AB0565 JAK INHIBITORS AND PSORIATIC ARTHRITIS: A SYSTEMATIC REVIEW AND META-ANALYSIS

Background:Despite the therapeutic armamentarium for the treatment of psoriatic arthritis (PsA) has considerably expanded over the last thirty years, there is a huge necessity of finding effective drugs for this disease. JAK inhibitors (JAKi) are small molecules able to interfere with the JAK/STAT pathway, involved in the pathogenesis of PsA (1). Up to now Tofacitinib is the only JAKi approved by the European Medicines Agency (EMA) for the treatment of PsA but in the next few years the number of approved JAKi is expected to rise significantly.Objectives:To assess the efficacy and safety of different JAKi for the treatment of PsA.Methods:A systematic review of the literature was performed to identify randomized controlled trials (RCTs), by electronic search of MEDLINE and EMBASE database until October 2020. Studies were considered eligible if they met the following criteria: I) study was a RCT; II) only patients with PsA were included; III) JAKi was compared to placebo in addition to the standard of care. Two reviewers (FC and AZ) performed study selection, with disagreements solved by the opinion of an expert reviewer (AS). The outcomes were expressed as odds ratio (OR) and 95% confidence intervals (95% CI). Statistical heterogeneity was assessed with the I2 statistic.Results:We identified 557 potentially relevant studies. A total of 554 studies were excluded based on title and/or abstract screening. Three RCTs for a total of 947 PsA patients treated with JAKi were included (2,3,4). Two were phase III studies on the efficacy and safety of Tofacitinib (OPAL Beyond and OPAL Broaden) and one was a phase II study on Filgotinib (Equator). All three studies were judged at low risk of bias according to Cochrane criteria (5). The primary efficacy outcome in all the studies was the number of patients who achieved the response rate of the American College of Rheumatology 20 score (ACR20). The outcomes evaluation was performed at 12 week for the Filgotinib trial and at 16 week for the Tofacitinib trials. We used for the main analyses the group of patients randomized to Tofacitinib 5 mg because this is the only dosage approved by the EMA for the treatment of PsA. JAKi showed a significantly higher ACR20 response rate compared to placebo (OR 3.54, 95% CI 1.76 - 7.09, I^2 = 74%). JAKi also showed a significantly higher ACR50 response rate (OR 3.36, 95% CI 2.22 - 5.09, I^2 = 0%), ACR70 response rate (OR 2.82, 95% CI 1.67 - 4.76, I^2 = 20%), PsARC response rate (OR 2.67, 95% CI 1.26 - 5.65, I^2 = 79%), PASI75 response rate (OR 3.15, 95% CI 1.61 - 6.15, I^2 = 45%) compared to placebo. JAKi were also associated with significantly better HAQ-DI (mean difference -0.23 95% CI -0.31 - -0.14) and fatigue, measured with FACIT-F (mean difference 3.54 95% CI 2.13 - 4.94). JAKi compared to placebo were associated with a non-statistically significant different risk of serious adverse events (OR 0.56, 95% CI 0.11 - 2.91, I^2 = 38%).Conclusion:This is the first published systematic review that performed a comprehensive and simultaneous evaluation of the efficacy and safety of JAKi for PsA in RCTs. Our analysis suggests a statistically significant benefit of JAKi, that appears to be effective and safe over placebo. The impact of these data on international clinical guidelines needs further investigation.References:[1]George E Fragoulis, et al. JAK-inhibitors. New players in the field of immune-mediated diseases, beyond rheumatoid arthritis, Rheumatology, Volume 58, Issue Supplement_1, February 2019, Pages i43–i54[2]Mease P, et al. Tofacitinib or adalimumab versus placebo for psoriatic arthritis. N Engl J Med 2017; 377: 1537-50.[3]Gladman D, et al. Tofacitinib for psoriatic arthritis in patients with an inadequate response to TNF inhibitors. N Engl J Med 2017; 377: 1525-36.[4]Mease P, et al. Efficacy and safety of filgotinib, a selective Janus kinase 1 inhibitor, in patients with active psoriatic arthritis (EQUATOR): results from a randomised, placebo-controlled, phase 2 trial. Lancet 2018;392:2367–77.[5]Higgins JP, et Al. Measuring inconsistency in meta-analyses. BMJ 2003;327:557-560Figure 1.ACR20 response rate of Jaki over PlaceboDisclosure of Interests:None declared.

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Update on the therapeutic management of patients with either psoriatic arthritis or ulcerative colitis: focus on the JAK inhibitor tofacitinib

Therapeutic Advances in Musculoskeletal Disease ◽

10.1177/1759720x20977777 ◽

2021 ◽

Vol 13 ◽

pp. 1759720X2097777

Author(s):

Maria Sole Chimenti ◽

Paola Conigliaro ◽

Livia Biancone ◽

Roberto Perricone

Keyword(s):

Ulcerative Colitis ◽

Psoriatic Arthritis ◽

Janus Kinase ◽

Phase Iii ◽

Jak Inhibitors ◽

Immune Mediated ◽

Significant Burden ◽

Phase Iii Trials ◽

Disease Modifying Agents ◽

Interleukin Inhibitors

Psoriatic arthritis (PsA) and ulcerative colitis (UC) are immune-mediated diseases that cause significant burden worldwide. Recent advances in their management have improved patient outcomes. However, significant unmet needs still remain as not all patients respond to current treatments, and patients may lose responsiveness over time. An improved understanding of the pathophysiology of these diseases has brought about the development of novel disease-modifying agents, including interleukin inhibitors and, more recently, Janus kinase (JAK) inhibitors. With the approval of tofacitinib for the treatment of adults with active PsA and in adult patients with moderately-to-severely active UC, JAK inhibitors have recently entered the treatment armamentarium for PsA and UC. A number of other JAK inhibitors are also undergoing clinical development and are currently in phase III trials. This review provides an overview of the current therapeutic options for PsA and UC, with a focus on the JAK inhibitors.

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SAT0136 RELATIVE EFFICACY AND SAFETY OF TOFACITINIB, BARICITINIB, UPADACITINIB, AND FILGOTINIB, IN COMPARISON WITH ADALIMUMAB IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS: A BAYESIAN NETWORK META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.658 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1005.1-1005

Author(s):

Y. H. Lee ◽

G. G. Song

Keyword(s):

Rheumatoid Arthritis ◽

Active Rheumatoid Arthritis ◽

Response Rate ◽

Meta Analysis ◽

Inadequate Response ◽

Efficacy And Safety ◽

Double Blind ◽

Acr20 Response ◽

Randomized Controlled ◽

Acr20 Response Rate

Background:Methotrexate (MTX), an effective disease-modifying antirheumatic drug (DMARD) [2], is the most widely used DMARD for the treatment of rheumatoid arthritis (RA). However, not all patients are responsive to the drug; 30% of the patients discontinue therapy within 1 year of commencing the treatment, usually because of the lack of efficacy or undesirable adverse effects Small-molecule Janus kinase inhibitors are clinically developed for the treatment of RA.Objectives:The aim of this study is to investigate the relative efficacy and safety of tofacitinib, baricitinib, upadacitinib, and filgotinib in comparison with adalimumab in patients with active RA and having inadequate responses to MTX.Methods:We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) to examine the efficacy and safety of tofacitinib, baricitinib, upadacitinib, filgotinib, and adalimumab in RA patients having inadequate responses to MTX.Results:Four RCTs, comprising 5,451 patients, met the inclusion criteria. The baricitinib 4mg+MTX and upadacitinib 15mg+MTX group showed a significantly higher American College of Rheumatology 20% (ACR20) response rate than the adalimumab 40mg+MTX group. The ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that baricitinib 4mg+MTX had the highest probability of being the best treatment for achieving the ACR20 response rate, followed by upadacitinib 15mg+MTX, tofacitinib 5mg+MTX, filgotinib 200mg+MTX, filgotinib 100mg+MTX, adalimumab 40mg+MTX, and placebo+MTX. The upadacitinib 15mg+MTX and baricitinib 4mg+MTX groups showed significantly higher ACR50 and ACR70 response rates than adalimumab 40mg+MTX. In terms of Herpes zoster infection, the ranking probability based on the SUCRA indicated that placebo+MTX were likely to be the safest treatments, followed by filgotinib 200mg+MTX, filgotinib 100mg+MTX, adalimumab 40mg+MTX, tofacitinib 5mg+MTX, upadacitinib 15mg+MTX, and baricitinib 4mg+MTX. Regarding safety analysis, no statistically significant differences were found between the respective intervention groups.Conclusion:In RA patients with an inadequate response to MTX, baricitinib 4mg+MTX and upadacitinib 15mg+MTX showed the highest ACR response rates, suggesting a difference in efficacy among the different JAK inhibitors.References:[1]Fleischmann R, Mysler E, Hall S, Kivitz AJ, Moots RJ, Luo Z, DeMasi R, Soma K, Zhang R, Takiya LJTL (2017) Efficacy and safety of tofacitinib monotherapy, tofacitinib with methotrexate, and adalimumab with methotrexate in patients with rheumatoid arthritis (ORAL Strategy): a phase 3b/4, double-blind, head-to-head, randomised controlled trial. 390:457-468[2]Taylor PC, Keystone EC, van der Heijde D et al (2017) Baricitinib versus Placebo or Adalimumab in Rheumatoid Arthritis. N Engl J Med 376:652-662[3]Fleischmann R, Pangan AL, Mysler E, Bessette L, Peterfy C, Durez P, Ostor A, Li Y, Zhou Y, Othman AA (2018) A phase 3, randomized, double-blind study comparing upadacitinib to placebo and to adalimumab, in patients with active rheumatoid arthritis with inadequate response to methotrexate. ARTHRITIS & RHEUMATOLOGY. WILEY 111 RIVER ST, HOBOKEN 07030-5774, NJ USA, pp[4]Combe B, Kivitz A, Tanaka Y, van der Heijde D, Matzkies F, Bartok B, Ye L, Guo Y, Tasset C, Sundy J (2019) LB0001 EFFICACY AND SAFETY OF FILGOTINIB FOR PATIENTS WITH RHEUMATOID ARTHRITIS WITH INADEQUATE RESPONSE TO METHOTREXATE: FINCH1 PRIMARY OUTCOME RESULTS. BMJ Publishing Group Ltd, ppDisclosure of Interests:None declared

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Efficacy and Safety of CE-224,535, an Antagonist of P2X7Receptor, in Treatment of Patients with Rheumatoid Arthritis Inadequately Controlled by Methotrexate

The Journal of Rheumatology ◽

10.3899/jrheum.110874 ◽

2012 ◽

Vol 39 (4) ◽

pp. 720-727 ◽

Cited By ~ 132

Author(s):

THOMAS C. STOCK ◽

BRADLEY J. BLOOM ◽

NATHAN WEI ◽

SALIHA ISHAQ ◽

WON PARK ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Disease Activity ◽

Response Rate ◽

Tolerability Profile ◽

Inadequate Response ◽

Efficacy And Safety ◽

Acr20 Response ◽

Link Type ◽

Significant Difference ◽

Acr20 Response Rate

Objective.To evaluate efficacy and safety of CE-224,535, a selective P2X7receptor antagonist, versus placebo, in patients with active rheumatoid arthritis (RA) and inadequate response to methotrexate (MTX).Methods.In our phase IIA study (ClinicalTrials.govno.NCT00628095; A6341009), patients aged ≥ 18 years with active RA were randomized to receive either CE-224,535 (500 mg bid) or placebo for 12 weeks; all patients continued a stable background dose of ≥ 7.5 mg MTX.Results.The American College of Rheumatology 20% (ACR20) response rate (primary efficacy endpoint) was not significantly different from placebo for CE-224,535 (34.0% vs 36.2%; p = 0.591) at Week 12, or at any timepoint over the 12-week treatment period. There was no significant difference at Week 12 for the ACR20 response rate following subgroup analyses by age, sex, baseline disease activity, baseline duration of disease, geographic region, or concomitant use of steroids. ACR50/ACR70 response rates and change from baseline in Disease Activity Score 28-joint C-reactive protein (DAS28-3-CRP) and Health Assessment Questionnaire-Disability Index for CE-224,535 were not significant at Week 12 versus placebo. Treatment-emergent adverse events (AE) were reported by 62.3% (CE-224,535) and 55.3% (placebo) of patients; the most common AE were nausea (11.3%, CE-224,535; 4.3%, placebo) and diarrhea (7.5%, CE-224,535; 4.3%, placebo). The proportion of patients discontinuing due to an AE was 9.4% (CE-224,535) and 6.4% (placebo); no deaths were reported. Serious AE occurred in 3.8% (CE-224,535) and 2.1% (placebo) of patients; none was considered treatment-related.Conclusion.CE-224,535 was not efficacious, compared with placebo, for the treatment of RA in patients with an inadequate response to MTX. CE-224,535 demonstrated an acceptable safety and tolerability profile.

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Efficacy and safety of IL-17 inhibitors for the treatment of ankylosing spondylitis: a systematic review and meta-analysis

10.21203/rs.2.22690/v2 ◽

2020 ◽

Author(s):

Yufeng Yin ◽

Mingjun Wang ◽

Mengru Liu ◽

Erye Zhou ◽

Tian Ren ◽

...

Keyword(s):

Systematic Review ◽

Ankylosing Spondylitis ◽

Adverse Events ◽

Response Rate ◽

Phase Iii ◽

Controlled Trials ◽

Efficacy And Safety ◽

End Point ◽

Increased Risk ◽

Severe Infections

Abstract Objectives: To systematically assess the efficacy and safety of IL-17 inhibitors in patients with active ankylosing spondylitis. Methods: A systematic review of the literature was performed for randomized controlled trials (RCTs) concerning IL-17 inhibitors in patients with ankylosing spondylitis. Meta-analyses were used to determine the efficacy and safety of the IL-17 inhibitors in the treatment of these patients. The primary end point was predefined as the proportion of patients with at least 20% improvement in the Assessment of Spondyloarthritis International Society (ASAS20) response criteria at week 16, and the secondary end point was defined as ASAS40 at week 16. Results: Six phase III randomized, double-blind, placebo-controlled trials including 1733 patients (1153 patients received IL-17 inhibitors, including secukinumab or ixekizumab, whereas 580 patients received a placebo as comparators) were included. At week 16, the IL-17 inhibitor regimen produced a significant increase in the ASAS20 response rate (RR=1.63, 95% CI 1.45 to 1.84, p=0.00) and the secondary endpoint ASAS40 response rate (RR=2.12, 95% CI 1.75 to 2.56, p=0.00) versus those for the placebo. With respect to the safety profile, more treatment-emergent adverse events (RR=1.11, 95% CI 1.01 to 1.22, p=0.03) and non-severe infections (RR=1.82, 95% CI 1.40 to 2.37, p<0.001) were described after treatment with IL-17 inhibitors than after treatment with placebo, while no increased risk of other adverse events was indicated after IL-17 inhibitor therapy, including death, discontinuation due to adverse events, or serious adverse events. Conclusions: IL-17 inhibitors produced favourable response rates but an increased risk of non-severe infections in the treatment of active ankylosing spondylitis.

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Efficacy and safety of netakimab in patients with psoriatic arthritis: results of the phase III PATERA clinical study

Rheumatology Science and Practice ◽

10.47360/1995-4484-2020-480-488 ◽

2020 ◽

Vol 58 (5) ◽

pp. 480-488

Author(s):

T. V. Korotaeva ◽

V. I. Mazurov ◽

A. M. Lila ◽

I. Z. Gaydukova ◽

A. L. Bakulev ◽

...

Keyword(s):

Placebo Group ◽

Psoriatic Arthritis ◽

Safety Profile ◽

Phase Iii ◽

Inadequate Response ◽

Efficacy And Safety ◽

Double Blind ◽

Acr20 Response ◽

American College Of Rheumatology ◽

Blinded Manner

Netakimab (NTK) is a humanized anti-interleukin-17А (IL-17A) monoclonal antibody approved for the treatment of psoriatic arthritis, ankylosing spondylitis, moderate to severe psoriasis. Here, we present the results of the 24-weeks double blind period of the PATERA study.Objective. The objective of the study was to evaluate the efficacy and safety of NTK compared to placebo in patients with psoriatic arthritis (PsA).Patients and methods. 194 patients with active PsA with an inadequate response to previous therapy with nonsteroidal anti-inflammatory drugs, conventional or biologic disease-modifying antirheumatic drugs, were randomized in a 1:1 ratio to receive subcutaneous 120 mg NTK or placebo at weeks 0, 1, 2, 4, 6, 8, 10, 14, 18, 22. At week 16 ACR20 (20% improvement in the American College of Rheumatology response criteria) non-responders in placebo group were reassigned to NTK in a blinded manner. The primary endpoint was the proportion of patients achieved ACR20 response at week 24.Results. 82,5% of patients in the NTK group and 9.3% of patients in the placebo group achieved ACR20 at week 24 with the 95% CI [0,63; 0,84] (p < 0,0001). Skin manifestations and axial disease significantly improved with NTK. The safety profile of NTK was comparable to placebo. The most frequent treatment-related AEs were expected and common for all other IL-17 inhibitors: increased alanine aminotransferase (ALT), infections, lymphopenia.Conclusion. NTK in the dose of 120 mg has superior efficacy over placebo in patients with active psoriatic arthritis. The safety profile is consistent with other IL-17 inhibitors.

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Efficacy and safety of peficitinib (ASP015K) in patients with rheumatoid arthritis and an inadequate response to conventional DMARDs: a randomised, double-blind, placebo-controlled phase III trial (RAJ3)

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2019-215163 ◽

2019 ◽

Vol 78 (10) ◽

pp. 1320-1332 ◽

Cited By ~ 32

Author(s):

Yoshiya Tanaka ◽

Tsutomu Takeuchi ◽

Sakae Tanaka ◽

Atsushi Kawakami ◽

Manabu Iwasaki ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Response Rates ◽

Janus Kinase ◽

Phase Iii ◽

Inadequate Response ◽

Efficacy And Safety ◽

Double Blind ◽

Acr20 Response ◽

Once Daily ◽

Conventional Dmards

ObjectivesTo investigate the efficacy and safety of peficitinib, an oral Janus kinase inhibitor, in patients with rheumatoid arthritis (RA).MethodsIn this double-blind phase III study, patients with RA and an inadequate response to prior disease-modifying anti-rheumatic drugs (DMARDs) were randomised to peficitinib 100 mg once daily, peficitinib 150 mg once daily, placebo or open-label etanercept for 52 weeks’ treatment; placebo-treated patients were switched at week 12 to peficitinib 100 or 150 mg once daily. The primary endpoint was American College of Rheumatology (ACR)20 response at week 12/early termination (ET). Secondary endpoints (assessed throughout) included ACR20, ACR50 and ACR70 response, changes from baseline in disease activity scores (DAS)28 and ACR core parameters, adverse events (AEs) and changes in clinical or laboratory measurements.ResultsIn total, 507 patients received treatment. ACR20 response rates at week 12/ET were significantly higher in the peficitinib 100 mg (57.7%) and 150 mg (74.5%) groups versus placebo (30.7%) (p<0.001). ACR50/70 response rates were also higher for both peficitinib doses versus placebo. Improvements in ACR response were maintained until week 52. Changes from baseline in DAS28-C-reactive protein/erythrocyte sedimentation rate and the ACR core set were significantly greater for both peficitinib doses versus placebo at week 12/ET (p<0.001). AE incidence was similar across treatment arms. Incidence of serious infection and herpes zoster-related disease was higher with peficitinib versus placebo, but with no clear dose-dependent increase.ConclusionsIn patients with RA and inadequate response to DMARDs, peficitinib 100 mg once daily or 150 mg once daily was efficacious in reducing RA symptoms and was well tolerated compared with placebo.Trial registration numberNCT02308163.

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Spleen and Symptom Responses of JAK Inhibitors in Myelofibrosis; A Systematic Review of Phase 2 and 3 Trials

Blood ◽

10.1182/blood-2020-140131 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 26-27

Author(s):

Muhammad Ans Sharif ◽

Muhammad Salman Faisal ◽

Yazan Samhouri ◽

Laila Hashim ◽

Muhammad Yasir ◽

...

Keyword(s):

Systematic Review ◽

Side Effects ◽

Phase Ii ◽

Janus Kinase ◽

Phase Iii ◽

Symptom Improvement ◽

Jak Inhibitors ◽

Phase Ii Trials ◽

Phase Iii Trials ◽

Symptom Response

Background: The JAK-STAT pathway is a vital signaling pathway for various cytokines and growth factors. An abnormal upregulation of this pathway is seen in myeloproliferative disorders, especially the classic BCR-ABL negative myelofibrosis (MF). Janus kinase inhibitors (JAKi) have been evaluated in various clinical trials regarding their efficacy in improving the outcomes for MF patients. In this review, we looked at the reduction of splenomegaly and symptom improvement as markers for efficacy of JAKi. Methods: We did a comprehensive literature search, following PRISMA guidelines, on PubMed, Cochrane, clinicaltrials.gov and Embase databases. We used MeSH terms and related keywords for MF and JAKi, including generic and trade names. We screened 3261 articles and selected 23 trials for our study. Case reports, case series, meta-analysis, review articles, observational studies, phase I trials and studies not reporting spleen response were excluded. Spleen and symptom responses were used to determine the efficacy of JAK inhibitors. Spleen volume reduction (SVR) by >35%, spleen length reduction (SLR) by >50% and total symptom score (TSS) improvement by >50% were set as benchmarks for a positive response. Results: We included 23 trials (n= 4739) in our review. There were 15 phase II trials (n=964) and 8 phase III trials (n=3775). Of these 23 trials, 7 trials (n=598) included patients with median age below 65 years, while 16 trials (n=4141) included patients of median age more than 65 years. Of the 9 of trials of ruxolitinib, 4 were phase III trials (n= 2809) and 5 were phase II trials (n= 416). The dose of ruxolitinib used in these trials ranged from 5 mg twice daily to 20 mg twice daily. The percentage of patients who achieved spleen response ranged from 15.6% to 71.7%. There were 5 trials (n= 861) that evaluated efficacy of momelotinib. Three were phase II trials (n= 221), while 2 were phase III trials (n=326). The doses ranged from 150mg to 300mg. The splenic response in patients ranged from 7% to 48%. In one phase 3 randomized control trial, efficacy of momelotinib (N=215)and roxulotinib (N=217) were compared, and were found to be equally efficacious in terms of spleen response (26.5% in the momelotinib group while 29% in the ruxolitinib group) and symptom response (28.4% in the momelotinib group and 42.2% in the ruxolitinib group). In 4 trials (n= 453) of fedratinib, there were 2 phase II trials (n= 127) and 2 phase III trials (n=326). The splenic response ranged from 31% to 73% of the patient population. In phase II JAKARTA2 study, patients who were resistant or intolerant to ruxolitinib showed SVR of 31%. Lestaurtunib, Ilgitanib, pacritinib and itacitinib were studied in 2,1,1, and 1 phase II trials, respectively. The splenic response was 75%, 31%, 31%, and 68.8% respectively. Symptom response was reported in 12 studies (N=1477). The percentage of patients who achieved symptom response receiving roxulotinib were 20.8-49%, momelotinib (28.4-30.7%), ictatinib (51.1-59.4%), practinib (48%), and fedratinib (27-36%). In terms of safety, the most common hematological side effects seen were anemia (15% - 65%), thrombocytopenia (1.3% - 64%) and neutropenia (1% - 28%). These side effects were seen equally with different medications. The most common non hematological adverse effects included diarrhea (4% - 32%), abdominal pain (2.6% - 27.1%) and fatigue (1.3% - 10%). Conclusion Splenomegaly and associated symptoms are major source of morbidity in MF patients. The rapid advancement in novel agents in the last decade changed the treatment paradigm in this disorder. Our systematic review summarizes the effect of JAKi on spleen and symptom responses. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau. Fazal:Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau; Karyopharm: Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; GlaxoSmithKline: Consultancy, Speakers Bureau; Gilead/Kite: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Stemline: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Janssen: Speakers Bureau.

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Efficacy and safety of peficitinib (ASP015K) in patients with rheumatoid arthritis and an inadequate response to methotrexate: results of a phase III randomised, double-blind, placebo-controlled trial (RAJ4) in Japan

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2019-215164 ◽

2019 ◽

Vol 78 (10) ◽

pp. 1305-1319 ◽

Cited By ~ 31

Author(s):

Tsutomu Takeuchi ◽

Yoshiya Tanaka ◽

Sakae Tanaka ◽

Atsushi Kawakami ◽

Manabu Iwasaki ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Japanese Patients ◽

Janus Kinase ◽

Phase Iii ◽

Tolerability Profile ◽

Inadequate Response ◽

Efficacy And Safety ◽

Double Blind ◽

Acr20 Response ◽

Once Daily

ObjectiveTo evaluate the efficacy and safety of the oral Janus kinase (JAK) inhibitor peficitinib versus placebo in Japanese patients with rheumatoid arthritis (RA).MethodsIn this multicentre, double-blind, parallel-group, placebo-controlled phase III study, patients with RA and inadequate response to methotrexate (MTX) were randomised 1:1:1 to placebo, peficitinib 100 mg once daily or peficitinib 150 mg once daily with MTX for 52 weeks. Based on baseline randomisation, at week 12, non-responders receiving placebo were switched to peficitinib until the end of treatment; the remaining patients were switched to peficitinib at week 28. Primary efficacy variables were American College of Rheumatology (ACR)20 response rate at week 12/early termination (ET) and change from baseline in van der Heijde-modified total Sharp score (mTSS) at week 28/ET.Results519 patients were randomised and treated. Significantly more (p<0.001) peficitinib (58.6%, 100 mg; 64.4%, 150 mg) than placebo (21.8%) recipients achieved ACR20 response at week 12/ET. Significantly lower (p<0.001) mean changes from baseline in mTSS at week 28/ET occurred in peficitinib (1.62, 100 mg; 1.03, 150 mg) than placebo (3.37) recipients. Peficitinib was associated with haematological and biochemical parameter changes, and increased incidence of serious infections and herpes zoster-related disease. One death from suicide occurred in a patient in the placebo group after switching to peficitinib 100 mg.ConclusionsIn Japanese patients with RA and inadequate response to MTX, peficitinib demonstrated significant superiority versus placebo in reducing RA symptoms and suppressing joint destruction. Peficitinib had an acceptable safety and tolerability profile, with no new safety signals compared with other JAK inhibitors.Trial registration numberNCT02305849.

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Efficacy and safety of biosimilar CT-P17 versus reference adalimumab in subjects with rheumatoid arthritis: 24-week results from a randomized study

Arthritis Research & Therapy ◽

10.1186/s13075-020-02394-7 ◽

2021 ◽

Vol 23 (1) ◽

Author(s):

Jonathan Kay ◽

Janusz Jaworski ◽

Rafal Wojciechowski ◽

Piotr Wiland ◽

Anna Dudek ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Response Rate ◽

Randomized Study ◽

Phase Iii ◽

European Medicines Agency ◽

Double Blind ◽

Acr20 Response ◽

Link Type ◽

Equivalent Efficacy ◽

Acr20 Response Rate

Abstract Background To demonstrate equivalent efficacy of the proposed high-concentration (100 mg/ml), citrate-free adalimumab biosimilar CT-P17 to European Union-approved adalimumab (EU-adalimumab) in subjects with active rheumatoid arthritis (RA). Methods This randomized, double-blind phase III study (ClinicalTrials.gov, NCT03789292) randomized (1:1) subjects with active RA at 52 centers to receive CT-P17 or EU-adalimumab 40 mg subcutaneously every 2 weeks until week 52. Results to week 24 are reported here. The primary endpoint was 20% improvement by American College of Rheumatology criteria (ACR20) response rate at week 24. Equivalence was concluded if the corresponding confidence intervals (CIs) for the estimate of treatment difference were within predefined equivalence margins: − 15 to 15% (95% CI; European Medicines Agency assumption); − 12 to 15% (90% CI; Food and Drug Administration assumption). Additional efficacy, pharmacokinetic, usability, safety, and immunogenicity endpoints were evaluated. Results 648 subjects were randomized (324 CT-P17; 324 EU-adalimumab). The ACR20 response rate at week 24 was 82.7% (n = 268/324) in both groups (intention-to-treat population). The 95% CI (− 5.94 to 5.94) and 90% CI (− 4.98 to 4.98) were within predefined equivalence margins for both assumptions and equivalent efficacy was concluded. Additional endpoints and overall safety were comparable between groups. Mean trough serum concentrations of CT-P17 were slightly higher than those of EU-adalimumab. Immunogenicity was slightly lower numerically for the CT-P17 group than for the EU-adalimumab group. Conclusions CT-P17 and EU-adalimumab have equivalent efficacy and comparable safety and immunogenicity in subjects with active RA. Overall safety of CT-P17 is consistent with the known safety profile of reference adalimumab. Trial registration ClinicalTrials.gov, NCT03789292. Registered 28 December 2018—retrospectively registered.

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Efficacy and safety of tofacitinib by background methotrexate dose in psoriatic arthritis: post hoc exploratory analysis from two phase III trials

Clinical Rheumatology ◽

10.1007/s10067-021-05894-2 ◽

2021 ◽

Author(s):

Alan J. Kivitz ◽

Oliver FitzGerald ◽

Peter Nash ◽

Shirley Pang ◽

Valderilio F. Azevedo ◽

...

Keyword(s):

Psoriatic Arthritis ◽

Small Sample ◽

Janus Kinase ◽

Phase Iii ◽

Efficacy And Safety ◽

Two Phase ◽

Double Blind ◽

Methotrexate Dose ◽

Post Hoc ◽

The Impact

Abstract Objective Analyze tofacitinib efficacy and safety by background methotrexate (MTX) dose in patients with psoriatic arthritis (PsA). Methods This post hoc analysis pooled data from two phase III, double-blind trials (OPAL Broaden, NCT01877668; OPAL Beyond, NCT01882439) including patients receiving tofacitinib 5 or 10 mg twice daily (BID), or placebo, with stable MTX. Efficacy outcomes at month 3 stratified by MTX dose (≤ 15 month 3 stratified by MTX dose vs > 15 mg/week) were American College of Rheumatology (ACR)20/50/70, Health Assessment Questionnaire-Disability Index (HAQ-DI); Psoriasis Area and Severity Index (PASI)50/75; change from baseline in HAQ-DI; physician’s global assessment of PsA (PGA-PsA-visual analog scale [VAS]); patient’s global joint and skin assessment (PGJS-VAS), Leeds Enthesitis Index (LEI); and Dactylitis Severity Score (DSS). Safety assessments included adverse events and laboratory parameters. Results Five hundred fifty-six patients received tofacitinib 5 mg BID (n = 186), 10 mg BID (n = 178), or placebo (n = 192), plus MTX (≤ 15 mg/week, n = 371; > 15 mg/week, n = 185). At month 3, tofacitinib efficacy was generally greater than placebo. Patients receiving tofacitinib 5 mg BID demonstrated greater numerical improvements in efficacy outcomes at month 3 with MTX > 15 mg/week vs MTX ≤ 15 mg/week; patients receiving tofacitinib 10 mg BID displayed the opposite. The safety profile was generally consistent between groups; headache was associated with MTX > 15 mg/week; decreased hemoglobin levels were observed in patients receiving tofacitinib 10 mg BID and MTX ≤ 15 mg/week. Conclusion Efficacy of tofacitinib was generally numerically greater than placebo, regardless of MTX dose. Tofacitinib 5 mg BID was generally more efficacious with MTX > 15 mg/week vs ≤ 15 mg/week; the opposite was observed for tofacitinib 10 mg BID. Headache was more frequent with MTX > 15 mg/week. Trial registration ClinicalTrials.gov. Identifier: NCT01877668 (registration: June 14, 2013) and NCT01882439 (registration: June 20, 2013). Key Points• Methotrexate is widely used in the treatment of psoriatic arthritis; however, there are limited data on the impact of varying background methotrexate doses on the efficacy and safety of Janus kinase inhibitors in patients with psoriatic arthritis.• This post hoc analysis assessed the impact of background methotrexate dose (≤ 15 or > 15 mg/week) on tofacitinib efficacy and safety in patients with psoriatic arthritis.• Results indicated that tofacitinib efficacy was generally numerically greater than placebo, regardless of methotrexate dose. Tofacitinib 5 mg twice daily, in combination with a higher dose of background methotrexate, was more efficacious compared with a lower dose of background methotrexate; the opposite was observed for tofacitinib 10 mg twice daily.• Headache was more frequent with the higher methotrexate dose. Data should be interpreted with caution due to the small sample sizes.

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