3, Human; Humans; Nocardia Infections; Opportunistic Infections; Piperidines; Pneumonia, Pneumocystis; Pyrimidines; Varicella Zoster Virus Infection; Virus Activation

We report tofacitinib efficacy and safety in Asia-Pacific patients who participated in the rheumatoid arthritis (RA) clinical development program.. This post-hoc analysis included pooled data from patients with RA in the Asia-Pacific region treated with tofacitinib with/without conventional synthetic disease-modifying antirheumatic drugs in Phase (P)1, 2, 3, and long-term extension (LTE) studies (one LTE ongoing; January 2016 data-cut). Efficacy was assessed over 24 months in patients who received tofacitinib 5 (N = 397) or 10 (N = 382) mg twice daily or placebo (N = 243) in three P2 and five P3 studies. Endpoints included American College of Rheumatology (ACR)20/50/70 responses, Disease Activity Score in 28 joints, erythrocyte sedimentation rate (DAS28-4[ESR]) and Clinical Disease Activity Index (CDAI) remission rates, and change from baseline in Health Assessment Questionnaire-Disability Index (∆HAQ-DI). Safety data pooled over 92 months from one P1, four P2, six P3, and two LTE studies for all tofacitinib doses (N = 1464) included incidence rates (IRs) (patients with events/100 patient-years) for adverse events (AEs) of special interest.. At month 3, patients receiving tofacitinib 5/10 mg twice daily improved vs placebo in ACR20 (69.2%/77.9% vs 27.5%), ACR50 (36.9%/44.4% vs 9.5%), and ACR70 (15.1%/22.4% vs 2.7%) responses, remission rates for DAS28-4(ESR) (8.5%/18.5% vs 2.6%) and CDAI (6.1%/12.3% vs 0.5%), and ∆HAQ-DI (-0.5/-0.6 vs -0.1); improvements were sustained through 24 months. IRs (95% CI) were 9.4 (8.5, 10.3) for serious AEs, 9.1 (8.3, 10.1) for discontinuations due to AEs, 3.7 (3.2, 4.3) for serious infections, 5.9 (5.2, 6.7) for herpes zoster, and 0.8 (0.6, 1.1) for malignancies (excluding non-melanoma skin cancer).. In Asia-Pacific patients, tofacitinib improved signs/symptoms over 24 months. Safety over 92 months was generally consistent with global tofacitinib studies; however, infection IRs were higher in Asia-Pacific patients.

Topics: Adult; Arthritis, Rheumatoid; Asia; Clinical Trials as Topic; Evidence-Based Medicine; Female; Humans; Janus Kinase Inhibitors; Male; Middle Aged; Neoplasms; Opportunistic Infections; Piperidines; Pyrimidines; Pyrroles; Recovery of Function; Remission Induction; Risk Factors; Time Factors; Treatment Outcome

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). To characterise the relative safety profile of tofacitinib to biologic disease-modifying antirheumatic drugs (bDMARDs), the accrued patient-years (pt-yrs) of exposure needed in an RA clinical trial programme to detect a potential increase in risk of specific adverse events (AEs) was determined. This case study/framework was constructed on the pt-yrs' accrual within pooled phase (P)1, P2 and P3, as well as long-term extension, studies of tofacitinib in RA (March 2015 data-cut) and published AE incidence rates for bDMARDs. Sample size calculations were based on a Poisson distribution to estimate pt-yrs' exposure required for 90 % probability that the lower bound of the 95 % confidence interval for tofacitinib/bDMARD would be >1, assuming that tofacitinib rates were 1.2×/1.5×/2.0× greater than comparator rates. AE rates for bDMARDs were derived from sources intended to optimise similarity with the tofacitinib database in terms of baseline characteristics, study duration and follow-up. Based on the tofacitinib exposure accrued (19,406 pt-yrs), data were sufficient (90 % probability) to detect potential differences over external bDMARD comparator rates in serious infections (≥1.2×), malignancies (excluding non-melanoma skin cancer [NMSC]), NMSC, major adverse cardiovascular events (MACE) and lymphoma (each ≥1.5×), as well as opportunistic infections and gastrointestinal perforations (≥2×), should they exist. This risk characterisation approach can support the comparative safety of new RA medications. To date, tofacitinib safety appears similar to approved published data from bDMARDs with respect to serious infections, malignancies (excluding NMSC), NMSC, MACE, lymphoma, opportunistic infections and gastrointestinal perforations.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Humans; Neoplasms; Opportunistic Infections; Piperidines; Pyrimidines; Pyrroles; Risk Assessment

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We report an integrated safety summary of tofacitinib from two phase I, nine phase II, six phase III and two long-term extension studies in adult patients with active RA.. Data were pooled for all tofacitinib-treated patients (data cut-off: 31 March 2015). Incidence rates (IRs; patients with event/100 patient-years) and 95% CIs are reported for adverse events (AEs) of interest.. 6194 patients received tofacitinib for a total 19 406 patient-years' exposure; median exposure was 3.4 patient-years. IR (95% CI) for serious AEs was 9.4 (9.0 to 9.9); IR for serious infections was 2.7 (2.5 to 3.0). IR for (all) herpes zoster was 3.9 (3.6 to 4.2); IR for disseminated or multidermatomal herpes zoster was 0.3 (0.2 to 0.4). IR for opportunistic infections (excluding tuberculosis) was 0.3 (0.2 to 0.4) and was 0.2 (0.1 to 0.3) for tuberculosis. IR for malignancies (excluding non-melanoma skin cancer (NMSC)) was 0.9 (0.8 to 1.0); NMSC IR was 0.6 (0.5 to 0.7). IR for gastrointestinal perforations was 0.1 (0.1 to 0.2). Analysis of IR for serious infections, herpes zoster and malignancies by 6-month intervals did not reveal any notable increase in IR with longer-duration tofacitinib exposure.. This analysis of tofacitinib exposure up to 8.5 years allowed estimation of safety events with improved precision versus previous tofacitinib reports. AEs were generally stable over time; no new safety signals were observed compared with previous tofacitinib reports.. NCT01262118, NCT01484561, NCT00147498, NCT00413660, NCT00550446, NCT00603512, NCT00687193, NCT01164579, NCT00976599, NCT01059864, NCT01359150, NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385, NCT01039688, NCT00413699, NCT00661661; Results.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Arthritis, Rheumatoid; Clinical Trials as Topic; Female; Herpes Zoster; Humans; Immunocompromised Host; Incidence; Infections; Male; Middle Aged; Neoplasms; Opportunistic Infections; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Time Factors; Tuberculosis; Young Adult