May 22
Tardella M, Di Carlo M, Carotti M, Ceccarelli L, Giovagnoni A, Salaffi F.
Inflammopharmacology. 2022. Epub ahead of print doi: 10.1007/s10787-022-00936-w
This study of the effectiveness of JAKinibs or abatacept in patients with RA-interstitial lung disease (RA-ILD) shows that treatment is related to stability or improvement of RA-ILD in over 80% of patients. Often associated with a worse prognosis and mortality, pulmonary involvement in RA has been the subject of increasing interest in recent years, with RA-ILD occurring in up to 67% of patients. However, little information and limited clinical data can make the treatment and management of RA-IL...
March 22
Strand V, Kaeley GS, Bergman MJ, Gladman DD, Coates LC, Sherif B, Hur P, Parikh B, Gilloteau I, Mease PJ.
Lancet. 2022. Epub ahead of print
Predefined analysis of FUTURE 5, the largest Phase 3 randomised trial of secukinumab in patients with PsA to date, demonstrates that secukinumab results in early, statistically significant, clinically meaningful, sustained improvements in PROs across all doses, compared with placebo. The fully human anti-interleukin 17A monoclonal antibody, secukinumab has shown clinical and radiographical efficacy in patients with PsA, yet the clinical significance of improvements across a wide variety of PROs...
Fleischmann R, Mysler E, Bessette L, Peterfy CG, Durez P, Tanaka Y, Swierkot J, Khan N, Bu X, Li Y, Song IH.
RMD Open. 2022;8(1):e002012 doi: 10.1136/rmdopen-2021-002012
Upadacitinib continues to show consistently better clinical responses, compared with adalimumab, through 3 years, including rates of remission and low disease activity, physical function and pain severity. Following the favourable upadacitinib efficacy data seen in the SELECT-COMPARE study at 72 weeks, Fleischmann, et al. assessed the long-term safety and efficacy of upadacitinib versus adalimumab over 3 years in the long-term extension of this study, with promising results.
Barbulescu A, Askling J, Chatzidionysiou K, Forsblad-d'Elia H, Kastbom A, Lindström U, Turesson C, Frisell T.
Rheumatology (Oxford). 2022. Epub ahead of print doi: 10.1093/rheumatology/keac068
Data from the Swedish Rheumatology Quality Register and Swedish Registries, show a higher treatment retention and overall equivalent or better treatment response on baricitinib, compared with bDMARDs or tofacitinib, but no statistically significant differences between tofacitinib and bDMARDs. In this largest population-based study to date, comparing RA patients initiating baricitinib, tofacitinib or bDMARDs, Barbulescu, et al. help to fill some of the current knowledge gaps surrounding the effic...
February 22
Mueller RB, Schulze-Koops H, Furst DE, Cohen SB, Kwok K, Wang L, Killeen T, von Kempis J.
Clin Rheumatol. 2022 Jan 1. Epub ahead of print doi: 10.1007/s10067-021-05908-z
Post-hoc analysis shows that dosing up from tofacitinib 5 to 10 mg BID is associated with improved efficacy for up to 12 months, versus staying on 5 mg BID, and dosing down from 10 to 5 mg BID is not generally associated with a significant loss of efficacy. Although clinical trials have generally shown no significant differences, in terms of efficacy and safety, when switching tofacitinib dose up or down, these per-protocol switches are not directly informative for clinical decision-making in da...
January 22
Pope JE, Lee YC, Curtis JR, Mo D, Xie L, Dickson CL, Schlichting DE, Cardoso A, Simon LS, Taylor PC.
ACR Open Rheumatol. 2021. Epub ahead of print. doi: 10.1002/acr2.11380
This post hoc analysis shows that pain reduction was similar between opioid users and nonusers with baricitinib 2 mg and 4 mg, but not adalimumab. Use of opioids to treat RA-related pain has increased, yet long-term use has been associated with reduced efficacy and safety concerns. In addition, the misuse of opioids has resulted in a public health crisis in the United States and highlights the need for safe, effective nonaddictive alternatives for pain management. As such, Pope, et al. assessed...
December 21
Deodhar A, Sliwinska-Stanczyk P, Xu H, Baraliakos X, Gensler LS, Fleishaker D, Wang L, Wu J, Menon S, Wang C, Dina O, Fallon L, Kanik KS, van der Heijde D.
Ann Rheum Dis. 2021 Apr 27;80(8):1004–13.
A Phase 3 study assesses the efficacy and safety of tofacitinib in adults with active AS. Deodhar, et al. found that ASAS20 and ASAS40 response rate significantly increased with tofacitinib 5 mg BID versus placebo at Week 16, with improvements maintained to Week 48. There were no new safety signals detected over the course of the study.
Ruperto N, Brunner HI, Synoverska O, Ting TV, Mendoza CA, Spindler A, et al.
Lancet. 2021;398(10315):1984–96
Pivotal trial data show that tofacitinib is an effective treatment in patients with polyarticular course juvenile idiopathic arthritis (pJIA). New oral therapies are particularly relevant for children and adolescents, who might prefer to avoid injections. To this end, Ruperto, et al. assessed the efficacy and safety of tofacitinib versus placebo in patients with pJIA (N=225). They observed a JIA flare rate at Week 44 of 29% and 53% for tofacitinib and placebo, respectively. Safety results were s...
November 21
McInnes IB, Szekanecz Z, McGonagle D, Maksymowych WP, Pfeil A, Lippe R, Song IH, Lertratanakul A, Sornasse T, Biljan A, Deodhar A.
Rheumatology (Oxford). 2021. Epub ahead of print. doi: 10.1093/rheumatology/keab740.
JAK inhibitors are likely to become an important part of the overall treatment paradigm for spondyloarthritis (SpA). Although not fully understood, the pathogenesis of SpA is complex and thought to involve both environmental and genetic factors that together elicit a chronic inflammatory response involving the innate and adaptive immune systems. Several different cytokines, TNF, IL-17A, IL-12/23 and IL-23, which are directly/indirectly affected by JAK molecules, are involved in the pathogenesis ...
McInnes IB, Kato K, Magrey M, Merola JF, Kishimoto M, Pacheco-Tena C, Haaland D, Chen L, Duan Y, Zueger P, Liu J, Lippe R, Pangan AL, Behrens F.
RMD Open. 2021;7(3):e001838
Analysis of data over 56 weeks shows that efficacy responses are maintained with upadacitinib 15 mg and 30 mg. Following the publication of 12-week data from the Phase III, randomised double-blind, SELECT-PsA 1 study, earlier this year, McInnes, et al. now report the 56-week efficacy and safety data of upadacitinib 15 mg and 30 mg in patients with PsA and an inadequate response to non-biological therapy Efficacy responses and inhibition of radiographic progression were maintained with upadacitin...
October 21
Miyazaki Y, Nakano K, Nakayamada S, Kubo S, Inoue Y, Fujino Y, Tanaka Y.
Ann Rheum Dis. 2021;80(9):1130-1136
Propensity score-based inverse probability of treatment weighting shows that efficacy may differ between tofacitinib and baricitinib. Miyazaki, et al. compared the efficacy and safety of the two JAK inhibitors in real-world clinical practice, after reduction to a minimum of the selection bias, using propensity score-based inverse probability of treatment weighting, and adjustment for confounding patient characteristics. They found that tofacitinib may be less effective in patients resistant to m...
September 21
Aletaha D, Westhovens R, Gaujoux-Viala C, Adami G, Matsumoto A, Bird P, Messina OD, Buch MH, Bartok B, Yin Z, Guo Y, Hendrikx T, Burmester GR.
RMD Open. 2021;7(2):e001621.
Post hoc analysis of the phase III FINCH study shows that filgotinib may be an alternative treatment option for patients with RA who have poor prognostic factors (PPFs), especially those not responding to standard treatment such as methotrexate (MTX). PPFs are associated with severe disease and risk for disease progression in patients with RA. Consequently, the 2019 EULAR management guidelines for RA recommend early treatment escalation for patients with PPFs who have inadequate response to fir...
August 21
Iwamoto N, Sato S, Kurushima S, Michitsuji T, Nishihata S, Okamoto M, Tsuji Y, Endo Y, Shimizu T, Sumiyoshi R, Suzuki T, Okada A, Koga T, Kawashiri SY, Fujikawa K, Igawa T, Aramaki T, Ichinose K, Tamai M, Nakamura H, Mizokami A, Origuchi T, Ueki Y, Eguchi K, Kawakami A.
Arthritis Res Ther. 2021;23(1):197
In a real-world setting, tofacitinib and baricitinib have comparable continuing efficacies and safety profiles in patients with RA. It is important to determine the differences and similarities of JAK inhibitors in a real-world setting so that the optimal agent can be administered. However, until now, no published data of a direct comparison among these agents in RA have been available. With this in mind, Iwamoto, et al. compared the efficacy and safety of tofacitinib with those of baricitinib ...
July 21
Mease PJ, Lertratanakul A, Papp KA, van den Bosch FE, Tsuji S, Dokoupilova E, Keiserman MW, Bu X, Chen L, McCaskill RM, Zueger P, McDearmon-Blondell EL, Pangan AL, Tillett W.
Rheumatol Ther. 2021;8(2):903–919
Fifty-six-week data suggest that upadacitinib could be a favourable long-term treatment option in patients with PsA who are refractory to biologic therapy. As the need for additional therapeutic agents that can effectively control disease activity continues, new data from a 56-week analysis of the oral reversible JAK1 inhibitor, upadacitinib, currently under investigation for the treatment of PsA, shows that efficacy of the drug is maintained over the duration of this study. Mease, et al. expl...
June 21
Smolen JS, Xie L, Jia B, Taylor PC, Burmester G, Tanaka Y, Elias A, Cardoso A, Ortmann R, Walls C, Dougados M.
Rheumatology (Oxford). 2021;60(5):2256-2266.
Baricitinib 4mg may be considered for long-term treatment of early and refractory rheumatoid arthritis following results demonstrating efficacy and tolerability for up to 3 years. Smolen JS, et al. analysed data from two completed 52-week, phase III studies, RA-BEGIN (DMARD-naïve) and RA-BEAM (MTX-IR), and one ongoing long-term extension study (RA-BEYOND) – providing data for 148 weeks in total. Results demonstrated that the long-term maintenance of clinically relevant treatment g...
Wells AF, Jia B, Xie L, Valenzuela GJ, Keystone EC, Li Z, Quebe AK, Griffing K, Otawa S, Haraoui B.
Wells AF, et al. Rheumatol Ther. 2021. Epub ahead of print. DOI: 10.1007/s40744-021-00317-9.
Analysis by Wells, et al. demonstrates long-term efficacy and tolerability of baricitinib 2 mg daily for up to 120 weeks in patients with rheumatoid arthritis. Using data from two completed phase III studies, RA-BEAM (csDMARD-IR patients) and RA-BEACON (TNFi-IR patients), and one ongoing long-term extension study (RA-BEYOND), results demonstrated that the long-term maintenance of clinically relevant treatment goals, including LDA, remission and normative physical function, is achievable with b...
May 21
Song GG, Lee YH.
Int J Clin Pharmacol Ther. 2021. Epub ahead of print.
Bayesian network meta-analysis of randomised controlled trials (RCTs) highlights the effectiveness of secukinumab, ixekizumab, and tofacitinib in patients with psoriatic arthritis (PsA) and an inadequate response to tumour necrosis factor inhibitors (TNFi). There is a current need for therapies with alternative mechanisms of actions to DMARDs and TNFi, for the significant proportion of patients with PsA who insufficiently respond to these therapies. While RCTs for therapies such as secukinum...
McInnes IB, Anderson JK, Magrey M, Merola JF, Liu Y, Kishimoto M, Jeka S, Pacheco- Tena C, Wang X, Chen L, Zueger P, Liu J, Pangan AL, Behrens F.
N Engl J Med. 2021;384(13):1227-1239.
Upadacitinib efficacy proves to be greater than placebo, and non-inferior to adalimumab, in treating patients with psoriatic arthritis (PsA). Already approved for the treatment of rheumatoid arthritis, McInnes, et al. studied oral upadacitinib at a dose of 15 mg or 30 mg, alongside placebo or adalimumab, in this 24-week, Phase III trial, in over 1700 patients with PsA. At the primary endpoint (Week 12), ACR20 response was greater with upadacitinib than placebo, and non-inferior to adalimumab; ...
April 21
Traves PG, Murray B, Campigotto F, Galien R, Meng A, Di Paolo JA.
Ann Rheum Dis. 2021 Mar 19:annrheumdis-2020-219012. Epub ahead of print. DOI: 10.1136/annrheumdis-2020-219012
The first study to combine in vitro inhibition of cytokine responses in whole blood with clinical pharmacokinetics of individual JAKinibs to model daily cytokine-mediated pharmacodynamic profiles in healthy individuals and patients with RA, has demonstrated that JAKinib potencies depended on cytokine stimulus, pSTAT readout and cell type. Traves and colleagues have observed that JAKinibs have unique, differential effects on specific cytokine signalling pathways, dependent on cytokine stimulus, S...
Tanaka Y, Kavanaugh A, Wicklund J, McInnes IB.
Mod Rheumatol. 2021 Mar 19:1-26. Epub ahead of print. DOI 10.1080/14397595.2021.1902617
Filgotinib is the latest JAKinib to enter the international market for the treatment of RA, receiving regulatory approval in Japan and Europe late last year. In this review paper, Tanaka Y et al. examine the clinical evidence supporting its use as a later-line treatment, in accordance with international RA management guidelines, and provide their expert opinions on JAKinibs from a clinical perspective. The core clinical programme evaluating filgotinib in patients with moderately-to-severely acti...
March 21
Kavanaugh A, Westhovens RR, Winthrop KL, Lee SJ, Tan Y, An D, Ye L, Sundy JS, Besuyen R, Meuleners L, Stanislavchuk M, Spindler AJ, Greenwald M, Alten R, Genovese MC.
J Rheumatol. 2021 Feb 1:jrheum.201183. DOI: 10.3899/jrheum.201183.
A long-term extension study of filgotinib showed consistent safety profile and sustained efficacy with the drug for up to four years. The DARWIN 3 study, for patients who previously completed either the 24-week DARWIN 1 study (filgotinib + MTX) or the DARWIN 2 study (filgotinib monotherapy), enrolled 739 patients with RA. At the time of analysis, 440 patients had received four years or more of filgotinib. Exposure-adjusted incidence rate per 100 patient-years-of-exposure for TEAEs was 24.6 i...
Keywords: JAK, Filgotinib, Clinical, Phase 2
February 21
Takeuchi T, Rischmueller M, Blanco R, Xavier RM, Ueki Y, Atsumi T, Chen S, Friedman A, Pangan AL, Strand V, van Vollenhoven RF.
Mod Rheumatol 2021;26:1–16.
In this sub-analysis of the Phase 3 SELECT-EARLY study, UPA demonstrated clinical efficacy superior to placebo in the Japanese subpopulation. Along with a favourable efficacy observed with the Japan-specific 7.5 mg dose of UPA for all secondary endpoints. SELECT-EARLY was designed to study the safety and efficacy of UPA 15 and 30mg as monotherapy, but it also included a subset of 138 Japanese patients, 40% of whom were randomised to receive UPA 7.5mg. This was designed to meet the requirements...
Keywords: JAK, Upadacitinib, Clinical, Phase 3
Combe B, Kivitz A, Tanaka Y, van der Heijde D, Simon JA, Baraf HSB, Kumar U, Matzkies F, Bartok B, Ye L, Guo Y, Tasset C, Sundy JS, Jahreis A, Genovese MC, Mozaffarian M, Landewé RBM, Bae S-C, Keystone EC, Nash P.
Ann Rheum Dis. 2021 Jan 27:annrheumdis-2020-219214
Filgotinib improved RA signs and symptoms, physical function, and inhibited radiographic progression. FIL 200mg plus MTX, but not FIL 100mg plus MTX showed non-inferiority to ADA plus MTX, based on DAS28(CRP) low disease activity. FIL was also well tolerated in RA patients with inadequate response to MTX. This 52-week, phase 3 randomised clinical trial (FINCH 1) evaluated the efficacy and safety of FIL in patients with RA randomised to FIL 200 or 100mg, ADA 40mg, or placebo, all with background...
Keywords: JAK, Filgotinib, Clinical, Efficacy
January 21
Mease PJ, Lertratanakul A, Anderson JK, Papp K, Van den Bosch F, Tsuji S, Dokoupilova E, Keiserman M, Wang X, Zhong S, McCaskill RM, Zueger P, Pangan AL, Tillett W.
Annals of the rheumatic diseases. 2021 Mar 1;80(3):312-20.
In this trial of patients with active PsA who had inadequate response or intolerance to at least one biologic DMARD, upadacitinib 15 mg and 30 mg was more effective than placebo over 24 weeks in improving signs and symptoms of PsA. Despite the availability of bDMARDs in PsA, only a small proportion of patients achieve the recommended target of minimal disease activity; as such, additional treatment options are needed. Upadacitinib is under evaluation for PsA. This paper reports the 24-week data...
Keywords: JAK, Upadacitinib, Clinical, Efficacy
Merola JF, Papp KA, Nash P, Gratacós J, Boehncke W-H, Thaçi D, Graham D, Hsu M-A, Wang C, Wu J, Young P.
J Eur Acad Dermatol Venereol 2020;34:2809–2820.
Considering the multi-domain nature of PsA, effective treatments must demonstrate efficacy across a range of clinical and patient-reported outcomes. Dermatologic symptoms often precede rheumatic manifestations in people with PsA, typically by 10 years. Tofacitinib demonstrated significant improvements across a range of outcomes including burdensome dermatologic symptoms. This post hoc analysis included data from two double-blind, Phase 3 studies in patients with active PsA and an inadequate res...
Keywords: JAK, Tofacitinib, Clinical, Phase 3
Pappas DA, St John G, Etzel CJ, Fiore S, Blachley T, Kimura T, Punekar R, Emeanuru K, Choi J, Boklage S, Kremer JM.
Ann Rheum Dis 2021;80:96–102.
RA treatment guidelines recommend a treat-to-target approach guided by disease stage and treatment history, yet the optimal sequence of different treatment modalities has not been established. Data from Corrona – were used to evaluate the comparative effectiveness of TNFi versus non-TNFi bDMARDs and tsDMARDs as first-line treatment following csDMARD failure. Results support RA guidelines recommending individualised care based on clinical judgement and consideration of patient preference. T...
Keywords: JAK, Real World, Efficacy
Nash P, Kerschbaumer A, Dorner T, Dougados M, Fleischmann RM, Geissler K, McInnes I, Pope JE, van der Heijde D, Stoffer-Marx M, Takeuchi T, Trauner M, Winthrop KL, de Wit M, Aletaha D, Baraliakos X, Boehncke W-H, Emery P, Isaacs JD, Kremer J, Lee EB, et al.
2021 Jan;80(1):71-87. doi: 10.1136/annrheumdis-2020-218398. Epub 2020 Nov 6.
JAKi are approved in various immune-mediated inflammatory diseases. With five JAKi now licensed, this paper reviews key points to consider in their use to assist clinicians, patients, and other stakeholders once the decision is made to commence JAKi. The consensus was developed by a Steering Committee and an expanded Task Force using EULAR standard operating procedures. The committee included patients as well as experts in rheumatology, gastroenterology, haematology, dermatology, and infectious ...
December 20
Smolen JS, Xie L, Jia B, Taylor PC, Burmester G, Tanaka Y, Elias A, Cardoso A, Ortmann R, Walls C, Dougados M.
Rheumatology 2020; doi:10.1093/rheumatology/keaa576
Three year follow up data for baricitinib demonstrated efficacy in populations that span the clinical disease continuum in RA, including DMARD-naïve, MTX-IR, csDMARD-IR, and bDMARD-IR and was well tolerated. This study evaluated achievement and maintenance of LDA, remission and physical functioning in patients treated with baricitinib for up to 3 years. Data were analysed from two 52-week, Phase 3 studies (RA-BEAM and RA-BEGIN), and one ongoing long-term extension (RA-BEYOND). Patients com...
Keywords: JAK, Baricitinib, Clinical, Phase 3
Kerschbaumer A, Smolen JS, Nash P, Doerner T, Dougados M, Fleischmann R, Geissler K, McInnes IM, Takeuchi T, Trauner M, Winthrop K, de Wit M, Boehncke W-H, Falzon L, van der Heijde D.
RMD Open 2020;6:e001374 doi:10.1136/rmdopen-2020-001374
Trials of JAKi have been conducted in many therapy areas, including rheumatology, dermatology and gastroenterology. In 2019, a task force was set up to create a consensus to guide clinicians on how to use JAKi in clinical practice. This systematic literature review conducted in 2019 support this consensus In line with EULAR’s standardised operating procedures for recommendations, a literature search was conducted in EMBASE, Medline and the Cochrane Library databases. To evaluate the effica...
Fleischmann RM, Blanco R, Hall S, Thomson GTD, Van den Bosch FE, Zerbini C, Bessette L, Enejosa J, Li Y, Song Y, DeMasi R, Song I-H.
Ann Rheum Dis 2020; doi:10.1136/annrheumdis-2020-21841220
Both ACR and EULAR recommend adding a biologic or targeted synthetic DMARD in patients who do not achieve treatment goals at follow-up. Findings indicated that an immediate switch in mechanism of action (from JAKi to TNFi and vice versa) following treat-to-target principles is feasible with minimal risk of flare regardless of whether patients are switched due to non-response or incomplete-response. SELECT-COMPARE followed treat-to-target principles to examine the efficacy of switching in two pat...
November 20
Rubbert‑Roth A, Enejosa J, Pangan AL, Haraoui B, Rischmueller M, Khan N, Zhang Y, Martin N, Xavier RM.
N Engl J Med 2020;383:1511–21 DOI: 10.1056/NEJMoa2008250
In patients with refractory RA to bDMARDs, upadacitinib was found to be superior to abatacept in DAS28-CRP change from baseline and the achievement of remission at week 12. 612 bDMARD-IR patients were randomised 1:1 to UPA 15 mg QD or ABA, each in combination with stable synthetic DMARDs. At Week 12, patients with <20% decrease in TJC and Swollen joint count (SJC) had background medication adjusted or added. All patients completing Week 24 were eligible to remain in an open-label, long-term ...
Keywords: JAK, Upadacitinib, Clinical, Efficacy
Translated by: Igor Kos
October 20
Alessandro M, Perillo F, Refini R, Bergantini L, Bellisai F, Selvi E, Cameli P, Manganelli S, Conticini E, Cantarini L, Sestini P, Frediani B, Bargagli E.
Int Immunopharmacol. 2020 Sep;86:106748.
BARI demonstrated to be a safe immune modulator that reduces the concentrations biomarkers of lung fibrosis and inflammation in RA patients, including a subgroup with interstitial lung involvement. Professor Alessandro and colleagues analysed the effects of baricitinib in a population of RA and RA-ILD patients in a real-life setting, describing any changes in lung function parameters, serum inflammatory biomarkers and fibrotic biomarkers after 6 months of treatment. Fifteen patients were recru...
Keywords: JAK, Baricitinib, Clinical, Efficacy
Translated by: Igor Kos
Zhang X, Zhang Y, Qiao W, Zhang J, Qi Z.
Journal of International Immunopharmacology. 2020 Sep;86:106749. doi: 10.1016/j.intimp.2020.106749.
BARI may potentially interrupt the passage of SARS-CoV-2 into the target cells by binding to AAK1 and GAK, which are regulators of the ACE2 receptor regulator identified for its uptake, and could also treat cytokine storm through suppression JAK1/JAK2. Professor Zhang and et al reviewed BARI, as a potential drug to prevent SARS-COV-2 from entering target cells. They also evaluated BARI’s ability to control COVID-19 induced cytokine storm. As a cell surface protein, ACE2 is involved in re...
Keywords: JAK, Baricitinib
Translated by: Igor Kos
Amrhein J, Drynda S, Schlatt L, Karst U, Lohmann C, Ciarimboli G, Bertrand J.
Int. J. Mol. Sci. 2020; 21:6632 DOI: 10.3390/ijms21186632
Amrhein et al examined the different uptake and expulsion mechanisms of BARI and TOF in cellular assays. Different cellular uptake mechanism for BARI and TOF was observed and showed that BARI’s transport was not dependent on organic cation transporters. Results indicated TOF was exported from RASF in a MATE-1 dependent way. TOF might be exported from healthy cells, thereby not inhibiting JAK pathway in these cells The interaction of BARI and TOF with OCTs was investigated using quenching ...
Keywords: JAK, Tofacitinib, Preclinical, MOA
Translated by: Igor Kos
September 20
Winthrop KL, Harigai M, Genovese MC, Lindsey S, Takeuchi T, Fleischmann R, Bradley JD, Byers NL, Hyslop DL, Issa M, Nishikawa A, Rooney TP, Witt S, Dickson CL, Smolen JS, Dougados M.
Annals of the Rheumatic Diseases, May 2020
Baricitinib, an oral selective JAK1 and JAK2 inhibitor,8 demonstrated significant clinical efficacy in phase 3 RA trials. Pooled data from these trials, including a long-term extension (LTE), inform the safety profile for baricitinib, mainly to evaluate the incidence of infection in patients with active rheumatoid arthritis (RA), with a focus on serious infection, tuberculosis (TB), herpes zoster (HZ) and opportunistic infection (OI). The data collected were from eight double-blind randomised ...
Keywords: JAK, Baricitinib, Clinical, Safety
Translated by: Igor Koz
August 20
Fleischmann R, Takeuchi T, Schiff M, Schlichting D, Xie L, Issa M, Stoykov I, Lisse J, Martinez-Osuna P, Rooney T, Zerbini CAF.
Arthritis Care Res (Hoboken) 2020;72(8):1112-1121
This 24-week update from the baricitinib RA-BEYOND LTE study follows patients previously treated in the pivotal study RA-BEGIN. It demonstrates the maintained safety and efficacy of baricitinib monotherapy, and the effects of concurrent MTX treatment on response rates and patient reported outcomes. Previous P3 study RA-BEGIN demonstrated the superior efficacy of 4mg baricitinib compared to MTX monotherapy up to 52 weeks, with no major safety events being identified. At the end of the trial, pa...
Keywords: JAK, Baricitinib, Efficacy
Translated by: Igor Koz
van Vollenhoven R, Takeuchi T, Pangan AL, Friedman A, Mohamed MEF, Chen S, Rischmueller M, Blanco R, Xavier RM, Strand V.
Arthritis Rheumatol 2020
Upadacitinib monotherapy demonstrated superior clinical, radiographic, and patient-reported outcomes versus methotrexate in methotrexate-naïve RA patients. This 48-week double-blind active comparator study investigated upadacitinib monotherapy in patients with early RA, who were either methotrexate-naïve, or who had very limited exposure. 947 patients were randomised to once-daily upadacitinib 15 or 30 mg, or weekly methotrexate. Unusually, there were two separate primary endpoints, s...
Keywords: JAK, Upadacitinib, Efficacy
Translated by: Igor Koz
July 20
Kerschbaumer A, Smolen JS, Dougados M, De Wit M, Primdahl J, McInnes I, Van Der Heijde D, Baraliakos X, Falzon L, Gossec L.
Annals of the Rheumatic Diseases 2020;79:778-786
This SLR reviewed data on pharmacological treatment of PsA. Findings informed the 2019 EULAR taskforce when updating recommendations for PsA management. Overall, no new safety signals were reported. Encouragingly, LTEs of JAKi did not report any venous thromboembolic events or PEs. Efficacy was demonstrated for a range of bDMARD and tsDMARD therapies in various disease domains. Efficacy varied between PsA manifestations and between therapies. Observational data demonstrated efficacy when switchi...
Keywords: Cytokine Signalling, Safety
Translated by: Igor Koz
Nash P, Coates LC, Kivitz AJ, Mease PJ, Gladman DD, Covarrubias-Cobos JA, FitzGerald O, Fleishaker D, Wang C, Wu J, Hsu M, Menon S, Fallon L, Romero AB, Kanik KS.
Rheumatol Ther 2020 doi.org/10.1007/s40744-020-00209-4
This 3-year, open-label, LTE study follows PsA patients previously treated in pivotal studies OPAL Broaden and OPAL Beyond. It demonstrates maintained safety and efficacy of tofacitinib up to 36 and 30 months, respectively. No new safety concerns are highlighted. Previous P3 studies, OPAL Broaden and OPAL Beyond, demonstrated safety and efficacy of 5mg and 10mg tofacitinib BID in PsA. These patients rolled over to OPAL Balance for a period of 36 months. 686 participants were used in this inter...
Keywords: JAK, Tofacitinib, Safety
Translated by: Igor Koz
Ebina K, Hirano T, Maeda Y, Yamamoto W, Hashimoto M, Murata K, Takeuchi T, Shiba H, Son Y, Amuro H, Onishi A, Akashi K, Hara R, Katayama M, Yamamoto K, Kumanogoh A, Hirao M.
Arthritis Res Ther 2020;22:142
This paper is based upon a long-term cohort study, namely the ANSWER cohort, an observational multi-centre registry of RA patients in the Kansai district of Japan. Analyses demonstrate a difference in observed drug retention between bDMARDs-naïve and bDMARDs-switched patients. 7 bDMARD treatments were compared in patients with no prior exposure to biologics, with abatacept showing the greatest retention rate. In patients that had switched between these same bDMARDs or to tofacitinib through...
Keywords: JAK, Tofacitinib
Translated by: Igor Koz
June 20
Finckh A, Tellenbach C, Herzog L, Scherer A, Moeller B, Ciurea A, von Muehlenen I, Gabay C, Kyburz D, Brulhart L, Müller R, Hasler P, Zufferey P.
RMD Open 2020;6:e001174 doi:10.1136/rmdopen-2020-001174
This nested cohort study found that, in Switzerland, there was a generally limited overall drug maintenance for b/tsDMARD options in RA. Using data from SCQM-RA – a prospective longitudinal registry, overall maintenance (drug survival) was calculated for TNFi, bDMARD-OMA or JAKi in patients with RA. After adjusting for potential confounding factors, there was a higher hazard of drug discontinuation with TNFi compared with tofacitinib; no significant difference was observed between non-TNF ...
Keywords: Cytokine Signalling, Real World, Efficacy
Translated by: Igor Kos
Emery P, Tanaka Y, Cardillo T, Schlichting D, Rooney T, Beattie S, Helt C, Smolen JS.
Arth Res Ther 2020;22:115 doi.org/10.1186/s13075-020-02199-8
This study aimed to characterize temporary interruptions of baricitinib and describe their impact on efficacy and safety. Brief interruptions during phase 3 baricitinib trials were associated with minor increases in symptoms which were resolved following treatment. In life-long, chronic conditions such as RA, interruption of therapy is common for various reasons, such as side effects, non-compliance, or because a patient requires surgery. Concerns have been raised that these treatment breaks c...
Keywords: JAK, Baricitinib, Clinical, Efficacy
Translated by: Igor Kos
Li Z, Hu J, Bao C, Li X, Li X, Xu J, Spindler AJ, Zhang X, Xu J, He D, Li Z, Wang G, Yang Y, Wu H, Ji F, Tao H, Zhan L, Bai F, Rooney TP, Zerbini CAF.
Clin Exp Rheumatol . Jul-Aug 2020;38(4):732-741. Epub 2020 May 20.
This study conducted mainly in Chinese patients with RA, and an inadequate response to MTX, showed that baricitinib 4mg was associated with significant improvements and consistent with the findings from previous clinical trials. The efficacy and safety of baricitinib have been assessed in several clinical trials, predominantly in Caucasian populations. However, evidence on the efficacy and safety of baricitinib in Chinese patients is limited, with only one of the main clinical trial program stu...
Keywords: JAK, Baricitinib, Clinical, Efficacy
Translated by: Igor Kos
May 20
Cohen S, Tuckwell K, Katsumoto TR, Zhao R, Galanter J, Lee C, Rae J, Toth B, Ramamoorthi N, Hackney JA, Berman A, Damjanov N, Fedkov D, Jeka S, Chinn LW, Townsend MJ, Morimoto AM, Genovese MC.
Arthritis Rheumatol. 2020 Sep; 72(9): 1435–1446.
In this randomised phase II trial with MTX treatment-refractory RA patients, greater efficacy was observed with fenebrutinib 150 mg once daily or 200 mg twice daily compared to placebo, while response rates were numerically similar to those observed with adalimumab. BTK inhibitors have demonstrated clinical efficacy in B cell malignancies and multiple sclerosis, although there is limited clinical evidence of its efficacy in RA. Fenebrutinib (FEN) an orally active and selective non-covalent inh...
Keywords: BTK, Clinical, Phase 2
Translated by: Igor Koz
April 20
Lee YH, Song GG.
Z Rheumatol. 2020 DOI: 10.1007/s00393-020-00750-1
This Bayesian network meta-analysis, comparing the relative efficacy and safety of JAK inhibitors, determined BARI 4mg + MTX and UPA 15mg + MTX were the most effective. The analysis included 5451 patients with an inadequate response to MTX and active RA, from four RCTs. Relative effects were converted into a probability allowing each treatment to be ranked. BARI and UPA had significantly higher ACR20 response rates than ADA 40mg + MTX whilst TOF 5mg and FIL 200mg had comparable ACR20 response ...
Keywords: JAK, Baricitinib
Translated by: Igor Koz
March 20
Costanzo G, Firinu D, Losa F, Deidda M, Barca MP, Del Giacco S.
Ther Adv Musculoskelet Dis. 2020;12:1759720X19899296
Broad and focused studies are required to have an insight of safety for small molecules, such as JAK inhibitors in the case of accidental exposure before or during pregnancy. This case study’s objective describes a case report of a 43-year-old woman affected by RA who became pregnant during BARI treatment. She has had two previous pregnancies at term without complications. After failure of bDMARDs due to loss of efficacy and adverse drug reactions, the patient was started on BARI when i...
Keywords: JAK, Baricitinib, Real World, Safety
Translated by: Igor Koz
January 20
Becker A, Martin EC, Mitchell DY, Grennigloh R, Bender AT, Mackenzie H and Johne A.
Clin Transl Sci . 2020 Mar;13(2):325-336. doi: 10.1111/cts.12713. Epub 2019 Nov 29.
In this first in-human phase I, double-blind, placebo-controlled trial, the Bruton’s tyrosine kinase (BTK) inhibitor evobrutinib was well-tolerated, showed linear and time-independent PK, induced long-lasting BTK inhibition, and was not associated with prolongation of QT/QTc interval in healthy subjects. Evobrutinib is an oral BTK inhibitor that has demonstrated efficacy in pre-clinical and autoimmune disease models. BTK is a key regulator of B cell receptor and Fc receptor signalling, an...
Keywords: BTK, Clinical, Safety
Translated by: Igor Koz
November 19
Nader A, Mohamed M-EF, Winzenborg I, Doelger E, Noertersheuser P, Pangan AL, Othman AA.
Clin Pharmacol Ther . 2020 Apr;107(4):994-1003. doi: 10.1002/cpt.1671.
UPA 15 mg provided the optimal benefit-risk in RA through maximizing efficacy with only small incremental benefit with 30 mg, and with consistency across RA subpopulations and with UPA monotherapy or combination with csDMARDs. Exposure-response analyses were conducted using combined data from two Phase 2b and five Phase 3 studies in order to characterise the relationship between plasma exposure and efficacy, as well as to select safety parameters using the totality of the data in subjects with...
Keywords: JAK, Upadacitinib, Clinical, Efficacy
Translated by: Igor Kos
Lee YH, Song GG.
Clin Drug Investig .2020 Jan;40(1):65-72. doi: 10.1007/s40261-019-00863-9.
TOF significantly modulated the Th1 response to Varicella-zoster-virus (VZV). The poor VZV-specific cellular immune responses in patients with RA may be considered in recommendations regarding appropriate vaccination strategies for enhancing the VZV-specific Th1 response. Previous studies have shown that treatment with JAKinibs increases HZ incidence compared with conventional DMARDs. This cross-sectional in vitro study aimed to investigate the effect of TOF on the VZV-specific T cell immune re...
Keywords: JAK, Peficitinib, Clinical, Efficacy
Translated by: Igor Kos
September 19
Mori S, Ueki Y.
Clin Rheumatol. 2019 Aug 9. DOI: 10.1007/s10067-019-04721-z
Following achievement of remission or low disease activity (LDA), a dose reduction strategy of TOF to a 5mg QD dose was preferable to immediate withdrawal of TOF, with lower relapse rates. Clinical remission or LDA early in the disease course is a target for every RA patient. Although maintaining a state of remission or LDA is beneficial to patients, the AEs and costs associated with DMARDs, have significant burdens on patients during life-long RA treatment. This long-term study was performed t...
Keywords: JAK, Tofacitinib, Clinical, Efficacy
McInnes IB, Byers NL, Higgs RE, Lee J, Macias WL, Na S, Ortmann RA, Rocha G, Rooney TP, Wehrman T, Zhang X, Zuckerman SH, Taylor PC.
Arthritis Res Ther. 2019 Aug 2;21(1):183
Different JAKinibs modulated distinct cytokine pathways to varying degrees, and no agent potently or continuously inhibited an individual cytokine signalling pathway throughout the dosing interval. This study aimed to compare the in vitro cellular pharmacology of BARI, TOF and UPA across relevant leukocyte subpopulations, coupled with their in vivo PK, to determine their effects on distinct cytokine pathways. Peripheral blood mononuclear cells from healthy donors were incubated with differen...
Keywords: JAK, Upadacitinib, Preclinical, Selectivity
Translated by: Igor Koz
August 19
Takeuchi T, Tanaka Y, Tanaka S, Kawakami A, Iwasaki M, Katayama K, Rokuda M, Izutsu H, Ushijima S, Kaneko Y, Shiomi T, Yamada E, van der Heijde D.
Ann Rheum Dis 2019 DOI: 10.1136/annrheumdis-2019-215164
Peficitinib (PEF) 100 and 150 mg demonstrated robust clinical and structural efficacy in patients with RA who have an inadequate response to MTX. In Japan, two JAK inhibitors, TOF and BARI are currently available for RA patients with an inadequate response to conventional therapies. This randomized phase 3 study (RAJ4), assessed the efficacy and safety of two PEF doses in combination with MTX compared to PBO, in Japanese MTX-IR. Patients were randomized 1:1:1 to PBO, PEF 100 mg and 150 mg with...
Keywords: JAK, Peficitinib, Clinical, Phase 3
Translated by: Igor Koz
Genovese MC, Kalunian K, Gottenberg JE, Mozaffarian N, �Bartok B, Matzkies F, Gao J, Guo Y, Tasset C, Sundy JS, de Vlam K, Walker D, Takeuchi T.
JAMA 2019 322(4):315-325
Among RA patients with an inadequate response or intolerance to bDMARDs, filgotinib (FIL) doses, compared to PBO resulted in significantly greater proportions achieving a clinical response at Wk12. Patients with active RA despite treatment with bDMARD therapy need treatment options. The FINCH 2 Phase 3 study compared the effects of FIL vs PBO for the treatment of RA patients with inadequate response or intolerance to ≥1 prior bDMARDs. Patients were randomized in a 1:1:1 ratio, receiving FI...
Keywords: JAK, Filgotinib, Clinical, Efficacy
Fleischmann R, Pangan AL, Song IH, Mysler E, Bessette L, Peterfy C, Durez P, Ostor AJ, Li Y, Zhou Y, Othman AA, Genovese MC.
Arthritis Rheumatol 2019 DOI: 10.1002/art.41032
UPA demonstrated superiority to ADA in terms of clinical, functional and patient-reported outcomes with comparable radiographic inhibition. As many RA patients fail to achieve LDA and remission with TNF inhibitors and MTX there is a requirement for additional treatment options. In this SELECT-COMPARE study the clinical and functional outcomes of UPA were compared to ADA in MTX-IR patients. 1629 MTX-IR were randomly assigned 2:2:1 to; UPA 15mg QD, ADA 40mg Q2W or PBO, with background MTX. Key e...
Keywords: JAK, Upadacitinib, Clinical, Efficacy
Fleischmann RM, Genovese MC, Enejosa JV, Mysler E, Bessette L, Peterfy C, Ostor P, Li Y, Song I.
Ann Rheum Dis 2019 DOI: 10.1136/annrheumdis-2019-215764
Consistent with Wk26 data, significantly more UPA patients achieved LDA and remission versus ADA and PBO over 48 weeks. RA patients often change therapy due to inadequate response and intolerance. The SELECT COMPARE study was designed to explore switching to JAK inhibitors from TNF inhibitors without a wash-out period (and vice versa). The long-term safety and efficacy of UPA was compared to ADA and PBO in MTX-IR. 1629 patients were blindly assigned 2:2:1 to; UPA 15mg QD, ADA 40mg Q2W and PBO, ...
Keywords: JAK, Upadacitinib, Clinical, Efficacy
July 19
Calabrese LH, Abud-Mendoza C, Lindsey SM, Lee SH, Tatulych S, Takiya L, Iikuni N, Soma K, Luo Z, Fleischmann R.
Arthritis Care and Research 2019 DOI: 10.1002/acr.24010
Live zoster vaccine (LZV) was well tolerated, and herpes zoster (HZ) incidence rates were generally similar between treatment groups in vaccinated versus non-vaccinated patients in a subset of RA who received LZV before TOF ± MTX, or ADA + MTX, in ORAL Strategy. It is known that patient with RA are at increased risk of developing HZ though the mechanisms behind this are currently not well understood though therapies, such as TOF, are thought to increase the risk. ACR and EULAR recommend...
Keywords: JAK, Tofacitinib, Clinical, Safety
Translated by: Igor
Tanaka Y, Fautrel B, Keystone EC, Ortmann RA, Xie L, Zhu B, Issa M, Patel H, Gaich CL, de Bono S, Rooney TP, Taylor PC.
Ann Rheum Dis. 2019 Jul;78(7):890-898.
Switching from ADA to BARI without a lengthy washout period can be executed with acceptable safety and tolerability and was associated with maintained disease control. Switching therapies in RA is commonplace in myriad scenarios including inadequate responses, intolerances and patient preference. Assessing the safety and efficacy of new treatments such as BARI, in the context of use as a replacement therapy, is beneficial. A previous study (RA-BEACON) has demonstrated that safely switching fro...
Keywords: JAK, Baricitinib, Clinical, Phase 3
Translated by: Igor
June 19
Westhovens R, Rigby WFC, van der Heijde D, Ching DWT, Bartok B, Matzkies F, Yin Z, Guo Y, Tasset C, Sundy JS, Mozaffarian N, Messina OD, Landewé RBM, Atsumi T, Burmester GR.
EULAR 2019 Abstract LB0003 Presentation
Filgotinib is an orally administered, selective inhibitor of JAK1. Filgotinib has shown good efficacy and was well tolerated for the treatment of RA in Phase 2 and 3 studies evaluating MTX-IR or bDMARD-IR patients. The objective of this study was to compare the efficacy and safety of filgotinib with and without MTX in patients with RA who were naïve to MTX therapy.
Combe BG, Kivitiz AJ, Tanaka Y, van der Heijde D, Matzkies F, Bartok B, Ye L, Guo Y, Tasset C, Sundy JS, Mozaffarian N, Landewé RBM, Bae SC, Keystone EC, Nash P.
EULAR 2019 Abstract LB0001 Presentation
Filgotinib is an orally administered, selective inhibitor of JAK1. Filgotinib has shown good efficacy and was well tolerated for the treatment of rheumatoid arthritis (RA) in Phase 2 studies.The objective of this Phase 3 study was to evaluate the efficacy and safety of filgotinib treatment in patients with RA who have had an inadequate response to methotrexate (MTX).
Haselmayer P, Camps M, Liu-Bujalski L, Nguyen N, Morandi F, Head J, O’Mahony A, Zimmerli SC, Bruns L, Bender AT, Schroeder P, Grenningloh.
J Immunol 2019;202:2888–2906. DOI: 10.4049/jimmunol.1800583
BTK is involved in both adaptive and innate immune responses and mediates signalling of several immune receptors of relevance to RA and SLE pathogenesis. Targeting BTK is a promising approach therefore for autoimmune disorders with aberrant B cell responses. Evobrutinib is a novel, highly specific, and irreversible BTK inhibitor. In vivo and animal models showed that evobrutinib modulated B cell and innate immune cell activation, was efficacious, and prevented joint damage. The potency of evob...
Smolen JS, Pangan AL, Emery P, Rigby W, Tanaka Y, Vargas JI, Zhang Y, Damjanov N, Friedman A, Othman AA, Camp HS, Cohen S.
Lancet. 2019 Jun 8;393(10188):2303-2311
UPA monotherapy showed statistically significant improvements in clinical and functional outcomes versus continuing MTX in MTX inadequate-responder patients with RA. Despite its proven effectiveness and safety, many patients are unable to tolerate MTX due to its side-effects. Therapies that can be used without concomitant MTX therefore, have an important place in RA management. In previous studies, UPA has shown efficacy in combination with stable background csDMARDs in RA patients who are DMA...
May 19
Wollenhaupt J, Lee EB, Curtis JR, Silverfield J, Terry K, Soma K, Mojcik C, DeMasi R, Strengholt S, Kwok K, Lazariciu I, Wang L, Cohen S.
Arthritis Res Ther. 2019 Apr 5;21(1):89.
TOF 5 mg and 10mg BID demonstrated a consistent safety profile and sustained efficacy for up to 9.5 years in this open-label LTE ORAL Sequel study. TOF 5 mg and 10 mg BID demonstrated consistent safety (as monotherapy and combination therapy) and efficacy within this open-label LTE study of RA patients. As RA requires long-term treatment, it’s important to assess the long-term efficacy and safety of RA therapies to understand the potential lifelong impact on patient health and quality of ...
April 19
Combe B, Balsa A, Sarzi-Puttini P, Tony HP, de la Torre I, Rogai V, Durand F, Witt S, Zhong J, Dougados M.
Ann Rheum Dis. 2019 Aug;78(8):1135-1138.
In a post-hoc analysis, BARI 4 mg showed similar efficacy and safety during placebo-controlled and LTE observation periods regardless of the presence or absence of select comorbidities in RA patients. Patients with RA have a high prevalence of comorbidities. This post-hoc analysis investigated the effect of select comorbidities (depression, osteoporosis, hepatic, cardiovascular or pulmonary disorders) on the efficacy and safety of BARI 4 mg QD in patients with moderate-to-severe active RA and i...
Keywords: JAK, Baricitinib, Clinical, Safety
Translated by: Igor
March 19
Harigai M, Takeuchi T, Smolen JS, Winthrop KL, Nishikawa A, Rooney TP, Saifan CG, Issa M, Isaka Y, Akashi N, Ishii T, Tanaka Y.
Mod Rheumatol. 2019 Feb 20:1-23. DOI: 10.1080/14397595.2019.1583711
In this integrated analysis, BARI showed an acceptable safety profile in Japanese patients with up to 3.2 years of exposure. Other than incidences of herpes zoster (HZ), no major differences were noted with BARI safety in Japanese patients with RA, compared to the patients in the integrated database. BARI has previously demonstrated significant clinical efficacy and acceptable safety. Japanese patients who participated in the BARI clinical development programme, were comparable to those from th...
Keywords: JAK, Baricitinib, Clinical, Safety
Translated by: Igor
Camean‐Castillo M, Gimeno‐Ballester V, Rios‐Sanchez E, Fenix‐Caballero S, Vázquez‐Real M, Alegre‐del Rey E.
J Clin Pharm Ther. 2019 Jun;44(3):384-396.
This study suggests that many bDMARDs and tsDMARDs can be considered equivalent therapeutic alternatives in bDMARD-naïve RA patients, with inadequate response to csDMARDs. In the absence of randomised controlled trials comparing drugs, indirect comparisons and network meta-analysis may provide information to help select an optimal treatment alternative. In this network meta-analysis, 27 randomized controlled trials were analysed to assess the possibility that some drugs on the market may b...
Keywords: JAK, Tofacitinib, Clinical, Efficacy
Translated by: Igor
February 19
van der Heijde D, Strand V, Tanaka Y, Keystone E, Kremer J, Zerbini CAF, Cardiel MH, Stanley Cohen S, Nash P, Song YW, Tegzová D, Gruben D, Wallenstein G, Connell CA, Fleischmann R, ORAL Scan investigators.
Arthritis Rheumatol. 2019 Jun;71(6):878-891
RA patients receiving TOF 5 or 10 mg BID plus MTX showed sustained clinical and radiographic treatment effects through months 12-24. The safety profile was consistent with previous TOF studies. The 12-month data from the ORAL Scan study have been previously reported. This report assesses durability of responses, including structural damage progression, and safety with TOF through 24 months. Patients were randomized 4:4:1:1 to receive TOF 5 or 10 mg BID, or PBO advanced to TOF with stable, ba...
January 19
Tanaka Y, McInnes IB, Taylor PC, Byers NL, Chen L, de Bono S, Issa M, Macias WL, Rogai V, Rooney TP, Schlichting DE, Zuckerman SH, Emery P.
Arthritis Rheumatol. 2018 Dec;70(12):1923-1932. doi: 10.1002/art.40680
This review shows that changes in lymphocyte subsets were largely within normal reference ranges and were not associated with efficacy or safety end points. BARI is a selective JAK1/JAK2 inhibitor, approved for the treatment of moderate to severe RA. BARI treatment is associated with changes to circulating lymphocyte and lymphocyte subsets, however detailed analyses of these effects, and their relevance to efficacy and safety is lacking. This study investigated the changes in lymphocyte cell s...
Keywords: JAK, Baricitinib, Clinical, Safety
Translated by: Igor
November 18
van Vollenhoven R, Helt C, Arora V, Zhong J, Correia AP, de la Torre I, Muram D.
Rheumatol Ther 2018 Dec;5(2):525-536. DOI 10.1007/s40744-018-0128-0
Baricitinib (BARI) in combination with MTX and concomitant csDMARDs was shown to be efficacious, regardless of corticosteroid use in RA patients. MTX is prescribed to most RA patients but concomitant csDMARDs and/or corticosteroids can be added. This study assessed the efficacy and safety of BARI in two arms; with/without corticosteroids and; with MTX only/MTX plus csDMARD/csDMARDs only. Baseline characteristics and adverse reactions were also compared. Data were pooled from two phase 3 studie...
Keywords: JAK, Baricitinib, Clinical, Phase 3
Translated by: Igor Kos
Van der Heijde D, Baraliakos X, Gensler LS, Maksymowych WP, Tseluyko V, Nadashkevich O, Abi-Saab W, Tasset C, Meuleners L, Besuyen R, Hendrikx T, Mozafarian N, Liu K, Greer JM, Deodhar A, Landewé R.
Lancet 2018 Dec 1;392(10162):2378-2387. DOI 10.1016/S0140-6736(18)32463-2
In this first clinical trial of filgotinib in patients with active AS, filgotinib significantly reduced disease activity, and the signs and symptoms of AS compared with placebo. The TORTUGA trial was a randomized, double-blind, placebo-controlled, Phase 2 trial, that enrolled 263 adult patients from 30 sites in seven countries. Patients with active AS and an inadequate response or intolerance to two or more NSAIDs were assigned 1:1 to receive filgotinib 200 mg or placebo once daily for 12 week...
Mease P, Coates LC, Helliwell PS, Stanislavchuk M, Rychlewska-Hanczewska A, Dudek A, Abi-Saab W, Tasset C, Meuleners L, Harrison P, Besuyen R, Van der Aa A, Mozafarian N, Greer JM, Kunder R, Van den Bosch F, Gladman DD.
Lancet. 2018 Dec 1;392(10162):2367-2377. DOI 10.1016/ S0140-6736(18)32483-8
In this first clinical trial of filgotinib in patients with PsA, filgotinib was effective in treating the signs and symptoms of active PsA across various disease manifestations. The EQUATOR trial was a randomized, double-blind, placebo-controlled, Phase 2 trial, that enrolled 191 adult patients from 25 sites in seven countries. Patients with active moderate-to-severe PsA and an insufficient response or intolerance to at least one csDMARD were assigned 1:1 to receive filgotinib 200 mg or placebo...
October 18
Bae SC and Lee YH.
Z Rheumatol. 2018 Sep 6. DOI 10.1007/s00393-018-0531-5
Tofacitinib (TOF) 10mg and baricitinib (BARI) 4mg, in combination with methotrexate (MTX), were the most efficacious treatments in RA patients with an inadequate response to DMARDs or biologics. Both combination treatments presented acceptable safety profiles and were not associated with a significant risk of serious adverse events. This study employed a Bayesian approach to Meta-Analysis; combining the available evidence across a network of Randomised Controlled trials (RCTs). Twelve RCTs cont...
Keywords: JAK, Tofacitinib, Clinical, Phase 3
Translated by: Igor Kos
Takeuchi T, Genovese MC, Haraoui B, Li Z, Xie L, Klar R, Pinto Correia A, Otawa S, Lopez-Romero P, de la Torre I, Rooney TP, Smolen JS.
Ann Rheum Dis. 2019 Feb;78(2):171-178. DOI 10.1136/annrheumdis-2018-213271
In active RA patients, with an inadequate response (IR) to DMARDs who achieve low disease activity (LDA) following baricitinib (BARI) 4 mg treatment, disease control is better maintained with continued BARI 4 mg compared to tapering to 2 mg. The objective of this study was to investigate the effect of BARI tapering in patients achieving sustained disease control with BARI 4 mg. In the long-term extension study RA-BEYOND, patients receiving BARI 4 mg who achieved sustained LDA or remission at two...
Keywords: JAK, Baricitinib, Clinical, Phase 3
Translated by: Igor Kos
Smolen J, Genovese M, Takeuchi T, Hyslop D, Macias W, Rooney T, Chen L, Dickson C, Riddle Camp J, Cardillo T, Ishii T and Winthrop K.
J Rheumatol. 2019 Jan;46(1):7-18. DOI: 10.3899/jrheum.171361
Baricitinib (BARI) showed an acceptable 5.5-year safety profile in this integrated analysis of patients with moderate-to-severe, active RA. This study evaluated the safety profile of the oral, once daily Janus kinase inhibitor, BARI, in adults with moderately to severely active RA. Data from eight randomised clinical trials and one long-term extension study were pooled and analysed for placebo comparison and dose response. There were 3492 patients who received BARI for a total of 6637 patient-y...
Keywords: JAK, Baricitinib, Clinical, Phase 3
Translated by: Igor Kos
September 18
van der Heijde D, Durez P, Schett G, Naredo E, Østergaard M, Meszros G, De Leonardis F, De La Torre I, López-Romero P, Schlichting D, Nantz E, Fleichmann R.
Clinical Rheumatology 2018;37:2381–90 DOI 10.1007/s10067-018-4221-0
Patients with active RA and little or no prior DMARD treatment, who achieved sustained clinical responses, were less likely to show structural damage progression, irrespective of treatment. RA-BEGIN was a 52-week double-blind, multicentre Phase 3 trial, which assessed the safety and efficacy of BARI as monotherapy or in combination with MTX versus MTX monotherapy, in RA patients with no or limited prior DMARDs use.1-4 This post-hoc analysis evaluated the structural damage progression in patients...
Keywords: JAK, Baricitinib, Clinical, Efficacy
Translated by: Igor Kos
Kremer JM, Rigby W, Singer NG, Birchwood C, Gill D, Reiss W, Pei J, Michalska M.
Arthritis Rheumatol 2018;70:1200–08 DOI 10.1002/art.40493
The COMP-ACT study showed patients achieving low disease activity (LDA) with tocilizumab (TCZ) plus methotrexate (MTX) can discontinue MTX, while maintaining disease control for up to 16 weeks. Previous studies have shown TCZ to be efficacious as a monotherapy or in combination with MTX in patients with RA1,2. Patients frequently discontinue taking DMARDs, such as MTX, due to intolerance or adverse events. COMP-ACT is a randomised, double-blind, 52-week study evaluating the sustained efficacy of...
Keywords: IL-6, Tocilizumab, Clinical, Efficacy
Translated by: Igor Kos
Emery P, Pope JE, Kruger K, Lippe R, DeMasi R, Lula S, Kola B.
ADV Ther 2018; 35(10):1525–63 DOI: 10.1007/s12325-018-0757-2
The b/tsDMARDs evaluated in this systematic literature review (SLR) were shown to be efficacious as monotherapies, although combination therapies usually achieved better treatment outcomes. Current treatment guidelines recommend combining b/tsDMARDs with MTX in the treatment of RA; however, up to a third of patients are treated with monotherapy. While previous SLRs1–3 have compared the efficacy of b/tsDMARD mono- versus MTX combination therapy they covered a limited number of randomised co...
Keywords: JAK, Baricitinib, Clinical, Efficacy
Translated by: Igor Kos
August 18
Kaneko Y, Kato M, Tanaka Y, Inoo M, Kobayashi-Haraoka H, Amano K, Miyata M, Murakawa Y, Yasuoka H, Hirata S, Tanaka E, Miyasaka N, Yamanaka H, Yamamoto K, Takeuchi T, the SURPRISE study group.
Ann Rheum Dis 2018; 77:1268–1275 DOI: 10.1093/rheumatology/key121
The second-year results from the SURPRISE study show that low disease activity (LDA) can be maintained after discontinuation of tocilizumab with continued methotrexate after remission is achieved. Discontinuation of biologic agents in patients who have achieved remission or low disease activity (LDA) is desirable from a risk–benefit point of view. Compared with TNF inhibitors, little is known regarding TCZ-free remission or LDA, but studies indicate that only a small proportion of patien...
Keywords: IL-6, Tocilizumab, Clinical, Efficacy
Translated by: Igor Kos
Genovese MC, van Adelsberg J, Fan C, Graham NMH, van Hoogstraten H, Parrino J, Mangan EK, Spindler A, Huizinga TWJ, van der Heijde D, for the EXTEND study investigators.
Rheumatology 2018;57:1423–1431 DOI: 10.1093/rheumatology/key121
Two-year treatment of active, moderate-to-severe RA with sarilumab, along with dose reduction in the event of laboratory abnormalities, resulted in durable efficacy outcomes and a safety profile consistent with previous reports involving IL-6R inhibition. Durable long-term safety and efficacy, reduced joint damage progression, and conserving health-related quality of life and work productivity are important goals of therapy in RA.1 Sarilumab significantly reduced disease activity, improved phy...
Keywords: IL-6, Sarilumab, Clinical, Safety
Translated by: Igor Kos
July 18
Bermejo I, Ren S, Simpson E, Clowes M, Scott DL, Young A, Stevenson M.
Pharmacoeconomics. 2018 Dec;36(12):1427-1437. doi: 10.1007/s40273-018-0677-7
In this National Institute for Health and Care (NICE) single technology appraisal of sarilumab (SAR) monotherapy and combination therapy with methotrexate (MTX), SAR was considered to have similar efficacy to other bDMARDs for treating moderate-to-severe RA with inadequate response to cDMARDs or TNFis. SAR was also considered a cost-effective use of National Health Service (NHS) resources versus some or all of its comparators in most considered populations. NICE is an independent organisation r...
Keywords: IL-6, Sarilumab, Clinical, Phase 3
Translated by: Igor Kos
Genovese MC, Fleischmann R, Combe B, Hall S, Rubbert-Roth A, Zhang Y, Zhou Y, Mohamed M-EF, Meerwein S, Pangan AL.
Lancet 2018;391:2513–24
Upadacitinib (UPA) extended release formulation was effective in treating patients with moderate-to-severe RA with an inadequate response to bDMARDs. Phase 2 study data has shown that UPA is an efficacious and safe treatment for active RA.1,2 SELECT-BEYOND was a double-blind, long-term extension, Phase 3 study to assess the efficacy of UPA in patients with RA who were bDMARD-IR. The first 12-weeks of SELECT-BEYOND were placebo-controlled, with a double-blind period followed by an ongoing double...
Keywords: JAK, Upadacitinib, Clinical, Phase 3
Translated by: Igor Kos
Burmester GR, Kremer JM, Van den Bosch F, Kivitz A, Bessette L, Li Y, Zhou Y, Othman AA, Pangan AL, Camp HS.
Lancet 2018;391:2503–12
Patients with moderate-to-severe active RA had significant improvements in clinical signs and symptoms with upadacitinib (UPA) compared with placebo. In Phase 2 studies, UPA showed favourable efficacy when administered twice daily as an immediate-release formulation at doses of 6–12 mg in patients with active RA who had TNFi-IR.1,2 An extended-release formulation allowing once-daily (QD) administration was developed for Phase 3 studies. SELECT-NEXT was a double-blind, multicentre, Phase 3...
Keywords: JAK, Upadacitinib, Clinical, Phase 3
Translated by: Igor Kos
June 18
Frisell T, Baecklund E, Bengtsson K, Giuseppe DD, Forsblad-d’Elia H, Askling J, on behalf of the ARTIS Study Group.
Ann Rheum Dis 2018; 77:650–57 DOI: 10.1136/annrheumdis-2017-212395
Analysis of patient characteristics revealed that older and less healthy patients with RA were more likely to receive non-TNFi bDMARDs as a first bDMARD compared to other treatments. This study aimed to describe patient characteristics at initiation of bDMARD treatment at two-time points: first bDMARD initiation and switch to second bDMARD after TNFi treatment. The second aim of the study was to estimate the potential of treatment channelling to confound results in comparative treatment studies...
Keywords: IL-6, Tocilizumab, Real World, Efficacy
Translated by: Igor Kos
van der Heijde D, Dougados M, Chen YC, Greenwald M, Drescher E, Klar R, Xie L, de la Torre I, Rooney TP, Witt SL, Schlichting DE, de Bono S, Emery P.
RMD Open. 2018 May 8;4(1):e000662. DOI: 10.1136/rmdopen-2018-000662
Once daily baricitinib (BARI) inhibited radiographic progression of structural joint damage in patients with an inadequate response or intolerance to csDMARDs over 48 weeks. Current treatment goals aim to use DMARDs to inhibit structural joint damage and prevent long-term functional disability. In RA-BUILD¹, BARI was shown to significantly reduce radiographic joint damage progression in patients with active RA, with an intolerance or inadequate response to csDMARDs. Here, the authors repor...
Keywords: JAK, Baricitinib, Clinical, Radiographic
Translated by: Igor Kos
Strand V, Kavanaugh A, Kivitz AJ, van der Heijde D, Kwok K, Akylbekova E, Soonasra A, Snyder M, Connell C, Bananis E, Smolen JS.
Rheumatol Ther. 2018 Dec;5(2):341-353. doi: 10.1007/s40744-018-0113-7
Tofacitinib (TOF) therapy reduced the progression of structural joint damage at 2 years, in patients of all disease states, compared with patients given methotrexate (MTX). Early intervention with DMARDs aim to prevent the development of future RA symptoms and inhibit the progression of structural damage to the joints. This post-hoc analysis uses data from two Phase 3 TOF studies, to examine the efficacy of early intervention with TOF on long-term radiographic outcomes and disease activity sta...
Keywords: JAK, Tofacitinib, Clinical, Radiographic
Translated by: Igor Kos
May 18
Van Vollenhoven RF, Lee EB, Fallon L, Zwillich SH, Wilkinson B, Chapman D, Demasi R, Keystone E.
Arthritis Care Res (Hoboken) 2019 Jan;71(1):71-79. DOI: 10.1002/acr.23585
This post-hoc analysis of two, Phase 3 studies, ORAL Start and ORAL Standard shows that early treatment response can predict long-term disease activity outcomes. EULAR recommendations suggest that treat-to-target strategies require regular target assessments with treatment approaches changed if targets are not reached at 6 months. To optimize this strategy, therapy outcomes should be known, and the relationship between short and long-term outcomes defined. The current analysis focused on the d...
Keywords: JAK, Tofacitinib, Clinical, Efficacy
April 18
Ren S, Bermejo I, Simpson E, Wong R, Scott DL, Young A, Stevenson M.
Pharmacoeconomics 2018 Jul; 36(7):769–78
In this National Institute for Health and Care (NICE) single technology appraisal of baricitinib (BARI) monotherapy and combination therapy with methotrexate (MTX), BARI efficacy was considered comparable to bDMARDs and a cost-effective use of National Health Service (NHS) resources. NICE is an independent organisation responsible for providing national guidance on health technologies in England. To be recommended by NICE, the company must provide evidence to prove BARI’s effectiveness, b...
Keywords: JAK, Baricitinib, Clinical, Phase 3
Uttley L, Bermejo I, Shijie R, Martyn-St James M, Wong R, Scott DL, Young A, Stevenson M.
Pharmacoeconomics 2018 Sep; 36(9): 1063–72
In this National Institute for Health and Care (NICE) single technology appraisal of tofacitinib (TOF) plus methotrexate (MTX), TOF had similar efficacy and comparable costs to recommended bDMARDs plus MTX in patients with RA. NICE is an independent organisation responsible for providing national guidance on health technologies in England. To be recommended by NICE, the company must provide evidence to prove TOF’s effectiveness, both clinically and costly. This evidence based review, rep...
Keywords: JAK, Tofacitinib, Clinical, Phase 3
Machado MAÁ, Moura CS, Guerra SF, Curtis JR, Abrahamowicz M, Bernatsky S.
Arthritis Res Ther 2018; 20(1):60 doi: 10.1186/s13075-018-1539-6
A retrospective cohort study of tofacitinib (TOF) revealed that patients previously treated with methotrexate who initiated TOF, presented no differences in hospitalised infections or effectiveness, compared with non-TNF biologics. Currently, TOF is recommended in ACR and EULAR guidelines as an alternative to biologics after first-line cDMARD therapy. Previous indirect comparisons have shown that patients with RA who experience cDMARD failure show similar efficacy when given TNFis, abatacept, ...
Keywords: JAK, Tofacitinib, Real World, Safety
March 18
Fleischmann R, Wollenhaupt J, Cohen S, Wang L, Fan H, Bandi V, Andrews J, Takiya L, Bananis E, Weinblatt ME.
Rheumatol Ther 2018 Jun; 5(1):203–14. DOI: 10.1007/s40744-018-0093-7
Methotrexate (MTX) or Glucocorticoid (GC) discontinuation has little effect on CDAI response in patients given tofacitinib (TOF) for up to 3 years. Patients receiving TOF who showed initial improvements benefitted from initiation of MTX or GCs. Concomitant treatments such as MTX or GC are commonly used in combination with RA therapies to improve or accelerate clinical responses. However, their use is associated with many adverse events so clinicians aim to use them for a minimal duration. This ...
Keywords: JAK, Tofacitinib, Clinical, Efficacy
Translated by: Igor Kos
Genovese MC, Kremer JM, Kartman CE, Schlichting DE, Xie L, Carmack T, Pantojas C, Burston JS, Tony HP, Macias WL, Rooney TP, Smolen JS.
Rheumatology (Oxford) 2018 May; 57(5):900-908
Baricitinib (BARI) 2 or 4 mg had a beneficial treatment effect on patients with moderate to severe RA compared with placebo (PBO), irrespective of the number or nature of prior patient bDMARD use. The current therapeutic target for patients with established RA is low disease activity, but many patients fail to achieve this due to inadequate responses to DMARD therapies. With this patient population growing, therapies for these patients are considered one of the greatest unmet needs in RA. This...
Keywords: JAK, Baricitinib, Clinical, Efficacy
Translated by: Igor Kos
February 18
Edwards CJ, Ӧstӧr AJK, Naisbett-Groet B, Kiely P.
Rheumatology (Oxford) 2018;57(1):84–91
Methotrexate (MTX) tapering in patients with active, severe RA receiving intravenous tocilizumab (TCZ) was non-inferior to continuing stable MTX doses in maintaining a good/moderate EULAR response. Although MTX and bDMARD combination therapy may produce better response rates than bDMARD monotherapy, one third of patients discontinue or are non-compliant with MTX due to preference or toxicity. This randomised, non-inferiority study investigated the efficacy and tolerability of MTX tapering and ...
Keywords: IL-6, Tocilizumab, Clinical, Phase 3
Translated by: Igor Kos
January 18
Choy E, Caporali R, Xavier R, Fautrel B, Sanmarti R, Bao M, Bernasconi C, Pethö-Schramm A.
Rheumatology (Oxford). 2018 Mar 1;57(3):499-507. DOI: 10.1093/rheumatology/kex443
This multi-national TOZURA study programme confirmed the efficacy and safety profile of subcutaneous tocilizumab (TC-SC) when administered as either monotherapy or in combination with csDMARDs. TOZURA was a Phase 4 study programme that evaluated open-label, TCZ-SC in patients with moderate-to-severe RA. A total of 1804 patients with active RA were enrolled in the study programme. Patients had inadequate responses to csDMARDs, anti-TNF therapies, or they were MTX-naïve. TCZ-SC was administe...
Keywords: IL-6, Tocilizumab, Clinical, Phase 4
Translated by: Igor Kos
Kivitz A, Olech E, Borofsky MA, Zazueta B, Navarro-Sarabia F, Radominski SC, Merrill JT, Pacheco-Tena C, Pei J, Nasmyth-Miller, Pope JE.
J Rheumatol 2018 Apr; 45(4):456-464
This 2-year Phase 3 study, proved that subcutaneous tocilizumab (TC-SC) has long-term efficacy and an acceptable safety profile. Patients enrolled had been previously diagnosed with RA with an inadequate response to DMARDs. Patients were randomised 2:1 to receive doses of TCZ-SC (n=437) or PBO (n=219) every other week for 6 months. After this time, all patients received TCZ-SC. Escape therapy, defined as weekly TCZ-SC, was available to patients from Month 3. Efficacy was analysed using ACR resp...
Keywords: IL-6, Tocilizumab, Clinical, Phase 3
Translated by: Igor Kos
Teitsma XM, Jacobs JWG, Welsing PMJ, Pethö-Schramm A, Borm MEA, Hendriks L, Denissen NHAM, van Laar JM, Lafeber FPJG, Bijlsma JWJ.
Rheumatology (Oxford) 2017 Dec 1;56(12):2179-2189 doi: 10.1093/rheumatology/kex319
Patient-reported outcomes (PROs) vastly improved in the first 24 weeks post-initiation of tocilizumab (TCZ) therapies compared to methotrexate (MTX) monotherapy in the U-Act-Early trial. U-Act-Early was a two-year, treat-to-target study that compared the safety and efficacy of TCZ and MTX treatment strategies in DMARD-naïve patients with early RA. Sustained remission was classed as more effective in patients given TCZ monotherapy or combination therapy with MTX compared to MTX alone. TCZ th...
Keywords: IL-6, Tocilizumab, Clinical, PRO
Translated by: Igor Kos
December 17
Baganz L, Richter A, Kekow J, Bussmann A, Krause A, Stille C, Listing J, Zink A, Strangfeld A.
Rheumatol Int 2018 Apr; 38(4):579-87
In this observational study, the German RABBIT cohort was used to assess the long-term effectiveness and retention rates of tocilizumab (TCZ) in patients with prior bDMARD failures. Results of the study suggested that TCZ could be an effective treatment option for patients with difficult-to-treat RA. A total of 885 patients were involved in the study and these were categorised dependent on the number of bDMARD failures they had prior to TCZ treatment. Patient data recorded in the cohort include...
Keywords: IL-6, Tocilizumab, Real World, Efficacy
Translated by: Igor Kos
Charles-Schoeman C, van der Heijde D, Bumester GR, Nash P, Zerbini CAF, Connell CA, Fan H, Kwok K, Bananis E, Fleischmann R.
J Rheumatol 2018 Feb; 45(2):177-87
In this post hoc analysis, six Phase 3 studies were used to analyse the effect of glucocorticoids (GC) on the efficacy of tofacitinib (TOF) in patients with RA. Concomitant use of GC did not affect the clinical or radiographic outcomes of patients treated with TOF. Data from all six clinical trials were evaluated, with four studies (ORAL Scan, ORAL Standard, ORAL Sync and ORAL Step) being pooled for analysis. In these studies, MTX was used as a comparison and patients were required to maintain ...
Keywords: JAK, Tofacitinib, Clinical, Phase 3
Translated by: Igor Kos
Schwartz DM, Kanno Y, Villarino A, Ward M, Gadina M, O’Shea JJ.
Nat Rev Drug Discov 2017;16:843–62 DOI: 10.1038/nrd.2017.201
Janus kinases (JAKs) are essential mediators of downstream signaling pathways in many inflammatory and autoimmune diseases. This review summarizes current clinical data on first- and second-generation JAK inhibitors (jakinibs) and discusses their use for the treatment of immune and inflammatory conditions. First generation jakinibs such as tofacitinib, baricitinib, and ruxolitinib, non-selectively inhibit JAK-dependent pro-inflammatory cytokines, which are major contributors to immunopathology. ...
Keywords: JAK, Tofacitinib, Clinical, Efficacy
Translated by: Igor Kos
Kim ST, Tayar J, Trinh VA, Suarez-Almazor M, Garcia S, Hwu P, Johnson DH, Uemura M, Diab A.
Ann Rheum Dis 2017;76:2061-64. doi: 10.1136/annrheumdis-2017-211560
This case series evaluated the use of tocilizumab (TCZ) as an effective treatment for patients who develop arthritis as an adverse event (AE) of immune checkpoint inhibitor (ICI) cancer treatment. Results suggested that TCZ was an effective treatment, as it reduced the arthritis disease progression. ICIs have been defined as a revolutionary treatment for metastatic melanomas; however, a common AE is the development of polyarthritis. Current arthritis treatments reduce the efficiency of ICI thera...
Keywords: IL-6, Tocilizumab, Clinical, PRO
Translated by: Igor Kos
Mori S, Yoshitama T, Ueki Y.
Intern Med. 2018 Mar 1;57(5):663-670. doi: 10.2169/internalmedicine.9341-17
This 6-month prospective direct comparison study analysed the effectiveness of tofacitinib (TOF) therapy on bDMARD-naïve and bDMARD-experienced patients. bDMARD-naïve patients were more responsive to TOF therapy than bDMARD-experienced patients. The study analysed the data of 113 patients diagnosed with high or moderate disease activity, defined using CDAI scores. All patients had failed to achieve CDAI low disease activity or remission with MTX therapy for ≥3 months. Patients were...
Keywords: JAK, Tofacitinib, Clinical, Efficacy
Translated by: Igor Kos
November 17
Winthrop KL, Curtis JR, Lindsey S, Tanaka Y, Yamaoka K, Valdez H, Hirose T, Nduaka CI, Wang L, Mendelsohn AM, Fan H, Chen C, Bananis E.
Arthritis Rheumatol 2017;69(10):1960–68
The results of this analysis of patients with herpes zoster (HZ) within the global tofacitinib (TOF) RA programme suggest that there is likely to be a greater HZ risk in patients receiving TOF and glucocorticoids compared with patients receiving TOF monotherapy. The global TOF RA development programme comprised 2 Phase 1, 9 Phase 2, 6 Phase 3 and 2 long-term extension studies. These studies included 6192 patients; data were reviewed to identify cases of HZ. Crude incidence rates of number of pa...
Keywords: JAK, Tofacitinib, Clinical, Safety
Translated by: Igor Kos
Mease P, Hall S, FitzGerald O, van der Heijde D, Merola J F, Avila-Zapata F, Cieslak D, Graham D, Wang C, Menon S, Hendrikx T, Kanik K S.
N Engl J Med 2017; 377:1537-50. DOI: 10.1056/NEJMoa1615975
In the Phase 3 OPAL Broaden trial of patients with active psoriatic arthritis (PsA) with inadequate response to ≥1 csDMARD, superior efficacy was observed in patients treated with tofacitinib (TOF) compared with those given placebo. Patients were randomised to: 5 mg TOF BID, 10 mg TOF BID, 40 mg adalimumab administered subcutaneously q2W, or placebo with a switch to 5 mg TOF at Month 3. Adalimumab was used as an active control in the study. A variety of primary and secondary endpoints wer...
Keywords: JAK, Tofacitinib, Clinical, Phase 3
Translated by: Igor Kos
Gladman D, Rigby W, Azevedo VF, Behrens F, Blanco R, Kaszuba A, Kudlacz E, Wang C, Menon S, Hendrikx T, Kanik KS.
N Engl J Med 2017;377:1525–36.
The study data presented that tofacitinib (TOF) improves efficacy response rates in patients with severe psoriatic arthritis (PsA) who have an inadequate response to TNF inhibitors. The Phase 3 Oral Psoriatic Arthritis Trial (OPAL) Beyond study evaluated patients with active PsA who had inadequate responses to more than one TNFi. Patients were randomised 2:2:1:1 to 5 mg TOF BID or 10 mg TOF BID for 6 months; or PBO, with a switch to 5 mg TOF BID or to 10 mg BID at 3 months. Primary endpoints w...
Keywords: JAK, Tofacitinib, Clinical, Phase 3
Translated by: Igor Kos
Fleischmann R, Alam J, Arora V, Bradley J, Schlichting DE, Muram D, Smolen JS.
RMD Open. 2017; 3(2): e000546. doi: 10.1136/rmdopen-2017-000546
In this post hoc analysis of pooled data from two randomised controlled trials, RA-BUILD and RA-BEAM, age was shown not to be a contraindication for use of baricitinib. Patients in RA-BUILD were csDMARD-inadequate responder(IR) patients who received an oral placebo or 2 mg or 4 mg baricitinib once daily. Patients in RA-BEAM were MTX-IR patients and received an oral placebo, 4 mg baricitinib once daily or subcutaneous adalimumab every 2 weeks. Efficacy and safety of baricitinib in elderly patie...
Keywords: JAK, Baricitinib, Clinical, Phase 3
Translated by: Igor Kos
September 17
Winthrop KL, Yamanaka H, Valdez H, Mortensen E, Chew R, Krishnaswami S, Kawabata T, Riese R.
Arthritis Rheumatol 2014;66:2675–84
Patients who were treated with tofacitinib in the RA clinical development programme were more likely to develop herpes zoster than were those who received placebo. Cases of herpes zoster reported by investigators in the Phase 2, Phase 3 and long-term extension studies of tofacitinib were evaluated. Herpes zoster was noted in 5% of tofacitinib-treated patients; only 7% of these cases were serious, no patients with herpes zoster died and only 10% permanently discontinued tofacitinib treatment. T...
Keywords: JAK, Tofacitinib, Clinical, Safety
Translated by: Igor Kos
Keystone EC, Genovese MC, Schlichting DE, de la Torre I, Beattie SD, Rooney TP, Taylor PC.
J Rheumatol. 2018 Jan;45(1):14-21. doi: 10.3899/jrheum.161161
This open-label extension (OLE) of a Phase 2b randomised controlled trial (RCT) found that safety data collected over 2 years of treatment were generally consistent with previous findings for baricitinib in RA. In the RCT, baricitinib demonstrated significant improvement in disease activity compared with placebo and an acceptable safety profile in patients with RA and an inadequate response to MTX. Patients who completed the 24-week double-blind period of the study were eligible for the OLE. Ra...
Keywords: JAK, Baricitinib, Clinical, Phase 2
Translated by: Igor Kos
August 17
Park JS-K, Lee MY, Jang E-J, Kim H-L, Ha D-M, Lee E-K.
Clin Exp Rheumatol 2017;35:689–99
Based on a Bayesian network meta-analysis (NMA) in patients with RA who previously showed failure with csDMARDs or biologics, discontinuation rates between tofacitinib (TOF) and biologics (TNFis, abatacept [ABT], rituximab [RTX] and tocilizumab [TCZ]) differed based on previous treatments and reasons for discontinuation. Data were collected from randomised controlled trials (RCT) found from literature searches from the Cochrane Central Register of Controlled Trials (CENTRAL) and MEDLINE. Discon...
July 17
Choy EH, Bernasconi C, Aassi M, Molina JF, Epis OM.
Arthritis Care Res (Hoboken). 2017 Oct;69(10):1484-1494. doi: 10.1002/acr.23303
To date, the comparative efficacy of tocilizumab and TNFi for patients with RA has only been investigated in a single head-to-head trial and network meta-analyses. This study, ACT-iON, is the first prospective, large-scale, global, multicentre, comparative effectiveness study comparing initiation of intravenous tocilizumab with initiation of a TNFi in patients with RA as the first-line biologic treatment after inadequate response to csDMARDs. Patients were observed in a real-world, clinical pra...
Keywords: IL-6, Tocilizumab, Real World, Efficacy
Translated by: Igor Kos
Fleischmann R, Mysler E, Hall S, Kivitz A, Moots R, Luo Z, DeMasi R, Soma K, Zhang R, Takiya L, Tatulych S, Mojcik C, Krishnaswami S, Menon S, Smolen J, on behalf of the ORAL Strategy investigators.
Lancet. 2017 Jul 29;390(10093):457-468. doi: 10.1016/S0140-6736(17)31618-5
In this first head-to-head non-inferiority trial assessing a JAKi ± MTX directly compared with a TNFi + MTX in patients with RA, tofacitinib (TOF) + MTX showed non-inferiority to adalimumab (ADA) + MTX. Non-inferiority was not shown for TOF monotherapy versus TOF + MTX, or versus ADA + MTX. In this 52-week study, MTX-inadequate responder (IR) patients were randomised 1:1:1 to receive TOF 5 mg BID monotherapy, TOF 5 mg BID + MTX or ADA 40 mg every other week + MTX. The primary endpoint, A...
Keywords: JAK, Tofacitinib, Clinical, Efficacy
Translated by: Igor Kos
Vanhoutte F, Mazur M, Voloshyn O, Stanislavchuk M, Van der Aa A, Namour F, Galien R, Meuleners L, van ‘t Klooster G.
Arthritis Rheumatol. 2017 Oct;69(10):1949-1959. doi: 10.1002/art.40186
In two 4-week exploratory Phase 2a trials in MTX-inadequate responder (IR) patients with RA, the highly selective JAK1 inhibitor filgotinib met the primary endpoint of ACR20 at Week 4, showing greater response than placebo. Study 1, a proof-of-concept study, included 127 patients randomised to placebo, filgotinib 100 mg BID or filgotinib 200 mg QD. Study 2, was a dose-ranging study and included 91 patients randomised to placebo, filgotinib 30 mg QD, filgotinib 75 mg QD, filgotinib 150 mg QD or ...
Keywords: JAK, Filgotinib, Clinical, Phase 2
Translated by: Igor Kos
June 17
A Kavanaugh, J Kremer, L Ponce, R Cseuz, O V Reshetko, M Stanislavchuk, M Greenwald, A Van der Aa, F Vanhoutte, C Tasset and P Harrison.
Ann Rheum Dis 2017;76:1009–19
In these two Phase 2b studies, filgotinib (a selective JAK-1 inhibitor) was shown to improve the signs and symptoms of RA (compared with placebo), either as monotherapy or when added to MTX. DARWIN 1 included 594 patients with moderate to severe RA on a stable dose of MTX, while DARWIN 2 included 283 patients who stopped taking MTX before the start of the study. After 12 weeks’ treatment, significantly more patients who were receiving filgotinib 100 mg or 200 mg daily in DARWIN 1 or any ...
Keywords: JAK, Filgotinib, Clinical, Phase 2
Translated by: Igor Kos
R Westhovens, P C Taylor, R Alten, D Pavlova, F Enríquez-Sosa, M Mazur, M Greenwald, A Van der Aa, F Vanhoutte, C Tasset and P Harrison.
Ann Rheum Dis 2017;76:998–100
In these two Phase 2b studies, filgotinib (a selective JAK-1 inhibitor) was shown to improve the signs and symptoms of RA (compared with placebo), either as monotherapy or when added to MTX. DARWIN 1 included 594 patients with moderate to severe RA on a stable dose of MTX, while DARWIN 2 included 283 patients who stopped taking MTX before the start of the study. After 12 weeks’ treatment, significantly more patients who were receiving filgotinib 100 mg or 200 mg daily in DARWIN 1 or any ...
Keywords: JAK, Filgotinib, Clinical, Phase 2
Translated by: Igor Kos
May 17
Rendas-Baum R, Kosinski M, Singh A, Mebus CA, Wilkinson BE and Wallenstein GV.
Rheumatology doi: 10.1093/rheumatology/kex087
The results of this post hoc analysis of two Phase 3 studies of tofacitinib (TOF) show that improvements in health-related quality of life related to TOF treatment are likely to translate into significant reductions in estimated medical expenditure and likelihood of current and future job loss. Data from 399 MTX inadequate responder (IR) patients from ORAL Step, and 716 TNF inhibitor (TNFi)-IR patients from ORAL Standard were included in this analysis. Patients were receiving 5 mg or 10 mg TOF...
Burmester GR, Rigby WF, van Vollenhoven RF, Kay J, Rubbert-Roth A, Blanco R, Kadva A and Dimonaco S.
Ann Rheum Dis Published Online First: 7 April 2017. Doi 10.1136/annrheumdis-20160210561
Burmester et al. present data showing that 52-week efficacy and safety of intravenous tocilizumab plus methotrexate, or tocilizumab monotherapy are maintained through to Week 104 in patients with early rheumatoid arthritis. Patients were assigned to four treatment groups: 4 mg/kg TCZ + MTX, 8 mg/kg TCZ + MTX, 8 mg/kg TCZ + placebo or placebo + MTX. Patients not achieving DAS28 ≤3.2 at Week 52 and who were not receiving 8 mg/kg TCZ were rescued to 8 mg/kg TCZ + MTX. Of the 1162 randomly assi...
April 17
Strand V, Reaney M, Chen C-I, Proudfoot CWJ, Guillonneau S, Bauer D, Mangan E, Graham NMH, van Hoogstraten H, Lin Y, Pacheco-Tena C, Fleischmann R.
RMD Open 2017;3:e000416. DOI:10.1136/rmdopen-2016-000416
Evidence is presented that treatment with sarilumab demonstrates patient-reported benefits in TNF-IR patients with moderate to severe RA. These improvements complement the clinical efficacy previously reported for sarilumab, and are consistent with those seen in the MOBILITY trial (MTX-IR patients)1, yet in a more difficult-to-treat population. Data were analysed from the 24-week Phase 3 TARGET randomised controlled trial in adult patients with active RA and previous inadequate response or into...
March 17
Kremer JM, Emery P, Camp HS, Friedman A, Wang L, Othman AA, Khan N, Pangan AL, Jungerwirth S and Keystone EC.
Arthritis Rheumatol 2016;68:2867–77
The summary and accompanying slide deck have been developed in conjunction with the Genovese et al. study (Study 1) which examined ABT-494 in MTX-IR patients in order to compare and contrast the data. In these two Phase 2b studies, ABT-494 (a novel selective JAK-1 inhibitor) was shown to be effective in patients with active RA who were non-responders to MTX or at least one TNF inhibitor. Patients with active RA who had an inadequate response to MTX (study 1) or were refractory to or intoleran...
Genovese MC, Smolen JS, Weinblatt ME, Burmester GR, Meerwein S, Camp HS, Wang L, Othman AA, Khan N, Pangan AL and Jungerwirth S.
Arthritis Rheumatol 2016;68:2857–66
The summary and accompanying slide deck have been developed in conjunction with the Kremer et al. study (Study 2) which examined ABT-494 in TNF-IR patients in order to compare and contrast the data. In these two Phase 2b studies, ABT-494 (a novel selective JAK-1 inhibitor) was shown to be effective in patients with active RA who were non-responders to MTX or at least one TNF inhibitor. Patients with active RA who had an inadequate response to MTX (study 1) or were refractory to or intolerant ...
Curtis JR, Schulze-Koops H, Takiya L, Mebus CA, Terry KK, Biswas P and Jones TV.
Clin Exp Rheumatol 2017 Jan 4
In this analysis of patients with moderate to severe RA treated with tofacitinib (TOF) in Phase 3 and long-term extension (LTE) studies, patients aged 65 years had similar efficacy and a numerically higher risk of SAEs and discontinuations due to AEs compared with younger patients. The Phase 3 population included patients from five trials (n=3111) of TOF 5 mg or 10 mg BID or placebo. The LTE population (n=4102) included patients from two studies who had participated in Phase 1, 2 or 3 TOF stud...
Aletaha D, Bingham CO 3rd, Tanaka Y, Agarwal P, Kurrasch R, Tak PP and Popik S.
Lancet 2017;pii:S0140-6736(17)30401-4
In this Phase 3 multicentre, randomised controlled trial in patients with active RA who were refractory or intolerant to previous biological treatment with at least one TNF inhibitor, sirukumab 50 mg every four weeks (Q4W) or 100 mg every two weeks (Q2W) was well tolerated and significantly improved signs and symptoms of disease. Patients were randomised 1:1:1 to placebo (n=294), sirukumab 50 mg Q4W (n=292) or sirukumab 100 mg Q2W (n=292), while continuing any concomitant DMARDs. Of the 878 ran...
February 17
Genovese MC, Greenwald M, Codding C, Zubrzycka-Sienkiewicz A, Kivitz AJ, Wang A, Shay K, Wang X, Garg JP, Cardiel MH.
Arthritis Rheumatol DOI 10.1002/art.40054. Accepted article.
In this Phase 2b study in patients with moderate to severe RA, once-daily peficitinib in combination with limited csDMARDs reduced the symptoms of RA, demonstrated a dose-dependent ACR20 response rate over 12 weeks, and showed acceptable tolerability. This 12-week study included patients who had an inadequate response or intolerance to csDMARDs (N=289). Patients were randomised 1:1:1:1:1 to peficitinib 25-, 50-, 100, 150 mg or matching placebo. Statistically significant differences in the AC...
Dougados M, van der Heijde D, Chen Y-C, Greenwald M, Drescher E, Liu J, Beattie S, Witt S, de la Torre I, Gaich C, Rooney T, Schlichting D, de Bono S, Emery P.
Ann Rheum Dis 2017;76:88–95.
Baricitinib improved symptoms of RA in the RA-BUILD trial, a Phase 3 study of baricitinib in patients with moderately to severely active RA, refractory to or intolerant to csDMARDs. As well as providing a short-term (24 weeks) benefit, there appeared to be joint damage benefit, considered a marker of long-term disability. RA-BUILD was a 24-week randomised, double-blind, placebo-controlled parallel-group study. Patients were randomised 1:1:1 to receive once-daily doses of placebo (n=228) or bari...
January 17
Jones G, Wallace T, McIntosh MJ, Brockwell L, Gómez-Reino JJ, Sebba A.
J Rheumatol 2017;44:2. DOI 10.3899/jrheum.160287.
Results from the AMBITION study (Actemra versus Methotrexate double-Blind Investigate Trial In mONotherapy), showed the continuing efficacy and safety of tocilizumab up to 264 weeks. AMBITION was a 24-week randomised controlled trial in patients with active RA who were either MTX-naïve or MTX-free for 6 months prior to study entry. Patients received TCZ 8 mg/kg IV Q4W or oral MTX weekly (7.5 mg dose escalating to 20 mg). For those patients who then entered the long-term extension (LTE) stu...
December 16
Fleischmann R, van Adelsberg J, Lin Y, da Rocha, Castelar-Pinheiro G, Brzezicki J, Hrycaj P, Graham NMH, van Hoogstraten H, Bauer D, Burmester GR.
Arthritis Rheumatol 2016. DOI:10.1002/art.39944.
In this Phase 3 study (TARGET) of TNF-IR patients, sarilumab plus csDMARD(s) demonstrated clinical efficacy and improvements in physical function versus placebo plus csDMARD(s). Patients (N=546) were randomised 1:1:1 to sarilumab 150 mg, 200 mg Q2W or placebo (all plus csDMARD[s]). Two co-primary endpoints versus placebo were investigated: ACR20 response rate at Week 24, and HAQ-DI change from baseline at Week 12. As well as improvements in ACR20 responses (33.7% vs 55.8 and 60.9%, for placebo...
Burmester GR, Lin Y, Patel R, van Adelsberg J, Mangan EK, Graham NMH, van Hoogstraten H, Bauer D, Vargas JI, Lee E-B.
Ann Rheum Dis 2016. DOI 10.1136/annrheumdis-2016-210310
In this Phase 3 superiority study (MONARCH) of patients with active RA who should not continue treatment with MTX because of intolerance or inadequate response, sarilumab monotherapy demonstrated superior efficacy to adalimumab (ADA) monotherapy. Patients receiving sarilumab versus ADA also reported greater improvement in health status, including a trend towards greater improvement in fatigue. In this randomised, multicentre study, patients received sarilumab 200 mg Q2W plus placebo (n=184) or ...
Kivitz AJ, Gutierrez-Ureña SR, Poiley J, Genovese MC, Kristy R, Shay K, Wang X, Garg JP, Zubrzycka-Sienkiewicz A.
Arthritis & Rheum 2016; ePub ahead of print
This Phase 2b study of peficitinib (ASP015K), an orally administered once-daily JAK inhibitor, plus MTX, demonstrated efficacy across multiple secondary endpoints with higher peficitinib doses. Peficitinib in combination with MTX was well tolerated with a safety profile that was consistent with previous studies. A high placebo response rate was seen in both Latin and North America, when patient data were stratified. This high placebo rate is problematic for the accurate interpretation of pefic...
Genovese M, Yang F, Østergaard M and Kinnman N.
Ann Rheum Dis 2016;75:1979–83
This Phase 2b study of VX-509 (decernotinib), a selective JAK3 inhibitor, showed that VX-509 in combination with stable DMARD therapy was effective for improving synovitis and osteitis as assessed by MRI in patients who had an inadequate response to DMARD therapy. Patients were randomised to treatment groups receiving either placebo, VX-509 100 mg, 200 mg or 300 mg for 12 weeks. Minimum inclusion criteria included Grade ≥2 clinical synovitis in either the wrist or two metacarpophalangeal joi...
Fleischmann F, Schiff M, van der Heijde D, Ramos-Remus C, Spindler A, Stanislav M, Zerbini CAF, Gurbuz S, Dickson C, de Bono S, Schlichting D, Beattie S, Kuo W-L, Rooney T, Macias W, Takeuchi T.
Arthritis Rheumatol 2016. DOI 10.1002/art.39953. Accepted article
In this 52-week study of patients receiving initial therapy for RA, baricitinib alone or in combination with MTX demonstrated superior efficacy compared with MTX alone. Patients naïve to csDMARD (no or <3 doses of MTX) or bDMARD were randomised 4:3:4 (N=588) to MTX QW, baricitinib 4 mg QD or baricitinib 4 mg QD + MTX QW. The primary endpoint assessment was noninferiority of baricitinib monotherapy to MTX based on ACR20 response at Week 24. Not only was the primary endpoint met, baricit...
October 16
Teitsma XM, Marijnissen AKA, Bijlsma JWJ, Lafeber FPJ, Jacobs JWG.
Arthritis Res Ther 2016; 18:211. DOI 10.1186/s13075-016-1108-9
This is the first meta-analysis comparing efficacy and safety of TCZ monotherapy (TCZMONO) versus TCZ + csDMARD (TCZCOMBI) in patients with RA. The findings show that similar efficacy can be expected with TCZ monotherapy in patients with intolerance to csDMARDs compared with inadequate responders to csDMARDs who switch to TCZ add-on therapy. A total of 6679 patients from 13 studies were included, receiving: 1298, TCZMONO; 3077, TCZCOMBI; 2204, csDMARDs. Meta-analyses were performed for the foll...
Strand V, Kosinski M, Chen C-I, Joseph G, Rendas-Baum R, Graham NMH, van Hoogstraten H, Bayliss M, Fan C, Huizinga T, Genovese MC.
Arthritis Res Ther 2016; 18:198. DOI.10.1186/s13075-016-9
Evidence is presented that treatment with sarilumab improves patient-reported outcomes (PROs). These improvements complement the clinical efficacy previously reported for sarilumab. Data were analysed from the 52-week Phase 3 MOBILITY randomised controlled trial in adult patients with active RA and previous inadequate response to MTX. Patients received subcutaneous placebo or sarilumab 150 mg or 200 mg every 2 weeks in combination with MTX, for 52 weeks. PROs assessed were: Patient Global Asse...
August 16
Genovese M, Smolen J, Weinblatt M, Burmester G, Meerwein S, Camp H, Wang L, Othman A, Khan N, Pangan A, Jungerwirth S.
Arthritis Rheumatol 2016; Accepted article DOI 10.1002/art-39808 [Epub 2016]
This dose-ranging study evaluated the efficacy of the novel, selective JAK1 inhibitor ABT-494 versus placebo in patients with moderate-to-severe RA and inadequate response (IR) to MTX. In this 12-week, randomised, double-blind study (BALANCE II), the efficacy and safety of ABT-494 dosed at 3mg, 6 mg, 12 mg, 18 mg (all twice daily) and 24 mg (once daily) was assessed. Patients included had not received prior biologic therapy. Of the 299 patients included in the analysis, the proportions of pati...
July 16
Genovese, et al.
Arthritis Research & Therapy. 2016. DOI 10.1186/s13075-016-1049-3 [Epub ahead of print]
Results are reported from an analysis exploring the safety and efficacy of open-label tofacitinib (TOF) following blinded treatment with TOF or adalimumab (ADA) in patients with moderate to severe RA. The analysis included patients from ORAL Sequel, an open-label long-term extension study, which all patients entered following ORAL Standard (one of the studies in the TOF phase 3 program). Only those patients who had been randomized to ADA 40 mg Q2W + MTX or 10 mg TOF + MTX in ORAL Standard were...
Takeuchi et al.
Ann Rheum Dis. 2016 Jun;75:1057-64. doi: 10.1136/annrheumdis-2015-208279. Epub 2015 Dec 15
Peficitinib (ASP015K) is a novel orally bioavailable JAK inhibitor in development for the treatment of RA. It inhibits JAK1, JAK2, JAK3 and Tyk2 enzyme activities and has moderate selectivity or JAK3 inhibition. Here the authors report the findings of a 12-week, randomized, double-blind, placebo-controlled phase IIb study evaluating efficacy, safety and dose response of peficitinib (25, 50, 100, or 150 mg) as once-daily oral monotherapy in Japanese patients with moderate to severe RA. The prim...
Notario Ferreira, Ferrer González MA, Morales Garrido P, et al.
Reumatol Clin. 2016; May 10 doi: 10.1016/j.reuma.2016.03.014 [Epub ahead of print]
The efficacy and safety of tocilizumab has been studied in several randomized clinical trials (RCTs) but due to the strict inclusion and exclusion criteria of RCTs, real-life observational studies are needed to supplement the findings from these trials. This small longitudinal, open-label study from an outpatient clinic in Spain evaluated the effectiveness, survival rate and reasons for treatment discontinuations in 85 patients treated with tocilizumab over a 24-month period. The study also as...
Tanaka Y, Emoto K, Cai Z, et al.
J Rheumatol. 2016;43(3):504–511.
Clinical trials have shown baricitinib once daily to be effective in patients with RA. However, this Janus kinase (JAK) 1/JAK2 inhibitor has not been evaluated in a Japanese population. In this 12-week, placebo-controlled study, 145 Japanese patients were enrolled and received placebo, 1 mg, 2 mg, 4 mg or 8 mg oral baricitinib daily. Efficacy results were encouraging and consistent with earlier trials. Significantly more baricitinib patients achieved ACR20 response at Week 12 of treatment compa...
May 16
Mease et al.
Arthritis Rheumatol. 2016 Mar 24. DOI 10.1002/art.39700 [Epub ahead of print]
Encouraging results have been seen with clazakizumab in RA, but the results of anti-IL6 therapy in patients with psoriatic arthritis (PsA) have so far been unclear. This Phase 2b dose-ranging study examined the efficacy and safety of clazakizumab given subcutaneously q4w, with or without MTX, in 165 patients with PsA who had inadequate response to NSAIDs. ACR20 response at Week 16, the primary endpoint, was significantly higher in patients receiving clazakizumab 100 mg compared with placebo (52...
Genovese et al.
N Engl J Med. 2016 Mar 31;374(13):1243-52. doi: 10.1056/NEJMoa1507247
For patients who have an inadequate response or unacceptable side effects associated with biologic DMARDs, the options for treatment beyond conventional DMARDs are limited. This phase 3 trial of the JAK 1/2 inhibitor, baricitinib, studied its efficacy in bDMARD-IR patients. 527 patients were randomized to either baricitinib 2mg, 4mg or placebo for up to 24 weeks. At week 12 the primary endpoints were tested hierarchically to control type 1 error; these endpoints were ACR20, HAQ-DI score, DAS28...
March 16
Weber-Schoendorfer et al.
Reproductive Toxicology doi:10.1016/j.reprotox.2016.01.002
MTX users have an increased incidence of spontaneous abortions (SABs) compared to baseline risk (42.5%1 vs. 13-17%2). Tocilizumab (TCZ) has been shown to have similar efficacy with or without MTX. There is currently limited data on the effect of TCZ on pregnancy, but with more safety data, TCZ could be an alternative for RA patients of reproductive age. The patients were enrolled at Embryotox Berlin, a pharmacovigilance center providing risk assessment during pregnancy, between 2011 and 2014 d...
Kaneko et al.
Ann Rheum Dis 2016 Jan 5 DOI: 10.1136/annrheumdis-2015-208426 [Epub ahead of print
MTX is the primary drug in RA management because of its long-term effectiveness and safety profile; however, in patients who have insufficient response (IR) to MTX, treatment adjustments are needed – either to combine a bDMARD with MTX or to switch to a bDMARD from MTX. In the SURPRISE study, the efficacy and safety of adding TCZ to MTX (ADD-ON) or switching MTX to TCZ (SWITCH) was evaluated in 233 patients with moderate to highly active RA who were randomised 1:1. Both treatment groups we...
January 16
Genovese MC, van Vollenhoven RF, Pacheco-Tena C, Zhang Y, Kinnman N.
Arthritis Rheumatol. 2016 Jan;68(1):46-55.
VX-509 (decernotinib) is a novel oral, selective inhibitor of JAK-3. JAK-3 is a member of the JAK signalling family that is primarily expressed in hematopoietic cells and associates with only the common γ-chain making it a promising therapeutic drug target. A phase IIb 24-week study of VX-509 in 358 patients with RA, who had prior inadequate response to MTX, uses ACR20 response rate and DAS28-CRP change at Week 12 to assess the efficacy of VX-509. Patients were administered either placebo+...
October 15
C Gabay, M Riek, ML Hetland, EM Hauge, K Pavelka, M Tomšič, H Canhao, K Chatzdionysiou, G Lukina, DC Nordström, E Lie, I Ancuta, MV Hernández, PLMC van Riel, R van Vollenhoven, TK Kvien.
Ann Rheum Dis. 2015 Sep 15. doi:10.1136/ annrheumdis-2015-207760
Biological DMARDs have markedly changed the management and outcome of rheumatoid arthritis. Most international guidelines recommend the use of biological DMARDs in combination with MTX or other synthetic DMARDs (sDMARDs) (where MTX is not tolerated or contraindicated), based primarily on the observation that MTX enhances the efficacy of TNF antagonists in both clinical trials and observational studies. This study examined the effectiveness of tocilizumab (TCZ), an anti-IL-6 monoclonal antibody,...
Takeuchi T, Tanaka Y, Yamanaka H, Amano K, Nagamine R, Park W, Shiozawa K, Tsukano M, Wei J, Shao J, Togo O, Mashimo H.
Modern Rheumatology. 2015 Sep 10:1-9. [Epub ahead of print]
This Phase II study assessed the safety and efficacy of olokizumab in Asian patients with moderate-to-severe rheumatoid arthritis, previously exposed to anti-TNF therapy. After 12 weeks of treatment, olokizumab was found to rapidly improve disease activity in patients who had previously failed anti-TNF therapy. There was also a significant decrease in ACR20 and ACR50 responder rates at week 12. The safety findings were consistent with the safety profile expected for this drug class. These findin...
Kubo S, Nakayamada S, Nakano K, Hirata S, Fukuyo S, Miyagawa I, Hanami K, Saito K, Tanaka Y.
Annals of the Rheumatic Diseases. 2015 Aug 5. doi:pii: annrheumdis-2015-207784. 10.1136/annrheumdis-2015-207784. [Epub ahead of print]
This study compared the clinical outcomes at one year after the treatment either abatacept or tocilizumab in routine clinical practice. This study employed propensity score matching and demonstrated that abatacept and tocilizumab had comparable continuing efficacies, and that treatment with the drugs resulted in comparable clinical and functional remission rates. Additionally, abatacept and tocilizumab showed similar effectiveness with or without MTX. While clinical efficacies, including SDAI,...
Keywords: IL-6, Tocilizumab, Clinical, Efficacy
Charles-Schoeman C, Burmester G, Nash P, Zerbini CA, Soma K, Kwok K, Hendrikx T, Bananis E, Fleischmann R.
Annals of the Rheumatic Diseases. 2015 Aug 14. doi:pii: annrheumdis-2014-207178.
This study evaluated the efficacy and safety of tofacitinib, an oral Janus kinase inhibitor, in patients with inadequate response to sDMARDs or bDMARDs. Findings from this study show both doses of tofacitinib were associated with improvements in efficacy parameters at month 3 versus placebo, and clinical response was numerically greater with bDMARD-naïve versus bDMARD-IR patients (95% CI overlapping). Safety parameters were generally similar; however, patients receiving glucocorticoids had ...
Keywords: JAK, Tofacitinib, Clinical, Phase 3
September 15
Tanaka Y, Takeuchi T, Yamanaka H, Nakamura H, Toyoizumi S, Zwillich S.
Modern Rheumatology. 2015 Jul;25(4):514-21. doi: 10.3109/14397595.2014.995875.
The oral Janus kinase (JAK) inhibitor, Tofacitinib, preferentially inhibits signalling by heterodimeric receptors associated with JAK3 and/or JAK1, blocking signalling for several cytokines. The purpose of this study was to evaluate the efficacy of tofacitinib monotherapy versus placebo in Japanese patients with inadequate response to disease-modifying anti-rheumatic drugs (DMARDs). Data on response rates – ACR20/50/70, DAS28-4(ESR), and HAQ-DI – laboratory parameters and adverse eve...
Weinblatt ME, Mease P, Mysler E, Takeuchi T, Drescher E, Berman A, Xing J, Zilberstein M, Banerjee S, Emery P.
Arthritis & Rheumatology. 2015 Jul 2. doi: 10.1002/art.39249. [Epub ahead of print]
The humanised monoclonal antibody, Clazakizumab (CLZ), binds to circulating interleukin-6 (IL-6) cytokine rather than the IL-6 receptor, blocking both classical and trans-signalling. The purpose of this phase 2B study was to evaluate the efficacy and safety of clazakizumab in patients with inadequate response to methotrexate (MTX). Data on selected response rates – ACR20/50/70, DAS28-CRP, SDAI ≤3.3, CDAI ≤2.8 and the ACR/EULAR Boolean definition – and adverse events were collec...
July 15
Papp KA, Menter MA, Abe M, Elewski B, Feldman SR, Gottlieb AB, Langley R, Luger T, Thaci D, Buonanno M, Gupta P, Proulx J, Lan S, Wolk R, OPT Pivotal 1 and OPT Pivotal 2 Investigators.
British Journal of Dermatology. 7 July 2015 DOI: 10.1111/bjd.14018. [Epub ahead of print]
The management of moderate to severe chronic plaque psoriasis has benefited from the introduction of biological therapies, but unmet needs still remain, especially for oral therapies. Tofacitinib is an orally active agent that blocks signalling of key cytokines implicated in the immune response and inflammatory pathways of psoriasis. The Phase III studies presented in this paper analysed efficacy and safety endpoints. Both studies demonstrated that tofacitinib in both 5 mg and 10 mg twice daily...
Gerd R Burmester, Andrea Rubbert-Roth, Alain Cantagrel, Stephen Hall, Piotr Leszczynski, Daniel Feldman, Madura J Rangaraj, Georgia Roane, Charles Ludivico, Min Bao, Lucy Rowell, Claire Davies, Eduardo F Mysler.
Ann Rheum Dis. 10 May 2015 doi:10.1136/annrheumdis-2015-207281 [Epub ahead of print]
Tocilizumab (TCZ) has demonstrated efficacy and a well-established safety profile for intravenous (IV) administration. The Phase III SUMMACTA study evaluated the efficacy and safety of subcutaneous tocilizumab (TCZ-SC) in combination with DMARDS in patients with moderate-to-severe RA and inadequate response to ≥1 DMARD. Patients were randomised to receive TCZ-SC 162 mg weekly or TCZ-IV 8 mg/kg q4w in combination with DMARDs. After a 24-week double-blind period, patients receiving TCZ-SC were ...
March 15
Fleischmann RM, Damjanov NS, Kivitz AJ, et al.
Arthritis Rheumatol. 2015;67(2):334–343.
Decernotinib (VX-509; Vertex Pharmaceuticals Incorporated) is a JAK 3 inhibitor currently under investigation for its potential use in the treatment of RA. The potency and selectivity profiles of this oral compound have already been established in previous trials, so this study aimed to establish the efficacy and safety profiles of the drug, in RA patients who have had an inadequate response to at least one DMARD. Four doses; 25 mg, 50 mg, 100 mg and 150 mg, were evaluated in this placebo-contr...
January 15
Tanaka Y, Takeuchi T, Yamanaka H, Nakamura H, Toyoizumi S, Zwillich S.
Mod Rheumatol. 2014 Dec 11:1–25. [Epub ahead of print]
In Japan, the biologic DMARDs infliximab, etanercept, adalimumab, golimumab and certolizumab pegol, as well as tocilizumab and abatacept are approved for use in patients with active RA and an inadequate response to existing therapies. However, not all patients respond to these therapies adequately, creating an unmet need for therapeutic options with alternative mechanisms of action. The oral JAK inhibitor tofacitinib has demonstrated efficacy as monotherapy or in combination with DMARDs for th...
December 14
Keystone EC, Taylor PC, Drescher E, Schlichting DE, Beattie SD, Berclaz PY, Lee CH, Fidelus-Gort RK, Luchi ME, Rooney TP, Macias WL, Genovese MC.
Ann Rheum Dis. 2015;74(2):333–340
Recent innovations in the treatment of RA have focused on the use of small molecules to inhibit intracellular kinases such as the JAK family. Baricitinib (LY3009104, formerly INCB028050) is an orally administered, potent, selective and reversible inhibitor of JAK1 and JAK2, which has shown anti-inflammatory effects, as well as preservation of cartilage and bone, in preclinical rodent studies. This phase IIb study was designed to investigate multiple doses and dosing regimens of baricitinib, fo...
Boyle DL, Soma K, Hodge J, Kavanaugh A, Mandel D, Mease P, Shurmur R, Singhal AK, Wei N, Rosengren S, Kaplan I, Krishnaswami S, Luo Z, Bradley J, Firestein GS.
Ann Rheum Dis. 2014 Nov 14. pii: annrheumdis-2014-206028. doi: 10.1136/annrheumdis-2014-206028. [Epub ahead of print]
Targeting intracellular pathways such as JAK/STAT represents a novel approach to the treatment of RA. Tofacitinib is an oral JAK inhibitor, proven to be effective in the treatment of RA, yet the pathways affected by tofacitinib and the effects on gene expression in situ are unknown. In this study, Boyle et al. tested the hypothesis that tofacitinib targets cytokine signalling critical to the pathogenesis of rheumatoid synovitis by investigating tofacitinib effects on synovial pathobiology. A...
October 14
Strand V, Burmester GR, Zerbini CA, Mebus CA, Zwillich SH, Gruben D, Wallenstein GV.
Arthritis Care Res (Hoboken). 2014 Sep 3. doi: 10.1002/acr.22453. [Epub ahead of print]
For many patients with rheumatoid arthritis, improvements in pain, physical function, fatigue, and health-related quality of life (HRQoL) are more important and meaningful than improvements in joint swelling, tenderness, or inhibition of structural damage. These patient-perceived benefits of RA therapy contribute importantly to overall clinical efficacy. This paper presents patient-reported outcomes (PROs) form the ORAL Step trail, which assessed tofacitinib 5 mg or 10 mg twice daily, or pla...
September 14
Langley RG, Elewski BE, Lebwohl M, et al.
N Engl J Med. 2014;371(4):326–338.
Secukinumab is a fully human monoclonal antibody that selectively binds to and neutralises interleukin-17A, a cytokine shown to play a crucial role in plaque psoriasis, as well as other immune-mediated diseases. These two pivotal phase 3 studies in plaque psoriasis, FIXTURE and ERAUSRE, were sponsored by Novartis Pharmaceuticals. Secukinumab met all primary endpoints, PASI 75 response and the response of 0 or 1 on the modified investigator’s global assessment, as well as key secondary ...
July 14
Lee EB, Fleischmann R, Hall S, et al.
N Engl J Med. 2014;370(25):2377–2386.
ORAL Start is the latest trial to be reported in the tofacitinib clinical development programme. It compares the use of tofacitinib monotherapy to MTX monotherapy, in RA patients who have had either no or a sub-therapeutic dose of MTX in the past. Nine hundred and fifty eight patients received either tofacitinib (5 mg or 10 mg) twice daily, or methotrexate at a dose that was incrementally increased to 20 mg per week over 8 weeks. The co primary efficacy endpoints were ACR 70 response, and mean c...
June 14
Hammaker D, Boyle DL, Topolewski K et al.
Journal of Inflammation 2014, 11:14
Several p38α inhibitors have been developed and evaluated in RA. However, despite pre-clinical data showing promise, the compounds have been shown to have little therapeutic efficacy. Previous studies have suggested this may be a result of inhibitors blocking the role of p38 in limiting inflammation. Previous studies by the same authors have shown that the targeting of MKK3 or MKK 6, which are the upstream activators of p38, may be superior to p38 blockade as the anti-inflammatory eff...
May 14
Wollenhaupt J, SIlverfield J, Lee Eb et al.
J Rheumatol 2014;41;837-852
This study pooled data from two LTE studies involving patients who had previously participated in qualifying phase I, II and III studies. Data up to 60 months was included for safety aspects and efficacy data up to 48 months. However data for 10 mg BID and tofacitinib monotherapy was limited after 24 and 36 months respectively. Over the two studies, 4102 patients were treated for a total of 5963 patient years. Herpes zoster, both serious and non-serious, had a higher incidence rate in tofacitini...
February 14
Sonomoto K, Yamaoka K, Kubo S et al.
Rheumatology doi:10.1093/rheumatology/ket466
Due to its function as a JAK1/3 inhibitor, tofacitinib has effects on a wide ranging variety of cells. The authors of this paper have previously reported a suppression in cytokine production by CD4+ T lymphocytes caused by tofacitinib, while others have reported reduced chemokine production from fibroblast-like synoviocytes. The effects of tofacitinib on other cells however remain largely unknown. This study focused on tofacitinib’s effects on CD4+ T lymphocyte proliferation and on subsets...
January 14
Winkler DG, Faia KL, DiNitto JP et al.
Chemistry and Biology Nov 13 20, 1364-1374
Phosphoinositide-3 kinases (PI3K) are cell signalling proteins that act as a central node for relaying signals from cell surface receptors and downstream mediators. Specifically they phosphorylate phosphatidylinositol to phosphatidylinositol-3,4,5-trisphosphate (PIP3). This acts a docking site for signalling proteins, leading to the activation of downstream effectors such as BTK. Therefore, inhibition of the PI3K-d and PI3K-? isoforms (PI3K-a and PI3K-ß demonstrated embryonic lethality in ...
Keywords: Cytokine Signalling, Preclinical, MOA
Dowty M, Jesson MI, Ghosh S, et al.
J Pharmacol Exp Ther. 2013. DOI:10.1124/jpet.113.209304
Preclinical studies can provide insight into mechanisms of efficacy and optimal dosing regimens. In this study, Dowty et al. compare the pharmacokinetic / pharmacodynamic profiles of tofacitinib in a murine arthritis model and in patients with rheumatoid arthritis from tofacitinib clinical trials. The main driver of efficacy in both preclinical murine arthritis models and clinical RA was found to be inhibition of JAK1 heterodimer signalling, where total drug exposure (Cave) was a predictor of pr...
Keywords: JAK, Tofacitinib, Preclinical, PK-PD
October 13
Van Rompaey L, Galien R, van der Aar EM, et al.
Journal of Immunology 2013;191:3568–77
JAK inhibitors have been identified as having a critical role as therapeutic targets for autoimmune, inflammatory and oncological diseases. GLPG0634 was shown to inhibit JAK1/JAK2 but with a much greater effect on JAK1, a critical pathway in the signal transduction of many inflammatory cytokines. In rodent testing, GLPG0634 showed significant dose-dependent reduction in disease progression in collagen-induced arthritis models, with comparable efficacy to etanercept. An orally bioavailable treatm...
Keywords: JAK, Filgotinib, Preclinical
Kremer J, Li ZG, Hall S et al.
Ann Intern Med. 2013;159;253-261
Many patients with active RA have an inadequate response to biologic and nonbiologic DMARDs. Kremer et al carried out a one year, randomized trial studying the efficacy of tofacitinib in conjunction with background nonbiologic DMARDs (primarily methotrexate) in these patients. The results showed that using tofacitinib in combination with nonbiologic DMARDs rapidly improved physical function and reduced signs and symptoms of RA versus placebo, measured by ACR20 rates, DAS28 and HAQ-DI. The data f...
Keywords: JAK, Tofacitinib, Clinical, Phase 3
September 13
Nijjar JS, Tindell A, McInnes ID and Siebert S.
Rheumatology 2013;52:1556–1562 doi:10.1093/rheumatology/ket225
Both the innate and adaptive immune responses are targeted by current RA treatments, but these treatments do not achieve consistent sustained disease remission. Protein kinase inhibitors represent a promising new therapeutic target, owing to their influence on downstream signalling and oral bioavailability. Fostamatinib (R788) has shown ACR20 responses of 67–72% in MTX inadequate responder patients at doses of 100mg bd and 150mg bd. However, the results in biologic non-responder patients w...
Keywords: Cytokine Signalling, Preclinical, MOA
August 13
Westhovens R, Keyser FD, Rekalov D, et al.
Ann Rheum Dis. 2013 May; 72(5):741–4
This phase2 trial assessed the efficacy of GLPG0259, a first-in-class ATP-competitive inhibitor of MAPKAPK5. The trail involved 31 patients with active RA and an inadequate response MTX. Patients received either 50 mg/day GLPG0259 with MTX or a placebo with MTX (patients randomised 2:1) for 12 weeks with the primary efficacy variable being ACR 20 response at week 12. Analysis showed that 5 patients (26.3%) in the GLPG0259 group and 3 patients (27.3%) in the placebo group achieved ACR 20 at 12 we...
Keywords: Cytokine Signalling, Clinical, Phase 2
Salgado E & Gomez-Reino JJ.
International Journal of Clinical Rheumatology June 2013; 8(3):311–13
The tofacitinib ORAL research program involves six phase 3 trials (Standard, Solo, Step, Scan, Sync and Start) to assess the safety and efficacy of tofacitinib 5 and 10 mg twice daily as monotherapy, or with either background MTX or traditional DMARD therapy. This report by Salgado et al. provides an overall analysis of the each of the study designs and the clinical results to date. The results show that tofacitinib effectively controlled the signs and symptoms of RA across a range of patient po...
Keywords: JAK, Tofacitinib, Clinical, Phase 3
June 13
Fridman JS, Scherle PA, Collins R, et al.
Journal of Immunology 2010; 184(9):5298-307
This preclinical characterisation study examined the efficacy and tolerability of the small molecule INCB028050 (now known as baricitinib), an orally bioavailable, selective Janus kinase (JAK) 1/JAK2 inhibitor, in rodent models of arthritis. The decision to investigate its effects of INCB028050 followed positive evidence for the related compound ruxolitinib, the JAK inhibitor tofacitinib and the IL-6 inhibitor tocilizumab in rheumatoid arthritis (RA). In this preclinical study, INCB028050 was sh...
Keywords: JAK, Baricitinib, Preclinical, Selectivity
Weinblatt ME, Kavanaugh A, Genovese MC, et al.
The New England Journal of Medicine 2010; 363(14):1303-12
This is the first phase 2 study to be published for spleen tyrosine kinase (Syk) inhibitor R788 (fostamatinib). This phase 2 study ingestigated the efficacy and safety of fostamatinib in patients with active RA despite long-term treatment with methotrexate. In this 6-month, double-blind, placebo-controlled trial, patients were randomised to receive two doses of R788 (100 mg twice daily or 150 mg once daily) or placebo once or twice daily. Significantly more patients on R788 achieved ACR 20 respo...
Keywords: Cytokine Signalling, Clinical, Phase 2
Genovese MC, Kavanaugh A, Weinblatt ME, et al.
Arthritis & Rheumatism 2011; 63(2):337-45
This was the first phase 2 study to be published investigating the efficacy and safety of the spleen kinase (Syk) inhibitor R788 (fostamatinib) in patients with refractory rheumatoid arthritis (RA). In this multicentre, randomised, double-blind, placebo-controlled, 3-month trial, patients with active RA on stable background treatment (excluding biologics) were randomised to receive 100 mg R788 or placebo twice daily. Differences in ACR20 responses were significant at week 6 (p=0.003), but not th...
Keywords: Cytokine Signalling, Clinical, Phase 2
Kremer JM, Cohen S, Wilkinson BE, et al.
Arthritis & Rheumatism 2012; 64(4):970-81
This study was one of two 24-week, phase 2b studies undertaken to characterise the efficacy and safety dose-response profile of the oral Janus kinase (JAK) inhibitor tofacitinib. Six doses of tofacitinib (20 mg daily and 1, 3, 5, 10 and 15 mg twice daily) and placebo were compared as add-on therapy in adults with active RA despite methotrexate (MTX) therapy. At week 12, ACR 20 response rates were significantly higher with all tofacitinib doses than with placebo (tofacitinib 45.7–58.1%...
Keywords: JAK, Tofacitinib, Clinical, Phase 2
van Vollenhoven RF, Fleischmann R, Cohen S, et al.
The New England Journal of Medicine 2012; 367(6):508-19
The ORAL Standard trial is one of six studies conducted as part of the phase 3 research programme for the oral Janus kinase (JAK) inhibitor tofacitinib. This 12-month, phase 3 study compared the efficacy of tofacitinib with the TNF inhibitor adalimumab or placebo. Patients with active RA despite background methotrexate (MTX) were randomised to 5 or 10 mg tofacitinib twice daily, 40 mg adalimumab fortnightly, or placebo, which was switched to tofacitinib at month 3 in non-responders and month 6 f...
Keywords: JAK, Tofacitinib, Clinical, Phase 3
Burmester GR, Blanco R, Charles-Schoeman C, et al.
The Lancet 2013; 381(9865):451-60
The ORAL Step trial is one of six studies conducted as part of the phase 3 research programme for the oral Janus kinase (JAK) inhibitor tofacitinib. This 6-month, double-blind, parallel-group phase 3 study investigated the efficacy and safety of tofacitinib in adults with moderate to severe rheumatoid arthritis (RA) with an inadequate response to tumour necrosis factor (TNF) inhibitors. Patients were randomised to 5 or 10 mg tofacitinib twice daily or placebo, which was switched to tofaciti...
Keywords: JAK, Tofacitinib, Clinical, Phase 3
McInnes IB, Ho-Youn K, Sang-Heon L, et al.
Annals of Rheumatic Diseases 2013; doi:10.1136/annrheumdis-2012-202442
This randomised, placebo-controlled, multicentre phase 2 study evaluated the efficacy and safety of atorvastatin versus placebo in modifying lipids in 111 patients with active rheumatoid arthritis (RA) receiving tofacitinib. All patients took tofacitinib 10 mg twice daily for 12 weeks, and after the first 6 weeks patients were randomised 1:1 to receive either atorvastatin 10 mg once daily (n=50) or matched placebo (n=48) in a double-blind phase for a further 6 weeks. Tofacitinib-induced elevatio...
Keywords: JAK, Tofacitinib, Clinical, Phase 2