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BackgroundNeutralising anti-drug antibodies (ADAb) are a problem in treatment with TNF-inhibitors (TNFi). Prospective data are needed to better understand how ADAb formation impacts safety and treatment outcomes of TNFi. Proactive therapeutic drug monitoring (TDM) allows for timely detection of ADAb and this strategy may have a role in reducing the negative clinical consequences of ADAb.ObjectivesTo explore the temporal relation between anti-infliximab antibody formation and treatment outcomes and adverse events, and to assess the impact of TDM as a strategy to reduce these consequences.MethodsPatients with immune mediated inflammatory diseases on infliximab therapy (n=615; 181 spondyloarthritis, 120 rheumatoid arthritis, 72 psoriatic arthritis, 114 ulcerative colitis, 83 Crohns disease and 45 psoriasis) were included in the Norwegian Drug Monitoring (NOR-DRUM) trials (1, 2) and randomised to TDM or standard infliximab therapy. Patients were followed for 30 and 52 weeks in the NOR-DRUM A (induction therapy) and NOR-DRUM B (maintenance therapy) trials, respectively. Neutralising ADAb were assessed with a drug sensitive automated fluorescence assay at each infusion. In this sub-study, we assessed the risk of; failure to achieve remission (analysis A), disease worsening during maintenance therapy (analysis B), treatment discontinuation (analysis C) and adverse events (analysis D) in patients developing ADAb compared to patients without ADAb using logistic- or cox regression and Kaplan-Meier survival analyses, stratified by TDM or standard therapy. Regression analyses were adjusted for potential confounders (Table 1). Remission and disease worsening were defined by disease specific composite scores (1, 2).ResultsADAb were detected in 147/615 (24 %) patients. Patients with ADAb had higher risk of not achieving remission 30 weeks after initiating infliximab therapy (odds ratio (OR) 2.4, 95 % confidence interval (CI) 1.3-4.2, P<0.01) (Table 1, Figure 1A) and of having a disease worsening during 52 weeks of infliximab maintenance therapy (hazard ratio (HR) 2.1, CI 1.4-3.3, P<0.001) (Figure 1B). ADAb formation was not significantly associated with adverse events in general, but the risk of infusion reactions was highly increased in patients with ADAb (HR 29, CI 11-78, P<0.001). The risk of infliximab treatment discontinuation was increased in ADAb positive patients (HR 6.5, CI 4.7-8.9, P<0.001). Patients developing ADAb in the TDM group had lower risk of disease worsening or an infusion reaction than patients with ADAb in the standard infliximab therapy group (Table 1, Figure 1B and C). Patients with ADAb discontinued infliximab treatment more often in the TDM group than in the control group (Table 1, Figure 1D).ConclusionFormation of ADAb led to poorer clinical outcomes both during induction and maintenance therapy with infliximab and increased the risk of infusion reactions. Early detection of ADAb by proactive TDM reduced the negative consequences of ADAb, both on infliximab effectiveness and safety, highlighting the role of proactive TDM in optimising TNFi therapy.References[1]Syversen SW et al. Jama. 2021;326(23)[2]Syversen SW et al. Jama. 2021;325(17)Table 1.Treatment and safety outcomes related to ADAb formation and TDMAnalysis A) Non-remissionOR (CI)PADAb2.4 (1.3-4.2)<0.01TDM1.0 (0.7-1.5)0.9Analysis B) Disease worseningHR (CI)PADAb2.1 (1.4,3.2)<0.01TDM0.4 (0.3-0.6)<0.001Analysis C) Infusion reactionHR (CI)PADAb29 (11-78)<0.001TDM0.3 (0.1-0.7)<0.01Analysis D) Treatment discontinuationHR (CI)PADAb6.5 (4.7-8.9)<0.001TDM1.4 (1.0-1.8)0.03Results from multivariable logistic (A)- or cox (B-D) regression models including the covariates: ADAb, TDM, age, sex, diagnosis, comedication. Results shown in table are risk of A) non-remission week 30, B) disease worsening during 52 weeks of maintenance therapy, C) infusion reactions and D) infliximab treatment discontinuation for patients developing ADAb and for patents in the TDM group.Figure 1.Acknowledgements:NIL.Disclosure of InterestsMarthe Kirkesæther Brun: None declared, Kristin Hammersbøen Bjørlykke Speakers bureau: Janssen, Grant/research support from: Olympus travel grant, Johanna Elin Gehin: None declared, David J Warren: None declared, Rolf A. Klaasen: None declared, Joseph Sexton: None declared, Øystein Sandanger: None declared, Tore K. Kvien Speakers bureau: Grünenthal, Sandoz, UCB, Consultant of: AbbVie, Amgen, Celltrion, Gilead, Novartis, Pfizer, Sandoz, UCB, Grant/research support from: AbbVie, Amgen, BMS, Galapagos, Novartis, Pfizer, UCB, Cato Mørk Speakers bureau: Novartis Norway, LEO Pharma, ACO Hud Norge, Cellgene, Abbvie, and Galderma Nordic AB, Jørgen Jahnsen Speakers bureau: AbbVie, Boerhinger Ingelheim, BMS, Celltrion, Giliad, Hikma, Janssen Cilag, Novartis, Orion Pharma, Pfizer, Roche, Takeda and Sandoz, Consultant of: AbbVie, Boerhinger Ingelheim, BMS, Celltrion, Giliad, Hikma, Janssen Cilag, Novartis, Orion Pharma, Pfizer, Roche, Takeda and Sandoz, Nils Bolstad: None declared, Kristin Kaasen Jørgensen Speakers bureau: Roche, BMS, Celltrion and Norgine, Espen A Haavardsholm Speakers bureau: Pfizer, UCB, Consultant of: AbbVie, Boehringer-Ingelheim, Eli Lilly, Gilead, Guro Løvik Goll Speakers bureau: AbbVie, Boehringer Ingelheim, Novartis, Pfizer, Orion Pharma, Eli Lilly, Roche, Sandoz, Silje Watterdal Syversen: None declared.

Background:A lack or loss of response to TNFα inhibitors (TNFi) has been associated with low serum drug levels and formation of anti-drug antibodies (ADAb). Therapeutic drug monitoring (TDM), an individualised treatment strategy based on regular assessments of serum drug levels, has been suggested to optimise efficacy of TNFi. It is still unclear if TDM improves clinical outcomes, and the value of TDM has recently been included in the research agenda across different specialities. This first randomised controlled trial on the effectiveness of TDM in a range of immune mediated inflammatory diseases including rheumatic diseases, the NORwegian DRUg Monitoring trial part A (NOR-DRUM (A)) focus on the induction period of infliximab (INX) treatment.Objectives:To assess if TDM is superior to standard treatment in order to achieve remission in patients starting INX.Methods:In the investigator-initiated, randomised, open-label, multicentre NOR-DRUM (A) study, adult patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), spondyloarthritis (SpA), ulcerative colitis (UC), Crohn’s disease (CD) and psoriasis (Ps) starting INX therapy were randomly assigned to administration of INX according to a treatment strategy based on TDM (TDM arm) or to standard administration of INX without TDM (control arm). Study visits were conducted at each infusion. The primary endpoint was remission at week 30. In the TDM arm, the dose and interval were adjusted according to INX trough levels to reach the therapeutic range (Figure 1). If the patient developed significant levels of ADAb, INX was terminated. To guide the investigators, the TDM strategy was integrated in an interactive eCRF. The primary endpoint was analysed by mixed effect logistic regression in the full analyses set (FAS), adjusting for diagnoses. Infections and infusion reactions were specified as adverse events (AEs) of special interest.Clinical trial.gov:NCT03074656Results:We enrolled 411 patients at 21 study centres between January 2017 and December 2018. 398 patients (RA 80, PsA 42, SpA 117, UC 80, CD 57, Ps 22) received the allocated strategy and were included in the FAS population. Demographic and baseline characteristics were comparable in both arms. TDM was not found to be superior to standard treatment with regard to the primary outcome. Remission at week 30 was reached in 100 (53%) and 106 (54%) of the patients in the TDM and control arm, respectively (adjusted difference, 1.5%; 95% confidence interval (CI), -8.2 to 11.1, p=0.78) (Figure 2). Consistent results were shown for all the secondary endpoints (Figure 3) and in the sensitivity analyses. Twenty patients (10%) in the TDM arm and 30 patients (15%) in the control arm developed significant levels of ADAb. The number of adverse events (AE) was similar in both groups, however infusion reactions were less frequent (5 patients (2.5%) vs 16 patients (8.0%)) in the TDM arm (difference 5.5% (95% CI 1.1, 9.8%))Conclusion:NOR-DRUM (A) is the first randomised trial to address effectiveness of TDM in the induction period of TNFi treatment, and the first trial to address TDM in rheumatic diseases. In this study, TDM was not superior to standard treatment in order to achieve remission. Although improved safety is indicated by a reduction in infusion reactions, implementation of TDM as a general strategy in the induction period of INX is not supported by the NOR-DRUM (A) study.Disclosure of Interests:Silje Watterdal Syversen Speakers bureau: Roche, Thermo Fisher, Guro Løvik Goll Consultant of: Novartis, Pfizer, Speakers bureau: Abbvie, Biogen, Boehringer Ingelheim, Orion Pharma, Eli Lilly, Novartis, Pfizer, MSD, Roche, UCB, Kristin Kaasen Jørgensen Consultant of: AOP Orphan, Celltrion, Sandoz, Speakers bureau: Norgine, Tillots, Øystein Sandanger: None declared, Joe Sexton: None declared, Inge Olsen: None declared, Johanna Gehin Speakers bureau: Roche, Marthe Kirksæther Brun: None declared, David Warren: None declared, Cato Mørk Consultant of: Abbot, Novartis, Celagene, Almiral, Galderma, ACO, Almiral, ACO, Speakers bureau: Novartis, Abbott, Abbvie, Celegene, LEO, Almiral, Galderma, Tore K. Kvien Grant/research support from: Received grants from Abbvie, Hospira/Pfizer, MSD and Roche (not relevant for this abstract)., Consultant of: Have received personal fees from Abbvie, Biogen, BMS, Celltrion, Eli Lily, Hospira/Pfizer, MSD, Novartis, Orion Pharma, Roche, Sandoz, UCB, Sanofi and Mylan (not relevant for this abstract)., Paid instructor for: Have received personal fees from Abbvie, Biogen, BMS, Celltrion, Eli Lily, Hospira/Pfizer, MSD, Novartis, Orion Pharma, Roche, Sandoz, UCB, Sanofi and Mylan (not relevant for this abstract)., Speakers bureau: Have received personal fees from Abbvie, Biogen, BMS, Celltrion, Eli Lily, Hospira/Pfizer, MSD, Novartis, Orion Pharma, Roche, Sandoz, UCB, Sanofi and Mylan (not relevant for this abstract)., Jørgen Jahnsen Consultant of: AbbVie, Boerhinger Ingelheim, Celltrion, Ferring, Janssen, Meda, MSD, Norgine, Novartis, Orion Pharma, Pfizer, Pharmacosmos, Takeda, and Sandoz., Speakers bureau: AbbVie, Astro Pharma, Boerhinger Ingelheim, BMS, Celltrion, Ferring, Hikma, Janssen, Meda, MSD, Napp Pharma, Orion Pharma, Pfizer, Pharmacosmos, Roche, Takeda, Tillotts and Sandoz, Nils Bolstad Consultant of: Pfizer, Janssen, Speakers bureau: Orion Pharma, Napp Pharmaceuticals, Takeda, Roche, Novartis, Espen A Haavardsholm Grant/research support from: AbbVie, UCB Pharma, Pfizer Inc, MSD Norway, Roche Norway, Consultant of: Pfizer, AbbVie, Janssen-Cilag, Gilead, UCB Pharma, Celgene, Lilly, Paid instructor for: UCB Pharma, Speakers bureau: Pfizer, AbbVie, UCB Pharma, Celgene, Lilly, Roche, MSD

BackgroundThe NOR-SWITCH study is a 52-week randomized, double-blind, non-inferiority, phase IV switch trial in patients with Crohn's disease (CD), ulcerative colitis (UC), spondyloarthritis (SpA), rheumatoid arthritis (RA), psoriatic arthritis (PsA) and plaque psoriasis (Ps) on stable treatment with originator infliximab (Remicade®, INX), funded by the Norwegian government. Previously, primary analyses of the pooled indications have been published1.ObjectivesTo investigate efficacy, safety and immunogenicity in SpA patients treated with continuous INX vs patients switched to CT-P13 (biosimilar infliximab, Remsima®) in the NOR-SWITCH study (explorative analyses).MethodsPatients were randomized 1:1 to continued INX or switch to CT-P13. Serum drug levels were analyzed by automated in-house assay. The primary endpoint was disease worsening according to disease-specific composite measures and/or consensus between investigator/patient. Exploratory subgroup analyses examined disease worsening and safety in SpA. The primary endpoint was analysed by logistic regression, adjusted for diagnosis and disease duration.ResultsDemographics, occurrence of disease worsening, change in disease measures and treatment-emergent adverse events (TEAE) were similar (Table), as were serum drug levels for INX and CT-P13 (Figure).Table 1.Demographics, baseline characteristics (FAS), percentage of patients with disease worsening, change in disease measures during 52 weeks follow-up (PPS)Demographics, baseline characteristicsINXCT-P13 Total number of SpA patients PPS/FAS43/4542/46Age (years) mean (SD)50.0 (10.3)52.8 (10.8)Females7 (16%)8 (17%)Duration of ongoing INX treatment (years) mean (SD)8.6 (3.1)8.7 (3.2)Immunosuppressive co-medication15 (33%)10 (22%)HLA B27 pos31 (94%)33 (87%)Disease worsening95% CI of group difference after 52 weeks All study patients53 (26.2%)61 (29.6%)-12.7–3.9% SpA17 (39.5%)14 (33.3%)-14.5–27.2%Change in disease measures from baseline Physician Global Assessment of Disease Activity (0–10)-0.1 (1.4)-0.5 (1.3)0.53–0.53 Patient Global Assessment of Disease Activity (0–10)0.1 (2.2)-0.4 (1.8)-0.08–0.62 Log10 erythrocyte sedimentation rate (mm/h)0.0 (0.3)-0.0 (0.3)-0.14–0.06 Log10 C-reactive protein (mg/L)-0.0 (0.4)-0.1 (0.4)-0.11–0.15 ASDAS0.1 (0.6)-0.2 (0.7)-0.27–0.24 BASDAI0.3 (1.0)-0.2 (1.4)-0.50–0.47TEAE (FAS)116102Data are n (%), mean (SD) or median (25–75 percentiles). 95% CI, 95% confidence interval of the adjusted treatment difference. BASDAI, Bath Ankylosing Spondylitis Disease Activity Index. ASDAS, Ankylosing Spondylitis Disease Activity Score. FAS, Full Analysis Set. PPS, Per Protocol Set. TEAE, treatment emergent adverse events.ConclusionsExplorative analyses in the NOR-SWITCH study showed similar efficacy, drug levels and safety in SpA patients switched to CT-P13 as those on continuous INX. The study was not powered to show non-inferiority within each diagnosis.References Jørgensen KK et al. Switching from originator infliximab to biosimilar CT-P13 compared to maintained treatment with originator inflixim...

BackgroundThe NOR-SWITCH study was a 52-week randomized, double-blind, non-inferiority, phase IV switch trial in patients with Crohn's disease (CD), ulcerative colitis (UC), spondyloarthritis (SpA), rheumatoid arthritis (RA), psoriatic arthritis (PsA) and plaque psoriasis (Ps) on stable treatment with originator infliximab (Remicade®, INX) and was funded by the Norwegian government. Previously, the primary analyses of the pooled indications have been published1.ObjectivesTo investigate efficacy, safety and immunogenicity in RA patients treated with continous INX vs patients switched to CT-P13 (biosimilar infliximab, Remsima®) in the NOR-SWITCH study (explorative analyses).MethodsPatients were randomized 1:1 to continued INX or switch to CT-P13. Serum drug levels were analysed in automated in-house assay. The primary endpoint was disease worsening according to disease-specific composite measures and/or consensus between investigator/patient leading to major treatment change. Exploratory subgroup analyses examined disease worsening and safety in RA. The primary endpoint was analysed using logistic regression, adjusted for diagnosis and disease duration.ResultsDemographics, occurence of disease worsening, change in disease measures and treatment-emergent adverse events (TEAE) were similar (Table). Serum drug levels for INX and CT-P13 were similar throughout the study (Figure)Table 1.Demographic and baseline characteristics (FAS), percentage of RA patients with disease worsening and change in disease measures during 52 weeks follow-up (PPS)Demographics and baseline characteristicsINXCT-P13 Total number of RA patients PPS/FAS30/3930/38Age (years) mean (SD)59.9 (11.5)60.4 (11.4)Females31 (79%)25 (66%)Duration of ongoing infliximab treatment (years) mean (SD)8.2 (3.7)9.9 (3.4)Concomitant immunosuppressive medication27 (69%)34 (89%)ACPA pos25 (83%)20 (74%)Disease worsening95% CI of group difference after 52 weeks All study patients53 (26.2%)61 (29.6%)-12.7–3.9% RA11 (36.7%)9 (30.0%)-20.3–29.3%Change in disease measures from baseline Physician Global Assessment of Disease Activity (0–10)-0.1 (1.3)0.1 (1.4)-0.58–0.68 Patient Global Assessment of Disease Activity (0–10)1.1 (1.4)0.4 (1.9)0.21–1.91 Log10 erythrocyte sedimentation rate (mm/h)0.0 (0.3)0.0 (0.3)-0.08–0.16 Log10 C-reactive protein (mg/L)0.1 (0.3)0.0 (0.5)-0.11–0.22 DAS280.2 (0.9)0.2 (0.9)-0.30–0.50TEAE (FAS)9462Data are n (%), mean (SD) or median (25–75 percentiles). 95% CI, 95% confidence interval of the adjusted treatment difference. DAS28, Disease Activity Score in 28 joints. FAS, Full Analysis Set. PPS, Per Protocol Set. TEAE, treatment emergent adverse events.ConclusionsExplorative analyses in the NOR-SWITCH study showed similar efficacy, serum drug levels and safety in RA patients switched to CT-P13 as those on continuous INX. The study was not powered to show non-inferiority within each diagnosis.References Jørgensen KK et al Switching from originator infliximab to biosimimlar CT-P13 compared to maintained treatment with originator infliximab (NOR-SWITCH):...