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Infections in Baricitinib Clinical Trials for Patients with Active Rheumatoid Arthritis

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Infections in Baricitinib Clinical Trials for Patients with Active Rheumatoid Arthritis Rheumatoid arthritis Ann Rheum Dis: first published as 10.1136/annrheumdis-2019-216852 on 11 August 2020. Downloaded from CLINICAL SCIENCE Infections in baricitinib clinical trials for patients with active rheumatoid arthritis Kevin L Winthrop ,1 Masayoshi Harigai ,2 Mark C Genovese ,3 Stephen Lindsey,4 Tsutomu Takeuchi,5 Roy Fleischmann ,6 John D Bradley,7 Nicole L Byers,7 David L Hyslop,7 Maher Issa,7 Atsushi Nishikawa,8 Terence P Rooney,7 Sarah Witt,7 Christina L Dickson,7 Josef S Smolen,9 Maxime Dougados10 Handling editor David S ABStract Key messages Pisetsky Objectives To evaluate the incidence of infection in patients with active rheumatoid arthritis (RA) treated ► Additional material is What is already known about this subject? published online only. To view with baricitinib, an oral selective Janus kinase (JAK)1 and ► Rheumatoid arthritis (RA) is a systemic please visit the journal online JAK2 inhibitor. autoimmune disease associated with an (http:// dx. doi. org/ 10. 1136/ Methods Infections are summarised from an integrated elevated risk of infection, which can be annrheumdis- 2019- 216852). database (8 phase 3/2/1b clinical trials and 1 long- term caused by the pathobiology of the disease, extension (LTE)) with data to 1 April 2017. The ’all- bari- For numbered affiliations see chronic comorbid conditions and use of RA’ analysis set included patients who received any end of article. immunosuppressive therapies, such as biologic baricitinib dose. Placebo comparison was based on six (b), conventional synthetic and targeted Correspondence to studies with 4 mg and placebo to week 24, including synthetic (ts) disease-modifying antirheumatic Dr Kevin L Winthrop, Oregon four trials with 2 mg (placebo-controlled set). Dose– drugs (DMARDs). Health and Science University, response assessment was based on four studies with Portland, OR 97201, USA; 2 mg and 4 mg, including LTE data (2–4 mg extended winthrop@ ohsu. edu What does this study add? set). This study provides data to inform the Received 17 December 2019 Results There were 3492 patients who received ► understanding of risk of infection in patients Revised 29 April 2020 baricitinib for 7860 patient-years (PY) of exposure Accepted 13 May 2020 with RA and the use of the emerging class of (median 2.6 years, maximum 6.1 years). Treatment- tsDMARDs, in particular Janus kinase (JAK) emergent infections were higher for baricitinib versus inhibitors. placebo (exposure- adjusted incidence rate (IR)/100 PY: Increased rates of treatment- emergent placebo 75.9, 2 mg 84.0 (p not significant), 4 mg 88.4 ► Watch Video infections including herpes zoster (HZ) were (p≤0.001)). The IR of serious infection was similar for www. ard. bmj. com observed in patients with RA treated with baricitinib versus placebo and stable over time (all-bari- baricitinib, similar to that observed for other RA IR 3.0/100 PY). There were 11 cases of tuberculosis JAK inhibitors. (all- bari- RA IR 0.1/100 PY); all occurred with 4 mg in http://ard.bmj.com/ The incidence of serious infection did not endemic regions. Herpes zoster (HZ) IR/100 PY was ► increase with baricitinib versus placebo in higher for baricitinib versus placebo (placebo 1.0, the 24- week randomised, controlled period 2 mg 3.1 (p not significant), 4 mg 4.3 (p≤0.01)); rates but was similar to that reported in other remained elevated and stable over time (all- bari- RA 3.3). recent tsDMARD and bDMARD development Opportunistic infections, including multidermatomal HZ, programmes with both short- term and long- were infrequent in the baricitinib programme (all- bari- RA term data. IR 0.5/100 PY). on September 29, 2021 by guest. Protected copyright. There were 11 cases of tuberculosis reported Conclusions Increased rates of treatment-emergent ► within the baricitinib RA programme; infections including HZ were observed in patients with all occurred with 4 mg and in endemic RA treated with baricitinib, consistent with baricitinib’s regions. Opportunistic infections, including immunomodulatory mode of action. multidermatomal HZ, were infrequent in the programme. © Author(s) (or their INTRODUCTION employer(s)) 2020. Re- use Rheumatoid arthritis (RA) is a systemic autoimmune inhibition is associated with increased infection.6 7 permitted under CC BY-­NC. No disease associated with an elevated risk of infec- Further analyses of additional and long- term data commercial re- use. See rights tion,1 2 which can be caused by the pathobiology of and permissions. Published are needed to understand this association and char- by BMJ. the disease, chronic comorbid conditions and use of immunosuppressive therapies, including conven- acterise the risk versus benefit. To cite: Winthrop KL, tional synthetic (cs) and biological (b) disease- Baricitinib, an oral selective JAK1 and JAK2 8 Harigai M, modifying antirheumatic drugs (DMARDs).1–4 inhibitor, demonstrated significant clinical effi- Genovese MC, et al. cacy in phase 3 RA trials.9–12 Pooled data from Ann Rheum Dis Epub ahead Within the emerging class of targeted synthetic of print: [please include Day DMARDs (tsDMARDs), Janus kinase (JAK) inhib- these trials, including a long- term extension (LTE), Month Year]. doi:10.1136/ itors target cytokine signalling pathways implicated inform the safety profile for baricitinib13; our objec- annrheumdis-2019-216852 in RA pathogenesis.5 Like other RA therapies, JAK tive was to further evaluate overall infection risk Winthrop KL, et al. Ann Rheum Dis 2020;0:1–8. doi:10.1136/annrheumdis-2019-216852 1 Rheumatoid arthritis Ann Rheum Dis: first published as 10.1136/annrheumdis-2019-216852 on 11 August 2020. Downloaded from Patients who completed the phase 3 trials and phase 2 trial Key messages NCT01185353 were eligible for the LTE. Patients randomised to 2 mg and not rescued in the originating study continued on How might this impact on clinical practice or future 2 mg in the LTE; all others received 4 mg. Patients who received developments? 4 mg for ≥15 months without rescue and achieved sustained As with biological DMARD therapy, screening and treatment ► low disease activity (Clinical Disease Activity Index (CDAI) for latent tuberculosis infection should be employed prior to score ≤10) or remission (CDAI score ≤2.8) were blindly reran- starting baricitinib. domised to 4 mg or 2 mg. Although data on HZ vaccination in a small subgroup did not ► Methods for infection screening and monitoring processes, demonstrate a protective effect, current treatment guidelines and case identification, description and review are included in recommend HZ vaccination prior to initiation of a Janus the online supplementary methods and table S2. kinase inhibitor, particularly in RA patients ≥50 years at high risk for infection. ► Long- term population- based studies are necessary to better Patient and public involvement understand the comparative real- world risk of baricitinib and This research was done without patient and public involvement. targeted synthetic DMARD therapies in RA. Analysis sets Baricitinib RA clinical trials, including treatment groups, datasets with baricitinib, with a focus on serious infection, tuberculosis and prior RA treatments, are described in online supplementary (TB), herpes zoster (HZ) and opportunistic infection (OI). table S1. 1. ‘Placebo controlled’ includes data for patients in phase 2 and P ATIENTS AND METHODS 3 trials randomised to placebo, 2 mg (four trials) or 4 mg (six Study designs and patients trials) through 24 weeks of treatment or end of the placebo- We present data from eight double- blind randomised trials (four controlled period with data censored at rescue. phase 3, three phase 2 and one phase 1b) and one ongoing phase 2. ‘2–4 mg extended’ includes data for patients randomised to 3 LTE trial, with data up to 6 years (as of 1 April 2017) (online 2 mg or 4 mg from four trials (phase 2 and 3), with data from supplementary table S1). Patients were ≥18 years with active the LTE up to 6 years. Data were censored at rescue or dose RA, including those naive to DMARDs, csDMARD-inadequate change. responders (csDMARD- IRs), and bDMARD- IRs. Exclusion 3. ‘All- bari- RA’ includes all available data for all patients who criteria included current or recent clinically serious infection received ≥1 dose of baricitinib without censoring for rescue requiring antimicrobial treatment (including active or untreated or dose change, with data up to 6 years. latent tuberculosis infection (LTBI)), immunocompromised patients (with an unacceptable risk for participation as deter- Statistical analysis mined by the investigator) and selected laboratory abnormalities. Each baricitinib dose was compared with placebo using the Baricitinib doses ranged from 1 to 15 mg daily, with 2 mg and Cochran- Mantel- Haenszel test stratified by study. For adverse 4 mg daily doses in phase 3 trials and LTE. All patients provided events including treatment- emergent (TE) events, exposure- written informed consent. adjusted incidence rates (EAIRs) were calculated as the number http://ard.bmj.com/ Table 1 Overview of treatment- emergent infections, serious infection, TB, HZ, opportunistic infection and infection leading to death Placebo- controlled (to Week 24)* 2–4 mg- extended† All- bari- RA Placebo Bari 2 mg§ Bari 4 mg Bari 2 mg Bari 4 mg All- bari- RA N=1070 N=479 N=997 N=479 N=479 N=3492¶ PYE=393.8‡ PYE=185.8‡ PYE=409.4‡ PYE=604.9‡ PYE=645.9‡ PYE=7860.3‡ on September 29, 2021 by guest. Protected copyright. TE infections, n (EAIR) 299 (75.9) 156 (84.0) 362 (88.4)*** 230 (38.0) 266 (41.2)
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