Stable MTX Research Articles

P312 Erythrocyte methotrexate polyglutamate concentrations in patients with Crohn’s Disease: towards a new therapeutic drug monitoring tool

Abstract Background Methotrexate (MTX) is an immunomodulatory drug for patients with Crohn’s Disease (CD), used as first-line therapy, as a second-line in case of failure to thiopurine, and concomitantly with anti-TNFα agents to decrease production of anti-drug antibodies. Nevertheless, MTX is underutilised in the treatment of CD, despite its proven efficacy and good safety profile. This is for a large part due to the lack of therapeutic drug monitoring (TDM) of MTX because no stable plasma MTX levels are reached. Intracellular MTX-polyglutamates (MTX-PGs), formed after folylpolyglutamate synthetase attaches glutamate residues to MTX, could be used as a TDM tool as MTX-PG is thought to mediate MTX’s efficacy. We present the results of our cross-sectional study in CD patients, aiming to gain insight into erythrocyte MTX-PG levels. Methods CD adults on MTX treatment who visited the outpatient clinic of Amsterdam UMC between May 2019 and February 2020 were included consecutively. An established LC-ESI-MS/MS method1 was used to measure erythrocyte MTX-PGs. Results Nineteen patients were included. Mean disease duration was 17 years (SD±13.7). Montreal disease location and behaviour were as follows (n=): L1 = 2, L2 = 4, L3 = 13; B1 = 11, B2 = 5, B3 = 3. Only 4 patients had a flare according to Physician Global Assessment. Twelve patients received MTX monotherapy, whereas 7 patients were on concomitant anti-TNFα agents. The mean dose of MTX was 15.5 mg (SD±2.8) and 12 (63%) patients had subcutaneous (sc.) MTX. We successfully measured MTX-PG2-5 in 18 patients, showing substantial variability in measured concentrations of total MTX-PG(tot) and the individual species. The median MTX-PGtot was 117.1 nmol/L [min:46.4-max:358.7] with preferential accumulation of MTX-PG3 (43.1 [15.3-96.1]); the least predominant species being MTX-PG5 (9.4 [1.1-24.1]). Patients on sc. compared to oral MTX had higher MTX-PGtot levels (177.8 [58.8-358.7] vs. 93.2 [46.4-120.8] nmol/L, p=0.067) and significantly higher long-chain MTX-PG4-5 levels (55 [3.7-84.3] vs. 8.9 [2.4-15.0] nmol/L, p=0.010); see figure. Conclusion We showed that erythrocyte MTX-PGs can be measured in CD patients by tandem MS. Large variability in concentrations was demonstrated, similar to our previously published results in rheumatoid and juvenile arthritis2,3 which is a pre-requisite for MTX-PG use as a TDM tool. We showed for the first time that MTX-PG accumulation was higher in sc. MTX vs. oral MTX treatment. This work provides the first step towards establishing TDM for MTX in CD, a goal we aim to realize in our upcoming longitudinal study. References

P133 Filgotinib in patients with RA with inadequate response to methotrexate: FINCH 1 52-week efficacy and patient reported outcomes data

P133 Filgotinib in patients with RA with inadequate response to methotrexate: FINCH 1 52-week efficacy and patient reported outcomes data

P128 A subgroup analysis of the efficacy of filgotinib for patients with moderately active RA following an inadequate response to methotrexate

P128 A subgroup analysis of the efficacy of filgotinib for patients with moderately active RA following an inadequate response to methotrexate

THU0198 EFFICACY AND SAFETY OF FILGOTINIB FOR PATIENTS WITH RHEUMATOID ARTHRITIS WITH INADEQUATE RESPONSE TO METHOTREXATE: FINCH 1 52-WEEK RESULTS

Background:Filgotinib (FIL) is an oral, potent, selective JAK1 inhibitor. FINCH 1 (NCT02889796) assessed FIL efficacy and safety in patients (pts) with rheumatoid arthritis (RA) with inadequate response to methotrexate (MTX-IR); primary outcome results at week (W)12 and W24 were previously reported.1Objectives:To present FINCH 1 W52 results.Methods:This global, phase 3, double-blind, active- and placebo (PBO)-controlled study randomised MTX-IR pts with active RA on a background of stable MTX 3:3:2:3 to oral FIL 200 mg or FIL 100 mg once daily, subcutaneous adalimumab (ADA) 40 mg every 2W, or PBO up to W52; pts receiving PBO at W24 were rerandomised to FIL 100 or 200 mg. Efficacy was assessed from clinical, radiographic, and pt-reported outcomes; W52 comparisons were not adjusted for multiplicity. Safety endpoints included adverse events (AEs) and laboratory abnormalities.Results:Of 1755 treated pts, 1417 received study drug through W52. The majority (81.8%) were female, mean (standard deviation [SD]) RA duration was 7.8 (7.6) years, and baseline mean (SD) DAS28(CRP) was 5.7 (0.9). FIL efficacy was sustained through W52; 54%, 43%, and 46% of pts receiving FIL 200 and 100 mg and ADA, respectively, had W52 DAS28(CRP) <2.6 (nominal p for FIL 200 vs ADA = 0.024) (Figures 1–2, Table 1). FIL safety profile through W52 was consistent with W24 data. AEs of interest were infrequent and balanced among treatments (Table 2); 82 pts (4.7%) discontinued treatment due to AEs.Table 1.Efficacy outcomes at week 52FIL 200 mg(n = 475)FIL 100 mg(n = 480)ADA(n = 325)ACR20/50/70, %78/62/4476/59/3874/59/39DAS28(CRP) ≤3.2, %66+5959mTSSa0.18+++0.450.61HAQ-DIb−0.93+−0.85−0.85SF-36 PCSb12.011.512.4FACIT-Fb11.912.211.7aLeast squares mean change from baseline.bMean change from baseline.+p <0.05,+++p <0.001 vs ADA; not adjusted for multiplicity.ADA, adalimumab; FIL, filgotinib; mTSS, modified van der Heijde TSS.Table 2.Treatment-emergent AEs through week 52Event, n (%)FIL 200(n = 475)FIL 100 mg(n = 480)ADA(n = 325)All AEs352 (74.1)350 (72.9)239 (73.5)Serious AEs35 (7.4)40 (8.3)22 (6.8)Infection206 (43.4)194 (40.4)129 (39.7)Serious infection13 (2.7)13 (2.7)10 (3.1)Herpes zoster6 (1.3)4 (0.8)2 (0.6)VTE1 (0.2)01 (0.3)MACE (adjudicated)02 (0.4)1 (0.3)Malignancy (excluding NMSC)2 (0.4)2 (0.4)2 (0.6)NMSC1 (0.2)1 (0.2)0Death3 (0.6)1 (0.2)1 (0.3)Data omitted for patients rerandomised from placebo to FIL.ADA, adalimumab; AE, adverse event; FIL, filgotinib; MACE, major adverse cardiovascular event; NMSC, nonmelanoma skin cancer; VTE, venous thromboembolism.Conclusion:Through W52, both FIL 200 and 100 mg showed sustained efficacy based on clinical and pt-reported outcomes and radiographic progression and were well tolerated in MTX-IR pts with RA, with faster onset and numerically greater efficacy for FIL 200 vs 100 mg.

P236 Baricitinib provides better pain relief across all disease activity levels compared with placebo and adalimumab in RA

Abstract Background In this post hoc analysis, we assessed relationship between pain improvement and disease activity and evaluated whether baricitinib (BARI) provided additional pain improvement vs. PBO and adalimumab (ADA) across levels of disease activity. Methods 1,305 patients on stable background MTX were randomized 3:2:3 (PBO:40-mg subcutaneous ADA every other week:daily, oral 4-mg BARI). Pain was assessed with 0-100-mm VAS; pain improvement (baseline to Week 12) was grouped by ≤ 30%, >30% to ≤ 50%, >50% to ≤ 70%, >70%. Disease activity was measured with CDAI, SDAI, DAS28 with CRP, and DAS28 with ESR. To evaluate change in pain with disease activity, regression was used with continuous change in pain VAS score from baseline to Week 12 as outcome and continuous CDAI/SDAI/DAS28-CRP/DAS28-ESR values, treatment, and interaction term between treatment and disease activity as explanatory variables. Last observation carried forward was used to impute missing values. Pain VAS change (Week 12) was estimated if patients achieved remission (REM)/low disease activity (LDA)/moderate disease activity (MDA) as defined by the corresponding clinical measure. Analyses were not adjusted for multiplicity. Data visualization (percentage of pain VAS improvement vs. disease activity) was created to examine pain improvement with treatment over time. Results With CDAI, 91%/9% of patients had high disease activity/MDA across all treatments (baseline). Percentage of patients achieving REM with PBO, ADA, and BARI were 2%, 7%, 8%; for LDA: 15%, 27%, 33%; for MDA: 33%, 40%, 38%. At all CDAI values, estimated change in pain VAS for BARI was greater vs. PBO and ADA (Week 12). Similar trends were observed with other measures (Table). BARI demonstrated greater pain improvement vs. ADA and PBO in percentage of patients with ≤30%, >30% to ≤ 50%, >50% to ≤ 70%, and >70% pain improvement from baseline at Week 12. . With CDAI/SDAI, greater differentiation between BARI and ADA was observed as CDAI/SDAI values increased. Conclusion BARI provided additional pain improvement vs. PBO and ADA when disease activity was controlled, across all levels of disease activity, measured by CDAI, SDAI, DAS28-CRP, or DAS28-ESR (Week 12). Disclosures P.C. Taylor (Presenter): Consultancies; PCT has been a consultant and/or received research support from: AbbVie, Eli Lilly and Company, Galapagos, and Pfizer. J. Pope: Consultancies; JP has been a consultant and/or has received grant/research support from: AbbVie, Amgen, Bayer, BMS, Eli Lilly and Company, Merck, Novartis, Pfizer, Roche, Sanofi, Sandoz, and UCB. K. Ikeda: Consultancies; KI has been a consultant and/or received research support and/or honoraria from: AbbVie, Astellas Pharma, Bristol-Myers K.K., Chugai Pharmaceutical, Eisai, Eli Lilly and Company, Kyowa Hakko Kir. X. Zhang: Corporate appointments; XZ is an employee of Eli Lilly and Company. Shareholder/stock ownership; XZ is a shareholder of Eli Lilly and Company. B. Jia: Corporate appointments; BJ is an employee of Eli Lilly and Company. Shareholder/stock ownership; BJ is a shareholder of Eli Lilly and Company. H. Zhang: None. A. Quebe: Corporate appointments; AQ is an employee of Eli Lilly and Company. Shareholder/stock ownership; AQ is a shareholder of Eli Lilly and Company. Y. Chen: Corporate appointments; Y-FC is an employee of Eli Lilly and Company. Shareholder/stock ownership; Y-FC is a shareholder of Eli Lilly and Company. C.L. Kannowski: Corporate appointments; CLK is an employee of Eli Lilly and Company. Shareholder/stock ownership; CLK is a shareholder of Eli Lilly and Company. T. Holzkaemper: Corporate appointments; TH is an employee of Eli Lilly and Company. Shareholder/stock ownership; TH is a shareholder of Eli Lilly and Company. A. Cardoso: Corporate appointments; AC is an employee of Eli Lilly and Company. Shareholder/stock ownership; AC is a shareholder of Eli Lilly and Company. A. Sebba: Consultancies; AS has been a consultant and/or speaker for: Eli Lilly and Company, Genentech, and Novartis.

Prediction of the therapeutic response to methotrexate at 24 weeks by methotrexate–polyglutamates concentration in erythrocytes at 8 weeks in patients with rheumatoid arthritis

Objectives: The objective of this study is to evaluate the pharmacokinetics and pharmacodynamics of methotrexate–polyglutamates (MTX-PGs) in erythrocytes in patients with rheumatoid arthritis and correlate them with the efficacy.Methods: MTX-PG concentrations in erythrocytes were measured in 42 MTX-naïve patients repeatedly for 24 weeks by high-performance liquid chromatography. In 56 patients receiving stable MTX doses for at least 12 weeks, the correlation between MTX doses and MTX-PG concentrations was examined. The efficacy was measured by the change of DAS28CRP (ΔDAS28CRP).Results: There were moderate correlations between MTX dose and MTX-PG 3, 4, and 5. At 24 weeks, MTX-PG2, 3, 4, and 1–5 were higher in patients with ΔDAS28CRP >1.2 than in those with ≤1.2. The cutoff value of MTX-PG1-5 to discriminate ΔDAS28CRP >1.2 from ≤1.2 at 24 weeks was 68.7 nM. Among 20 patients with MTX-PG1-5 > 50.6 nM at 8 weeks, seven already improved at 8 weeks and additional 11 improved at 24 weeks (p < 0.001). On the contrary, among the nine patients with MTX-PG1-5 ≤ 50.6 nM at 8 weeks, none improved at 8 weeks and only one improved at 24 weeks (p = 0.500).Conclusions: Erythrocyte MTX-PGs might be a potential indicator and predictor of MTX efficacy.

AB0444 Assessment of Structural Benefits of SC Abatacept Using MRI in Patients with RA Who Have Failed 1 or 2 TNFS and Correlated with Clinical Outcomes as Measured by DAS28(ESR)

BackgroundPrevious studies1–2 suggest the structural benefit of IV abatacept in patients with RA who have previously failed MTX, TNF therapy or combination of both.ObjectivesThis study evaluates the structural effect of...

THU0109 Lack of Efficacy of CCR1 Antagonist BMS-817399 in Patients with Moderate to Severe Rheumatoid Arthritis: Results of 12-Week Proof-Of-Concept Study

BackgroundC-C chemokine receptor 1 (CCR1) and its ligands are overexpressed in synovial tissue and fluid suggesting a role in rheumatoid arthritis (RA). Early clinical studies hinted that CCR1 inhibition may...

SAT0396 Efficacy and Safety of Ustekinumab in Patients with Active Psoriatic Arthritis: 2-Year Results from A Phase 3, Multicenter, Double-Blind, Placebo-Controlled Study

ObjectivesTo evaluate long-term clinical/radiographic efficacy of subcutaneous UST 45/90 mg in patients with active psoriatic arthritis (PsA) through wk108 of the PSUMMIT 1 trial.MethodsAdult PsA pts (n=615) with active disease...

AB0400 Intravenous Golimumab Inhibits Radiographic Progression and Maintains Clinical Efficacy and Safety in Patients with Active Rheumatoid Arthritis despite Methotrexate Therapy: 2-Year Results of A Phase 3 TRIAL of Intravenous Golimumab

ObjectivesTo evaluate long-term clinical/radiographic efficacy of IV GLM 2mg/kg+MTX in active RA despite MTX through wk112.Methods592 pts with active RA (≥6/66 SJC, ≥6/68 TJC, CRP≥1.0mg/dL, RF and/or anti-CCP positive) despite...

A148: A Multi‐Center, Double‐Blind, Randomized‐Withdrawal Trial of Subcutaneous Golimumab in Pediatric Patients With Active Polyarticular Course Juvenile Idiopathic Arthritis Despite Methotrexate Therapy: Week 48 Results

Background/Purpose:To assess efficacy and safety of SC golimumab (GLM) in polyarticular pediatric juvenile idiopathic arthritis pts (aged 2 to &lt;18 yrs) with active arthritis despite MTX for ≥3 months.Methods:In GO‐KIDS, a 3‐part randomized double‐blind, PBO‐controlled, withdrawal trial in pts with active JIA with a polyarticular course (≥5 active joints) and disease duration of ≥6 months despite current MTX (10–30 mg/m2/wk). In Part 1(wk 0–12), all pts received open‐label (OL) 30 mg/m2 GLM SC (max 50 mg) q4 wks with stable MTX dose. At wk 16, pts with ACR JIA 30 response entered Part 2 (wk 16–48). In Part 2, pts were randomized to continue GLM or switch to PBO q4 wks. Upon Part 2 completion at wk 48 or ACR JIA flare in Part 2, pts received OL GLM in Part 3. Primary endpoint was proportion of ACR JIA 30 responders at wk 16 without a JIA flare in Part 2 using wk 16 as baseline measurement. Secondary outcomes were ACR JIA 30/50/70/90 response rates and inactive disease rates at wk 16 and wk 48 by group and safety.Results:173 pts (Caucasian 87.9%, 75.7% females; age [median/range] 12 yrs/2–17 yrs) with moderately active disease were enrolled (Table ); 19 (11%) were d/c in Part 1 (lack of efficacy n = 14, AE n = 4, withdrawal of consent n = 1). In Part 1, 151 of 173 (87.3%) achieved an ACR JIA 30 response and 36.1% inactive disease status (Table ). There were 154 pts randomized double‐blind in Part 2 (PBO n = 76; continued GLM n = 78). At the end of Part 2, no significant differences between groups in JIA ACR non‐flare rates and trial did not meet primary endpoint [PBO‐grp vs. GLM‐grp: 52.6% vs. 59.0%, p = 0.41) nor were there differences for major secondary endpoints (Table 2). In contrast, sustained response in both groups (PBO, GLM) relative to wk 0 (Table 1 and 2). 6.5% (10 of 154) of pts d/c therapy after wk16 through wk 48. Through wk 48, AEs, serious AE (SAE), and serious infections were reported in 87.9%, 13.3%, and 2.9% of all randomized pts, respectively. Most common SAE was JIA exacerbation. No deaths, active TB or malignancies were reported (1). GLM‐treated pt experienced SAE of toxic hepatitis and 1 had SAE of hepatic enzyme increase. One pt switched from PBO to GLM experienced SAE of serum sickness reaction, resulting in GLM d/c. Proportion of pts with ≥1 injection site reaction was 8.1%. None of the reactions were serious, severe, or led to GLM d/c. At Baseline (All enrolled patients n=173) At wk16 (All randomized patients prior to randomization, n=154) At wk48 Values are medians (interquartile range) PBO + MTX (n=76) GLM + MTX (n=78) Physicians global assessment 5.40 (3.90; 7.00) 0.50 (0.10; 1.30) 0.30 (0.00; 1.00) 0.30 (0.00; 1.30) Patient/parent global assessment 4.50 (2.80; 6.10) 0.90 (0.30, 2.30) 0.60 (0.20; 1.65) 0.45 (0.10; 1.70) Number of active joints 12.0 (8.0; 18.0) 1.0 (0.0; 3.0) 1.0 (0.0; 3.0) 0.0 (0.0; 2.0) Number of joints with limited range of motion 8.0 (6.0; 15.0) 1.0 (0.0, 4.0) 0.5 (0.00; 4.0) 1.0 (0.0; 3.0) Physical function by CHAQ 0.94 (0.38; 1.50) 0.25 (0.00; 0.75) 0.13 (0.00; 0.63) 0.00 (0.00; 0.63) ESR (mm/hr) 16.00 (8.00; 28.00) 9.00 (5.00; 19.00) 9.50 (5.00; 16.50) 10.00 (5.00; 19.00) Methotrexate (mg/wk) 15t(5.00; 30.00) 15t(5.00; 30.00) 15t(5.00; 30.00) 15t(5.00; 30.00) ACR JIA response and flare rates PART 1 [WK 0ndash;16] Percentage of ACR JIA responders at end of Part 1 [WK 16] (n = 173) JIA ACR 30 87.3%t(151) JIA ACR 50 79.2%t(137) JIA ACR 70 65.9%t(114) JIA ACR 90 36.4%t(63) Inactive disease 36.1%t(62) PART 2 [WK 16ndash;48] Percentage of ACR JIA 30 responders without flare in Part 2 (n = 154) PBO + MTX (n=76) 52.6%t(40) P=0.41 GLM + MTXt(n=78) 59.0%t(46) Inactive disease 21.6%/39.7% Clinical remission 11.8%/12.8% Percentage of ACR JIA responders at WK48 (vs. wk0) by treatment in Part 2 [PBO +MTX/GLM +MTX] JIA ACR 30 95.9%/89.0% JIA ACR 50 91.8%/86.3% JIA ACR 70 78.1%/78.1% JIA ACR 90 53.4%/56.2% Pts experiencing flares/those considered treatment failures due to protocol violations are considered ACR non‐responders from the flair/failure visit to wk 48 Observed dataConclusion:JIA pts with active polyarticular dis ease demonstrated rapid response to GLM with 16 wks of OL treatment, resulting in inactive disease in 36% of the pts. The lack of differences in flare rates between GLM and PBO arms from wk 16 to 48 among OL GLM responders needs further evaluation. Safety profile was acceptable and injections well tolerated.

SAT0112 Improvements in Patient-Reported Physical Function, Pain and Global Disease Activity in Patients with Rheumatoid Arthritis after Treatment with Nnc0109-0012 (Anti-IL-20 Mab) in a Phase 2A Trial

BackgroundNNC0109-0012 (anti-IL-20 mAb) is a novel human monoclonal IgG4 antibody which binds to IL-20 and neutralises its activity. The primary endpoint in this multicentre, randomised, double-blind, placebo-controlled, parallel group trial...

THU0218 Intravenous Golimumab Inhibits Radiographic Progression and Maintains Clinical Efficacy and Safety in Patients with Active Rheumatoid Arthritis Despite Methotrexate Therapy: 1-Year Results of a Phase 3 Trial

ObjectivesEvaluate long-term efficacy of IV GLM 2mg/kg+MTX in active RAdespite MTX thru wk52.MethodsPts(n=592)with active RA(≥6/66 SJ,≥6/68TJ, CRP≥1.0mg/dL, RF&/or anti-CCP+at screen)despite ≥3mo of MTX(15-25mg/wk)participated. Pts rand to IV GLM2mg/kgorPBO at wks0&4...

FRI0169 Intravenous golimumab is effective in patients with active rheumatoid arthritis despite methotrexate therapy with results observed by 2 weeks: Results of the phase 3, multicenter, double-blind, placebo-controlled trial

ObjectivesTo evaluate the efficacy of IV GLM 2mg/kg+MTX in pts with active RA despite MTX.MethodsPts (n=592) with active RA (≥6/66 swollen joints, ≥6/68 tender joints, CRP≥1.0mg/dL, rheumatoid factor and/or anti-CCP...

OP0158 Ustekinumab in patients with active psoriatic arthritis: Results of the phase 3, multicenter, double-blind, placebo-controlled psummit I study

ObjectivesTo assess efficacy and safety of UST in reducing signs and symptoms of active PsA in a large, multicenter, double-blind, placebo (PBO)-controlled, Ph3 trial.MethodsAdult PsA pts (n=615) w/ active disease...

SAT0271 Continued Improvement of Signs and Symptoms in Ustekinumab-Treated Patients with Active Psoriatic Arthritis: Week 52 Results of a Phase 3, Multicenter, Double-Blind, Placebo-Controlled Study

ObjectivesWe report safety & efficacy results through wk52 of PSUMMIT I, a large, multicenter, double-blind, PBO-controlled, Phase 3 trial of ustekinumab (UST) in pts with active psoriatic arthritis (PsA).MethodsAdult PsA...

FRI0494 Determinants of erythrocyte methotrexate polyglutamates levels in rheumatoid arthritis

BackgroundMethotrexate (MTX) is the gold standard in the management of rheumatoid arthritis (RA) and other arthritic diseases. Stable plasma MTX levels are not reached in RA but in the cell...

AB0480 Certolizumab pegol plus methotrexate is similarly effective in active rheumatoid arthritis regardless of prior TNF inhibitor use: Analysis of the doseflex PHASE IIIB study

BackgroundCertolizumab pegol (CZP) was associated with a rapid, consistent clinical response in a diverse group of RA patients (pts), including those with prior TNF inhibitor exposure.1ObjectivesTo investigate the efficacy of...

OP0043 Twenty-Four Weeks of Treatment with a Novel Anti-IL-6 Receptor Nanobody® (ALX-0061) Resulted in 84% ACR20 Improvement and 58% DAS28 Remission in a Phase I/Ii Study in RA

BackgroundALX-0061 is a monovalent IL-6R targeting Nanobody. It inhibits signalling via soluble and membrane IL-6R. PK/PD modelling resulted in a condensed study design, combining single ascending dose (SAD), multiple ascending...

LB0004 Efficacy and safety of nnc0109-0012 (anti-IL-20 MAB) in patients with rheumatoid arthritis: Results from a phase 2a trial

BackgroundNNC0109-0012 is a novel human monoclonal IgG4 antibody which binds to and neutralises the activity of IL-20. Phase 1 single-dose results did not raise any safety concerns for NNC0109-0012 in...