Tofacitinib, an oral Janus kinase inhibitor, for the treatment of Latin American patients with rheumatoid arthritis: Pooled efficacy and safety analyses of Phase 3 and long-term extension studies (original) (raw)
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Reumatología Clínica, 2017
OBJECTIVES: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We characterized efficacy and safety of tofacitinib in Mexican patients from RA Phase 3 and long-term extension (LTE) studies. METHODS: Data from Mexican patients with RA and an inadequate response to disease-modifying antirheumatic drugs (DMARDs) were taken from four Phase 3 studies (pooled across studies) and one open-label LTE study of tofacitinib. Patients received tofacitinib 5 or 10mg twice daily, adalimumab (one Phase 3 study) or placebo (four Phase 3 studies) as monotherapy or in combination with conventional synthetic DMARDs. Efficacy up to Month 12 (Phase 3) and Month 36 (LTE) was assessed by American College of Rheumatology 20/50/70 response rates, Disease Activity Score (erythrocyte sedimentation rate), and Health Assessment Questionnaire-Disability Index. Safety, including incidence rates (IRs; patients with events/100 patient-years) for adverse events (AEs) of special interest, was assessed throughout the studies. RESULTS: 119 and 212 Mexican patients were included in the Phase 3 and LTE analyses, respectively. Tofacitinib-treated patients in Phase 3 had numerically greater improvements in efficacy responses versus placebo at Month 3. Efficacy was sustained in Phase 3 and LTE studies. IRs for AEs of special interest were similar to those with tofacitinib in the global and Latin American RA populations. CONCLUSIONS: In Mexican patients from the tofacitinib global RA program, tofacitinib efficacy was demonstrated up to Month 12 in Phase 3 studies and Month 36 in the LTE study, with a safety profile consistent with tofacitinib global population.
International Journal of Rheumatic Diseases, 2016
Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Here, the safety and efficacy data from five Phase 2 studies of tofacitinib in patients with RA are summarized. Tofacitinib 1-30 mg twice daily was investigated, as monotherapy and in combination with methotrexate, in patients with RA. Tofacitinib 20 mg once daily was investigated in one study. Tofacitinib 5 and 10 mg twice daily were selected for investigation in Phase 3 studies; therefore, the efficacy and safety of tofacitinib 5 and 10 mg twice daily in Phase 2 studies are the focus of this review. Tofacitinib ≥ 5 mg twice daily was efficacious in a dose-dependent manner, with statistically significant and clinically meaningful reductions in the signs and symptoms of RA and patient-reported outcomes. The safety profile was consistent across studies. The efficacy and safety profile of tofacitinib in Phase 2 studies supported its further investigation and the selection of tofacitinib 5 mg twice daily and tofacitinib 10 mg twice daily for evaluation in Phase 3 studies.
Arthritis Care & Research, 2017
Objective. Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We compared patient-reported outcomes (PROs) in patients with RA treated with tofacitinib or placebo in combination with conventional disease-modifying antirheumatic drugs (DMARDs). Methods. In a 12-month, phase III randomized controlled trial (ORAL Sync), patients (n 5 795) with active RA and previous inadequate response to therapy with ‡1 conventional or biologic DMARD were randomized 4:4:1:1 to tofacitinib 5 mg twice daily (BID), tofacitinib 10 mg BID, placebo advanced to 5 mg BID, or placebo to 10 mg BID, in combination with stable background DMARD therapy. PROs included patient global assessment of arthritis (PtGA), patient assessment of arthritis pain (Pain), physical function (Health Assessment Questionnaire disability index [HAQ DI]), health-related quality of life (Short Form 36 health survey [SF-36]), fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-F]), and sleep (Medical Outcomes Study Sleep [MOS Sleep]). Results. At month 3, statistically significant improvements from baseline versus placebo were reported in PtGA, Pain, HAQ DI, all 8 SF-36 domains, FACIT-F, and MOS Sleep with tofacitinib 10 mg BID, and in PtGA, Pain, HAQ DI, 7 SF-36 domains, FACIT-F, and MOS Sleep with tofacitinib 5 mg BID. Improvements were sustained to month 12. Significantly more tofacitinib-treated patients reported improvements of greater than or equal to the minimum clinically important differences at month 3 versus placebo in all PROs, except the SF-36 role-emotional domain (significant for tofacitinib 10 mg BID). Conclusion. Patients with active RA treated with tofacitinib combined with background conventional DMARD therapy reported sustained, significant, and clinically meaningful improvements in PROs versus placebo. ClinicalTrials.gov identifier: NCT00856544.
Annals of Internal Medicine, 2013
Background: Many patients with rheumatoid arthritis (RA) do not achieve adequate and safe responses with disease-modifying antirheumatic drugs (DMARDs). Tofacitinib is a novel, oral, Janus kinase inhibitor that treats RA. Objective: To evaluate the efficacy and safety of tofacitinib in combination with nonbiologic DMARDs. Design: 1-year, double-blind, randomized trial (ClinicalTrials.gov: NCT00856544). Setting: 114 centers in 19 countries. Patients: 792 patients with active RA despite nonbiologic DMARD therapy. Intervention: Patients were randomly assigned 4:4:1:1 to oral tofacitinib, 5 mg or 10 mg twice daily, or placebo advanced to tofacitinib, 5 mg or 10 mg twice daily. Measurements: Primary end points were 20% improvement in American College of Rheumatology (ACR20) criteria; Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate (DAS28-4[ESR]) of less than 2.6; DAS28-4(ESR)defined remission, change in Health Assessment Questionnaire Disability Index (HAQ-DI) score, and safety assessments. Results: Mean treatment differences for ACR20 response rates (month 6) for the 5-mg and 10-mg tofacitinib groups compared with the combined placebo groups were 21.2% (95% CI, 12.2% to 30.3%; P Ͻ 0.001) and 25.8% (CI, 16.8% to 34.8%; P Ͻ 0.001), respectively. The HAQ-DI scores (month 3) and DAS28-4(ESR) less than 2.6 response rates (month 6) were also superior in the tofacitinib groups versus placebo. The incidence rates of serious adverse events for patients receiving 5-mg tofacitinib, 10-mg tofacitinib, or placebo were 6.9, 7.3, or 10.9 events per 100 patientyears of exposure, respectively. In the tofacitinib groups, 2 cases of tuberculosis, 2 cases of other opportunistic infections, 3 cardiovascular events, and 4 deaths occurred. Neutrophil counts decreased, hemoglobin and low-and high-density lipoprotein cholesterol levels increased, and serum creatinine levels had small increases in the tofacitinib groups. Limitations: Placebo groups were smaller and of shorter duration. Patients received primarily methotrexate. The ability to assess drug combinations other than tofacitinib plus methotrexate was limited. Conclusion: Tofacitinib improved disease control in patients with active RA despite treatment with nonbiologic DMARDs, primarily methotrexate.
Journal of Pharmacology and Experimental Therapeutics, 2013
A critical piece in the translation of preclinical studies to clinical trials is the determination of dosing regimens that allow maximum therapeutic benefit with minimum toxicity. The preclinical pharmacokinetic (PK)/pharmacodynamic (PD) profile of tofacitinib, an oral Janus kinase (JAK) inhibitor, in a mouse collageninduced arthritis (mCIA) model was compared with clinical PK/PD data from patients with rheumatoid arthritis (RA). Preclinical evaluations included target modulation and PK/PD modeling based on continuous subcutaneous infusion or oral once-or twice-daily (BID) dosing paradigms in mice. The human PK/PD profile was obtained from pooled data from four phase 2 studies in patients with RA, and maximal effect models were used to evaluate efficacy after 12 weeks of tofacitinib treatment (1-15 mg BID). In mCIA, the main driver of efficacy was inhibition of cytokine receptor signaling mediated by JAK1 heterodimers, but not JAK2 homodimers, and continuous daily inhibition was not required to maintain efficacy. Projected efficacy could be predicted from total daily exposure irrespective of the oral dosing paradigm, with a total steady-state plasma concentration achieving 50% of the maximal response (C ave50 ) of~100 nM. Tofacitinib potency (ED 50 ) in clinical studies was ∼3.5 mg BID (90% confidence interval: 2.3, 5.5) or total C ave50 of ∼40 nM, derived using Disease Activity Scores from patients with RA. The collective clinical and preclinical data indicated the importance of C ave as a driver of efficacy, rather than maximum or minimum plasma concentration (C max or C min ), where C ave50 values were within ∼2-fold of each other.
The 6-month drug survival rate in patients with rheumatoid arthritis treated with tofacitinib
Annals of Medical Research, 2021
Aim: Rheumatoid arthritis (RA) is a progressive, inflammatory, autoimmune disease that particularly affects the joints. Tofacitinib is the first oral Janus kinase inhibitor approved for RA treatment. We aimed to analyze the 6-month drug survival rate and factors affecting the discontinuation of tofacitinib in RA patients. Materials and Methods: Age, gender, rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) levels, whether to continue treatment tofacitinib, if treatment is not continued what treatment is applied, use of biological agent before tofacitinib treatment were retrospectively recorded from the patient data. Results: 30 RA patients included in the study (29 female, 1 male) with a mean age of 50.5 ± 11.3 years. At the 6th month of treatment of tofacitinib, the drug survival rates were 50%. There was no significant difference between CCP positive and negative patients as well as between RF positive and negative patients in terms of drug survival rates (p = 0.92 and p = 0.90, respectively). The drug survival rates were alike in tofacitinib monotherapy and combined therapy of tofacitinib with any conventional DMARD (p = 0.36). The tofacitinib survival rates were similar in biologically naïve patients and in patients who had received at least one previous biological DMARD (p = 0.70). Conclusion: Half of the RA patients receiving tofacitinib treatment continue their treatment at the 6th month. The drug survival rate was not associated with co-treatment with conventional DMARD, auto-antibody positivities, and previously used biological DMARD therapy. These findings support that tofacitinib shows similar efficacy when used as combined or monotherapy, in seronegative or seropositive patients, and in biologic resistant or naive patients.
Biologics: Targets and Therapy
Tofacitinib is recommended for treatment of rheumatoid arthritis (RA) in patients with moderate to severe disease activity, but there is not enough evidence on its effectiveness after conventional DMARDs vs its use after biologics. The aim was evaluating the effectiveness of tofacitinib in RA as first-line treatment (after conventional DMARDs) in a real-life setting in Colombian (Latin-American) patients. Patients and Methods: Retrospective cohort study conducted at a specialized center for RA management. A complete statistical analysis was performed to compare the values of the change in the DAS28 at months 3, 6, and 12 in both treatment groups. Results: A total of 152 RA patients who received tofacitinib: first-line 85 patients (55.9%) after failure on conventional DMARDs or second-line 67 patients (44.1%) after failure on biologic DMARDs. Comparative analysis of response to treatment showed a reduction in DAS28 at 3, 6, and 12 months in both study groups without statistical differences, but a higher proportion of firstline patients achieved remission (45% vs 23%). Nonresponse at three months were associated with no response at six months of follow-up. Baseline DAS28 was significantly associated with response at 12 months (OR: 1.87, 95%CI: 1.06-3.30, p-value 0.028). In second-line patients, response to tofacitinib was not related to number of biologic DMARDs previously used. Conclusion: Tofacitinib is an effective treatment option for patients with RA, maybe better after conventional DMARDs than after biologic therapy failure. Further studies are required to determine the role of tofacitinib in different lines of RA treatment and in other groups of patients.
Annals of the rheumatic diseases, 2017
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 (N...
Effectiveness and safety of tofacitinib in rheumatoid arthritis: a cohort study
Arthritis research & therapy, 2018
Tofacitinib is the first oral Janus kinase inhibitor approved for the treatment of rheumatoid arthritis (RA). We compared the effectiveness and safety of tofacitinib, disease-modifying antirheumatic drugs (DMARDs), tumor necrosis factor inhibitors (TNFi), and non-TNF biologics in patients with RA previously treated with methotrexate. We used MarketScan® databases (2011-2014) to study methotrexate-exposed patients with RA who were newly prescribed tofacitinib, DMARDs other than methotrexate, and biologics. The date of first prescription was defined as the cohort entry. The therapy was considered effective if all of the following criteria from a claims-based algorithm were achieved at the first year of follow-up: high adherence, no biologic or tofacitinib switch or addition, no DMARD switch or addition, no increase in dose or frequency of index drug, no more than one glucocorticoid joint injection, and no new/increased oral glucocorticoid dose. The safety outcome was serious infection...