Long-term safety of tofacitinib up to 9.5 years: a comprehensive integrated analysis of the rheumatoid arthritis clinical development programme

Cohen, Stanley; Tanaka, Yoshiya; Mariette, Xavier; Curtis, Jeffrey R.; Lee, Eun Bong; Nash, Peter; Winthrop, Kevin; Charles‐Schoeman, Christina; Wang, Lisy; Chen, Connie; Kwok, Kenneth; Biswas, Pinaki; Shapiro, Allan P.; Madsen, Ann; Wollenhaupt, J.

doi:10.1136/rmdopen-2020-001395

Cited by 131 publications

(146 citation statements)

References 68 publications

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“…The safety profile of tofacitinib in RA has been mainly characterized in extensive RCTs, LTE studies (ORAL SEQUEL up to 9.5 years), and the phase IV Oral Surveillance trial [ 11 ]. The summary of safety results from studies in the tofacitinib clinical development program is shown in Table 1 .…”

Section: Overall Safety Profilementioning

confidence: 99%

“…HZ and pneumonia were the infections that most frequently led to the discontinuation of the treatment. Cohen et al [ 11 ], in an ISS of 9.5 years of experience with tofacitinib and 7061 patients (22,875 PYs of exposure), described an incidence rate (IR) for SAEs of 9.0 [95% confidence interval, (CI): 8.6–9.4]. Wollenhaupt et al [ 12 ], in a LTE study of up to 9.5 years of experience, showed that 52% of patients (from a total of 4481) discontinued the treatment with tofacitinib, 24% due to AEs and 4% because of inadequate response.…”

Section: Overall Safety Profilementioning

confidence: 99%

“…In patients receiving tofacitinib as combination therapy, the IRs were higher with tofacitinib 10 mg BID versus 5 mg BID for all serious infections (3.0 versus 1.9, respectively). In the ISS, the IR for serious infection was 2.5 (95% CI 2.3–2.7), 2.3 (95% CI 2.1–2.5) when excluding HZ [ 11 ]. The IRs gradually reduced over time with longer exposure to tofacitinib.…”

Section: Overall Safety Profilementioning

confidence: 99%

“…Data obtained during the tofacitinib RA clinical development program derive from randomized controlled trials (RCTs) of 6–24-month duration and long-term extension (LTE) studies [ 3 – 11 ]. For instance, the efficacy of tofacitinib and its safety profile were studied in the ORAL program, which consisted of diverse phase III RCTs using a variety of treatment schemes with tofacitinib, such as monotherapy, MTX and other DMARD combinations, comparisons with placebo or adalimumab (ADA) [ 5 ] and in different RA populations such as MTX-naïve patients or MTX- and bDMARD-insufficient responders [ 3 – 10 ].…”

Section: Introductionmentioning

confidence: 99%

“…One of these studies shows the sustained efficacy and consistent safety profile of tofacitinib for > 9.5 years of treatment [ 12 ]. Integrated safety summary (ISS) data (compiling all data from phase I, II, III, IV trials and LTE studies) have additionally provided a complete view of data across the development program for up to 9.5 years and involved > 7061 patients and 22,875 patient-years (PYs) of exposure [ 11 ]. A phase IV clinical trial, ORAL Surveillance, in a special population subgroup of > 4300 patients [> 50 years old, with at least 1 cardiovascular (CV) risk factor and followed-up for at least 3 years] was performed as an FDA requirement to study the safety profile of RA patients treated with MTX and tofacitinib 5 mg and 10 mg versus anti-TNF (clinicaltrials.gov #NCT02092467) [ 1 ].…”

Section: Introductionmentioning

confidence: 99%

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Update on the Safety Profile of Tofacitinib in Rheumatoid Arthritis from Clinical Trials to Real-World Studies: A Narrative Review

et al. 2020

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Tofacitinib is approved for the treatment of moderate to severe active rheumatoid arthritis (RA) in adult patients who do not respond adequately or are intolerant to one or more disease-modifying anti-rheumatic drugs. The tofacitinib RA clinical development program included randomized controlled trials of 6-24month duration and long-term extension studies with [ 7061 patients and 22,875 patientyears of exposure. To date, there are no data from other randomized studies in patients with cardiovascular risk factors comparing the longterm safety of a JAK inhibitor versus an anti-TNF. Real-world studies are necessary to complete the body of evidence supporting the effectiveness and safety of a therapeutic agent. In the case of tofacitinib, real-world data derive from health insurance claims databases, registries (US Corrona Registry, Swiss Registry, and others), national pharmacovigilance programs, and hospital databases (case series). The present article provides complete and up-to-date information on the safety profile of tofacitinib in RA, from clinical trials to real-world studies. Tofacitinib has demonstrated a consistent safety profile during up to 9.5 years of experience in randomized controlled trials and long-term extension studies. Real-world evidence has not added new safety issues with respect to those found in the clinical program. In general, the safety profile of tofacitinib is consistent with that of biologic disease-modifying anti-rheumatic drugs, with an increased risk of herpes zoster that seems to be a class effect of Janus kinase inhibitors. The continuous follow-up of therapeutic agents to treat rheumatoid arthritis is needed to adequately establish the safety profile for new mechanisms of action and potential risks associated with their longer term use.

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Section: Overall Safety Profilementioning

confidence: 99%

Section: Overall Safety Profilementioning

confidence: 99%

Section: Overall Safety Profilementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Update on the Safety Profile of Tofacitinib in Rheumatoid Arthritis from Clinical Trials to Real-World Studies: A Narrative Review

et al. 2020

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Effectiveness and Safety of Tofacitinib in Canadian Patients With Rheumatoid Arthritis: Primary Results From a Prospective Observational Study

Khraishi

Choquette²,

Lisnevskaia

et al. 2022

Arthritis Care & Research

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Objective. The Canadian Tofacitinib for Rheumatoid Arthritis Observational (CANTORAL) is the first Canadian prospective, observational study assessing tofacitinib. The objective was to assess effectiveness and safety for moderate to severe rheumatoid arthritis (RA). Coprimary and secondary outcomes are reported from an interim analysis.Methods. Patients initiating tofacitinib from October 2017 to July 2020 were enrolled from 45 Canadian sites. Coprimary outcomes (month 6) included the Clinical Disease Activity Index (CDAI)-defined low disease activity (LDA) and remission. Secondary outcomes (to month 18) included the CDAI and the 4-variable Disease Activity Score in 28 joints (DAS28) using the erythrocyte sedimentation rate (ESR)/C-reactive protein (CRP) level to define LDA and remission; the proportions of patients achieving mild pain (visual analog scale <20 mm), and moderate (≥30%) and substantial (≥50%) pain improvements; and the proportions of patients achieving a Health Assessment Questionnaire disability index (HAQ DI) score greater or equal to normative values (≤0.25) and a HAQ DI score greater or equal to minimum clinically important difference (MCID) (≥0.22). Safety was assessed to month 36.Results. Of 504 patients initiating tofacitinib, 44.4% received concomitant methotrexate. At month 6, 52.9% and 15.4% of patients were in CDAI-defined LDA and remission, respectively; a similar proportion of patients achieved outcomes by month 3 (first post-baseline assessment). By month 3, 27.2% and 41.7% of patients, respectively, were in DAS28-ESRdefined LDA and DAS28-CRP <3.2; 14.7% and 25.8% achieved DAS28-ESR remission and DAS28-CRP <2.6. By month 3, mild pain and moderate and substantial pain improvements occurred in 29.6%, 55.6%, and 42.9% of patients, respectively; 19.9% and 53.7% of patients achieved a HAQ DI score greater than or equal to normative values and a HAQ DI score greater than or equal to MCID, respectively. Outcomes were generally maintained to month 18. Incidence rates (events per 100 patientyears) for treatment-emergent adverse events (AEs), serious AEs, and discontinuations due to AEs were 126.8, 11.9, and 14.5, respectively, and AEs of special interest were infrequent.Conclusion. Tofacitinib was associated with early and sustained improvement in RA signs and symptoms in realworld patients. Effectiveness and safety were consistent with the established tofacitinib clinical profile.

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A Decade of JAK Inhibitors: What Have We Learned and What May Be the Future?

Liu

Kieltyka

Fleischmann

et al. 2021

Arthritis & Rheumatology

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The discovery of cytokines and their role in immune and inflammatory disease led to the development of a plethora of targeted biologic therapies. Later, efforts to understand mechanisms of cytokine signal transduction led to the discovery of JAKs, which themselves were quickly identified as therapeutic targets. It has been a decade since the first JAK inhibitors (jakinibs) were approved, and there are now 9 jakinibs approved for the treatment of rheumatic, dermatologic, hematologic, and gastrointestinal indications, along with emergency authorization for COVID-19. In this review, we will summarize relevant discoveries that led to first-generation jakinibs and review their efficacy and safety as demonstrated in pivotal clinical studies. We will discuss the next generation of more selective jakinibs, along with agents that target kinase families beyond JAKs. Finally, we will reflect on both the opportunities and challenges ahead as we enter the second decade of the clinical use of jakinibs.

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Long-term safety of tofacitinib up to 9.5 years: a comprehensive integrated analysis of the rheumatoid arthritis clinical development programme

Cited by 131 publications

References 68 publications

Update on the Safety Profile of Tofacitinib in Rheumatoid Arthritis from Clinical Trials to Real-World Studies: A Narrative Review

Update on the Safety Profile of Tofacitinib in Rheumatoid Arthritis from Clinical Trials to Real-World Studies: A Narrative Review

Effectiveness and Safety of Tofacitinib in Canadian Patients With Rheumatoid Arthritis: Primary Results From a Prospective Observational Study

A Decade of JAK Inhibitors: What Have We Learned and What May Be the Future?

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