Maintenance Risankizumab Sustains Induction Response in Patients with Crohn's Disease in a Randomized Phase 3 Trial.

BACKGROUND AND AIMS: Durable clinical remission, endoscopic healing, and biomarker normalization are key treatment goals for Crohn's disease. The selective anti-interleukin-23 p19 inhibitor risankizumab has demonstrated efficacy and safety in moderately to severely active Crohn's disease. This post-hoc analysis of data from the pivotal risankizumab maintenance study assessed whether risankizumab maintenance therapy sustained the clinical and endoscopic outcomes achieved with risankizumab induction therapy. METHODS: We evaluated 462 patients who achieved a clinical response to risankizumab intravenous induction treatment and were re-randomized to receive subcutaneous risankizumab 360 mg, subcutaneous risankizumab 180 mg, or placebo [withdrawal] every 8 weeks for 52 weeks in the randomized, controlled FORTIFY maintenance study. Maintenance of clinical, endoscopic, and biomarker endpoints at week 52 among patients who achieved these endpoints after 12 weeks of induction treatment was evaluated. RESULTS: A significantly higher proportion of patients receiving maintenance treatment with risankizumab 360 or 180 mg compared with placebo [withdrawal] maintained Crohn's Disease Activity Index remission [68.6%, 70.8%, vs 56.3%; p < 0.05], stool frequency/abdominal pain remission [69.2%, 64.1%, vs 50.5%; p < 0.01], endoscopic response [70.2%, 68.2%, vs 38.4%; p < 0.001], endoscopic remission [74.4%, 45.5%, vs 23.9%; p < 0.05], and Simple Endoscopic Score for Crohn's Disease of 0-2 [65.5%, 36.7%, vs 21.9%]. Most patients [56.8-83.3%] who achieved normalized faecal calprotectin or C-reactive protein during induction sustained them with maintenance risankizumab. CONCLUSIONS: Subcutaneous risankizumab maintenance therapy results in durable improvement in clinical and endoscopic outcomes over 1 year in patients with moderately to severely active Crohn's disease. CLINICAL TRIAL REGISTRATION NUMBER: NCT03105102.

Clinical Bridging From Prefilled Syringe to On-body Injector for Risankizumab in Crohn's Disease.

PURPOSE: This article describes the clinical development bridging strategy and key data to support the marketing application of the risankizumab on-body injection (OBI) system for the treatment of moderately to severely active Crohn's disease (CD), even though the OBI was not evaluated directly in the pivotal Phase III studies in CD. METHODS: Three studies were conducted as part of the clinical bridging strategy. The pilot pharmacokinetics (PK) study was a Phase I, single-dose, 4-arm, open-label, randomized, parallel-group exploratory PK and tolerability study that assessed the effect of rate and volume of administration on the bioavailability (BA) of risankizumab and the extent of injection site-related pain after subcutaneous (SC) administration in healthy subjects. The pivotal BA/bioequivalence (BE) study was a relative BA/BE bridging study in healthy subjects to assess the relative BA of the to-be-marketed risankizumab OBI compared with the prefilled syringe (PFS) used in the Phase III CD studies. The OBI adhesive study was a randomized, open-label, non-drug interventional study in healthy subjects to assess the OBI adhesive effectiveness and skin tolerability at 2 different locations (abdomen and upper thigh) over different periods of time (5 and 30 minutes). FINDINGS: The pilot PK study showed that risankizumab exposures were similar across different rates/volumes of SC administration in healthy subjects, thereby supporting further development of the OBI. Second, a pivotal BA/BE study showed comparability between the OBI and Phase III PFS with bioequivalent risankizumab AUCs and no clinically meaningful difference for Cmax based on the wide therapeutic window of risankizumab. In both studies, no new safety risks were identified. No impact of immunogenicity on PK profile or safety was observed for the OBI. Third, an adhesive OBI (without risankizumab) study showed that there were no differences in adhesion/skin tolerability observed over time (up to 30 minutes) or for location of adhesion, and the OBI device adhesion was well tolerated at both the abdomen and thigh locations. IMPLICATIONS: These results supported the risankizumab OBI presentation approval in CD.

Risankizumab Induction Therapy Achieves Early Symptom Improvements That Are Associated With Future Clinical and Endoscopic Outcomes in Crohn's Disease: Post Hoc Analysis of the ADVANCE, MOTIVATE, and FORTIFY Phase 3 Studies.

BACKGROUND AND AIMS: Crohn's disease (CD) symptoms are a main driver for impaired quality of life and fast relief is important for patient care. Stool frequency (SF) and abdominal pain score (APS) are patient reported outcomes (PROs) measuring symptom severity, which are supported as treatment targets by the STRIDE-II consensus. This post hoc analysis examined the efficacy of risankizumab (RZB), a humanised monoclonal antibody with high specificity for interleukin-23 p19, for providing early symptom relief, along with the prognostic value of early symptom relief for achieving future clinical and endoscopic endpoints. METHODS: Individual and combined measures of SF and AP at weeks 1, 2, and 3 were assessed in patients with moderate to severe CD who received 600 mg intravenous RZB or placebo (PBO) in the ADVANCE or MOTIVATE induction studies. Multivariate logistic regression was used to examine the predictiveness of early symptom improvement for clinical and endoscopic outcomes following RZB induction and maintenance. RESULTS: Higher rates of SF/APS clinical remission and enhanced clinical response were observed as early as week 1 with RZB versus PBO. A larger proportion of patients achieved clinical endpoints with RZB versus PBO, irrespective of prior bio-failure status. Early PRO improvement was associated with a greater likelihood of achieving clinical and endoscopic improvement following 12-weeks induction and 52-weeks maintenance RZB dosing. CONCLUSIONS: After the first intravenous RZB induction dose, significantly greater rates of symptom improvement versus PBO were achieved. Improvements could be observed as early as week 1 and were predictive of week 12 and 52 clinical and endoscopic improvement.

Efficacy, Safety, Patient Experience, and Tolerability of Risankizumab Administered by On-Body Injector for Moderate to Severe Crohn's Disease.

INTRODUCTION: In patients with moderate to severe Crohn's disease (CD), intravenous induction and subcutaneous maintenance dosing with risankizumab was efficacious and well tolerated. Long-term management of CD via self-administration of risankizumab using an on-body injector (OBI) may improve treatment adherence through convenience and ease of use. METHODS: Within the FORTIFY maintenance study, 46 patients from the United States (US) sites participated in an open-label extension Substudy and received 180 mg or 360 mg risankizumab delivered subcutaneously via OBI [360 mg (2.4 mL, 150 mg/mL) or 180 mg (1.2 mL, 150 mg/mL)]. At the Week 0 visit, patients were trained (pre-injection) by site staff, using Instructions for Use (IFU) and a training video, to self-administer risankizumab at Weeks 0 (on site), 8 (at home), and 16 (on site). Key objectives of the Substudy 4 were to assess OBI usability (observer rating of successful self-administration), hazard-free self-injection at Weeks 0 and 16, and patient rating of acceptability using the Self-Injection Assessment Questionnaire (SIAQ) at Weeks 0, 8, and 16. Additionally, the proportion of patients in clinical remission (CD Activity Index < 150) was collected at Weeks 0 and 16. RESULTS: All patients successfully self-administered risankizumab via OBI, including two patients who successfully self-administered with a second OBI (i.e., required two injection attempts). Acceptability of self-injection was high. Two patients (n = 2) experienced a use-related hazard. Stable clinical remission was observed with both risankizumab doses. Two patients experienced injection site reactions; neither was related to the OBI per investigator's assessment. Two device-related adverse events related to topical adhesive reactions were reported, both mild and resolved. No new safety risks were observed. CONCLUSION: The efficacy and safety of maintenance risankizumab delivered via OBI and OBI usability support the use of this device in patients with moderate to severe CD. TRIAL REGISTRATION: ClinicalTrials.gov identifiers NCT03105102 (FORTIFY).

Risankizumab as maintenance therapy for moderately to severely active Crohn's disease: results from the multicentre, randomised, double-blind, placebo-controlled, withdrawal phase 3 FORTIFY maintenance trial.

BACKGROUND: There is a great unmet need for new therapeutics with novel mechanisms of action for patients with Crohn's disease. The ADVANCE and MOTIVATE studies showed that intravenous risankizumab, a selective p19 anti-interleukin (IL)-23 antibody, was efficacious and well tolerated as induction therapy. Here, we report the efficacy and safety of subcutaneous risankizumab as maintenance therapy. METHODS: FORTIFY is a phase 3, multicentre, randomised, double-blind, placebo-controlled, maintenance withdrawal study across 273 clinical centres in 44 countries across North and South America, Europe, Oceania, Africa, and the Asia-Pacific region that enrolled participants with clinical response to risankizumab in the ADVANCE or MOTIVATE induction studies. Patients in ADVANCE or MOTIVATE were aged 16-80 years with moderately to severely active Crohn's disease. Patients in the FORTIFY substudy 1 were randomly assigned again (1:1:1) to receive either subcutaneous risankizumab 180 mg, subcutaneous risankizumab 360 mg, or withdrawal from risankizumab to receive subcutaneous placebo (herein referred to as withdrawal [subcutaneous placebo]). Treatment was given every 8 weeks. Patients were stratified by induction dose, post-induction endoscopic response, and clinical remission status. Patients, investigators, and study personnel were masked to treatment assignments. Week 52 co-primary endpoints were clinical remission (Crohn's disease activity index [CDAI] in the US protocol, or stool frequency and abdominal pain score in the non-US protocol) and endoscopic response in patients who received at least one dose of study drug during the 52-week maintenance period. Safety was assessed in patients receiving at least one dose of study medication. This study is registered with ClinicalTrials.gov, NCT03105102. FINDINGS: 712 patients were initially assessed and, between April 9, 2018, and April 24, 2020, 542 patients were randomly assigned to either the risankizumab 180 mg group (n=179), the risankizumab 360 mg group (n=179), or the placebo group (n=184). Greater clinical remission and endoscopic response rates were reached with 360 mg risankizumab versus placebo (CDAI clinical remission was reached in 74 (52%) of 141 patients vs 67 (41%) of 164 patients, adjusted difference 15% [95% CI 5-24]; stool frequency and abdominal pain score clinical remission was reached in 73 (52%) of 141 vs 65 (40%) of 164, adjusted difference 15% [5-25]; endoscopic response 66 (47%) of 141 patients vs 36 (22%) of 164 patients, adjusted difference 28% [19-37]). Higher rates of CDAI clinical remission and endoscopic response (but not stool frequency and abdominal pain score clinical remission [p=0·124]) were also reached with risankizumab 180 mg versus withdrawal (subcutaneous placebo; CDAI clinical remission reached in 87 [55%] of 157 patients, adjusted difference 15% [95% CI 5-24]; endoscopic response 74 [47%] of 157, adjusted difference 26% [17-35]). Results for more stringent endoscopic and composite endpoints and inflammatory biomarkers were consistent with a dose-response relationship. Maintenance treatment was well tolerated. Adverse event rates were similar among groups, and the most frequently reported adverse events in all treatment groups were worsening Crohn's disease, arthralgia, and headache. INTERPRETATION: Subcutaneous risankizumab is a safe and efficacious treatment for maintenance of remission in patients with moderately to severely active Crohn's disease and offers a new therapeutic option for a broad range of patients by meeting endpoints that might change the future course of disease. FUNDING: AbbVie.

Risankizumab as induction therapy for Crohn's disease: results from the phase 3 ADVANCE and MOTIVATE induction trials.

BACKGROUND: Risankizumab, an interleukin (IL)-23 p19 inhibitor, was evaluated for safety and efficacy as induction therapy in patients with moderately to severely active Crohn's disease. METHODS: ADVANCE and MOTIVATE were randomised, double-masked, placebo-controlled, phase 3 induction studies. Eligible patients aged 16-80 years with moderately to severely active Crohn's disease, previously showing intolerance or inadequate response to one or more approved biologics or conventional therapy (ADVANCE) or to biologics (MOTIVATE), were randomly assigned to receive a single dose of intravenous risankizumab (600 mg or 1200 mg) or placebo (2:2:1 in ADVANCE, 1:1:1 in MOTIVATE) at weeks 0, 4, and 8. We used interactive response technology for random assignment, with stratification by number of previous failed biologics, corticosteroid use at baseline, and Simple Endoscopic Score for Crohn's disease (SES-CD). All patients and study personnel (excluding pharmacists who prepared intravenous solutions) were masked to treatment allocation throughout the study. Coprimary endpoints were clinical remission (defined by Crohn's disease activity index [CDAI] or patient-reported outcome criteria [average daily stool frequency and abdominal pain score]) and endoscopic response at week 12. The intention-to-treat population (all eligible patients who received at least one dose of study drug in the 12-week induction period) was analysed for efficacy outcomes. Safety was assessed in all patients who received at least one dose of study drug. Both trials were registered on ClinicalTrials.gov, NCT03105128 (ADVANCE) and NCT03104413 (MOTIVATE), and are now complete. FINDINGS: Participants were enrolled between May 10, 2017, and Aug 24, 2020 (ADVANCE trial), and Dec 18, 2017 and Sept 9, 2020 (MOTIVATE trial). In ADVANCE, 931 patients were assigned to either risankizumab 600 mg (n=373), risankizumab 1200 mg (n=372), or placebo (n=186). In MOTIVATE, 618 patients were assigned to risankizumab 600 mg (n=206), risankizumab 1200 mg (n=205), or placebo (n=207). The primary analysis population comprised 850 participants in ADVANCE and 569 participants in MOTIVATE. All coprimary endpoints at week 12 were met in both trials with both doses of risankizumab (p values ≤0·0001). In ADVANCE, CDAI clinical remission rate was 45% (adjusted difference 21%, 95% CI 12-29; 152/336) with risankizumab 600 mg and 42% (17%, 8-25; 141/339) with risankizumab 1200 mg versus 25% (43/175) with placebo; stool frequency and abdominal pain score clinical remission rate was 43% (22%, 14-30; 146/336) with risankizumab 600 mg and 41% (19%, 11-27; 139/339) with risankizumab 1200 mg versus 22% (38/175) with placebo; and endoscopic response rate was 40% (28%, 21-35; 135/336) with risankizumab 600 mg and 32% (20%, 14-27; 109/339) with risankizumab 1200 mg versus 12% (21/175) with placebo. In MOTIVATE, CDAI clinical remission rate was 42% (22%, 13-31; 80/191) with risankizumab 600 mg and 40% (21%, 12-29; 77/191) with risankizumab 1200 mg versus 20% (37/187) with placebo; stool frequency and abdominal pain score clinical remission rate was 35% (15%, 6-24; 66/191) with risankizumab 600 mg and 40% (20%, 12-29; 76/191) with risankizumab 1200 mg versus 19% (36/187) with placebo; and endoscopic response rate was 29% (18%, 10-25; 55/191) with risankizumab 600 mg and 34% (23%, 15-31; 65/191) with risankizumab 1200 mg versus 11% (21/187) with placebo. The overall incidence of treatment-emergent adverse events was similar among the treatment groups in both trials. Three deaths occurred during induction (two in the placebo group [ADVANCE] and one in the risankizumab 1200 mg group [MOTIVATE]). The death in the risankizumab-treated patient was deemed unrelated to the study drug. INTERPRETATION: Risankizumab was effective and well tolerated as induction therapy in patients with moderately to severely active Crohn's disease. FUNDING: AbbVie.

Observational data from the adalimumab post-marketing PYRAMID registry of patients with Crohn's disease who became pregnant: A post hoc analysis.

BACKGROUND: PYRAMID was an international post-marketing registry that aimed to collect data on the long-term safety and effectiveness of adalimumab treatment per local standard of care in patients with moderately to severely active Crohn's disease (CD). Here, we present post hoc analyses of observational data from patients who became pregnant while participating in this registry and receiving adalimumab. METHODS: From the subpopulation of patients receiving adalimumab who became pregnant while taking part in PYRAMID, data on patient characteristics, pregnancy outcomes, and complications of pregnancy were analysed retrospectively. RESULTS: Across the PYRAMID registry, 293 pregnancies occurred in patients who had gestational adalimumab exposure (average disease duration at last menstrual period: 8.6 years), resulting in 300 pregnancy outcomes. A total of 197 pregnancies (67.2%) were exposed to adalimumab in all trimesters per physician's decision. Of the known reported outcomes (96.3%), 81.7% (236/289) were live births, 10.4% (30/289) were spontaneous abortions, 4.8% (14/289) elective terminations, 2.8% (8/289) ectopic pregnancies, and 0.3% (1/289) was a stillbirth. Congenital malformations (pulmonary valve stenosis and tricuspid valve incompetence) were reported in one infant. In addition to the pregnancy outcomes described above, 23 complications of pregnancy were reported in 20 patients. CONCLUSIONS: This analysis showed that adalimumab treatment in patients with CD, who became pregnant whilst participating in the PYRAMID registry, contributed no additional adverse effects during the pregnancy course or on pregnancy outcomes.

Higher vs Standard Adalimumab Induction and Maintenance Dosing Regimens for Treatment of Ulcerative Colitis: SERENE UC Trial Results.

BACKGROUND & AIMS: SERENE UC (Study of a Novel Approach to Induction and Maintenance Dosing With Adalimumab in Patients With Moderate to Severe Ulcerative Colitis) evaluated the efficacy of higher adalimumab induction and maintenance dose regimens in patients with ulcerative colitis. METHODS: This phase 3, double-blind, randomized trial included induction and maintenance studies, with a main study (ex-Japan) and Japan substudy. Eligible patients (18-75 years, full Mayo score 6-12, centrally read endoscopy subscore 2-3) were randomized 3:2 to higher induction regimen (adalimumab 160 mg at weeks 0, 1, 2, and 3) or standard induction regimen (160 mg at week 0 and 80 mg at week 2); all received 40 mg at weeks 4 and 6. At week 8, all patients were rerandomized 2:2:1 (main study) to 40 mg every week (ew), 40 mg every other week (eow), or exploratory therapeutic drug monitoring; or 1:1 (Japan substudy) to 40 mg ew or 40 mg eow maintenance regimens. RESULTS: In the main study, 13.3% vs 10.9% of patients receiving the higher induction regimen vs standard induction regimen achieved clinical remission (full Mayo score ≤2 with no subscore >1) at week 8 (induction primary end point; P = .265); among week-8 responders, 39.5% vs 29.0% receiving 40 mg ew vs 40 mg eow achieved clinical remission at week 52 (maintenance primary end point; P = .069). In the integrated (main + Japan) population, 41.1% vs 30.1% of week-8 responders receiving 40 mg ew vs 40 mg eow achieved clinical remission at week 52 (nominal P = .045). Safety profiles were comparable between dosing regimens. CONCLUSION: Although primary end points were not met, a >10% absolute difference in clinical remission was demonstrated with higher adalimumab maintenance dosing. Higher dosing regimens were generally well tolerated and consistent with the known safety profile of adalimumab in ulcerative colitis. CLINICALTRIALS: gov, Number: NCT002209456.

Long-Term Safety and Efficacy of Risankizumab Treatment in Patients with Crohn's Disease: Results from the Phase 2 Open-Label Extension Study.

BACKGROUND AND AIMS: Risankizumab, an interleukin-23 antibody, demonstrated efficacy and acceptable safety in a phase 2 study of patients with moderate-to-severe refractory Crohn's disease. This open-label extension investigated the long-term safety, pharmacokinetics, immunogenicity and efficacy of risankizumab in responders to risankizumab in the parent phase 2 study. METHODS: Enrolled patients had achieved clinical response [decrease in Crohn's Disease Activity Index from baseline ≥100] without clinical remission [Crohn's Disease Activity Index <150] at Week 26, or clinical response and/or remission at Week 52 in the parent phase 2 study and received open-label subcutaneous risankizumab 180 mg every 8 weeks. RESULTS: Sixty-five patients were enrolled, including four who had lost response in the parent study and were first reinduced with risankizumab 600 mg every 4 weeks [three infusions]. Patients received risankizumab for a median of 33 months [total: 167.0 patient-years]. The rate of serious adverse events was 24.6 events/100 patient-years; the majority were gastrointestinal in nature. Rates of serious infections, opportunistic infections and fungal infections were 4.2, 1.8, and 6.6 events/100 patient-years, respectively. No deaths, malignancies, adjudicated major adverse cardiovascular events, latent/active tuberculosis or herpes zoster were reported. Treatment-emergent anti-drug antibodies developed in eight patients [12.3%]; none were neutralizing. Efficacy outcomes were maintained during the study, including the proportions of patients [observed analysis] with clinical remission [>71%] and endoscopic remission [>42%]. CONCLUSIONS: Long-term maintenance treatment with subcutaneous risankizumab 180 mg every 8 weeks was well tolerated by patients with Crohn's disease, with no new safety signals. Clinical trial registration number: NCT02513459.

Pharmacokinetic Comparability of Risankizumab Formulations in Prefilled Syringe and Auto-injector for Subcutaneous Injection.

PURPOSE: Risankizumab is a humanized immunoglobulin G1 monoclonal antibody that inhibits the p19 subunit of interleukin 23 from interacting with its receptor for the treatment of moderate to severe plaque psoriasis. The aim of this Phase I biopharmaceutics bridging study was to evaluate the pharmacokinetic comparability, immunogenicity, and tolerability of the risankizumab 90 mg/mL prefilled syringe (PFS) and the risankizumab 150 mg/mL PFS and auto-injector (AI) in healthy subjects. METHODS: Healthy subjects received one 150-mg dose of risankizumab in 1 of 3 ways (226 subjects randomized 3:3:1 to 3 treatment arms): 150 mg/mL by PFS × 1 SC injection, 90 mg/mL by PFS × 2 SC injections, or 150 mg/mL by AI × 1 SC injection, and were followed up for 140 days after dosing for the collection of pharmacokinetic, immunogenicity, and tolerability data. FINDINGS: Risankizumab concentration-time profiles overlapped with comparable pharmacokinetic parameters across all treatment arms, indicating similar pharmacokinetic characteristics. The CIs with both formulations and forms of administration were within the bioequivalence range of 0.80-1.25 across all measures of exposure. The prevalence of treatment-emergent anti-drug antibodies and the percentages of subjects who reported at least 1 treatment-emergent adverse event were comparable across all treatment arms. IMPLICATIONS: Bioequivalence was established between risankizumab 150 mg/mL PFS and 90 mg/mL PFS, and between 150 mg/mL PFS and AI, along with comparable immunogenicity profiles across all 3 treatment arms. Risankizumab 150 mg SC delivered by PFS or AI was well tolerated, with comparable safety profiles across all treatment arms, and no new safety risks were identified.

Efficacy and safety of adalimumab in Chinese patients with moderately to severely active Crohn's disease: results from a randomized trial.

BACKGROUND AND AIMS: Efficacy of adalimumab in Crohn's disease (CD) has not been shown in China. The aim of this study was to evaluate the efficacy and safety of adalimumab in Chinese patients with CD. METHODS: This 26-week, multicenter, phase III study evaluated patients with moderately to severely active CD and elevated high-sensitivity C-reactive protein (⩾3 mg/l) who were naïve to anti-tumor necrosis factor therapy. Patients were randomized to double-blind adalimumab 160/80 mg at weeks 0/2 and 40 mg at weeks 4/6 or placebo at weeks 0/2 followed by blinded adalimumab 160/80 mg at weeks 4/6. At week 8, all patients received open-label 40 mg adalimumab every other week through week 26. The primary endpoint was clinical remission [CD activity index (CDAI) <150] at week 4. Clinical remission at week 26 was assessed in week-8 responders (decrease in CDAI ⩾70 points at week 8 from baseline) and compared with a clinically meaningful threshold of 30%. Adverse events (AEs) were recorded throughout the study. RESULTS: At baseline, 205 patients were enrolled, with mean [standard deviation (SD)] age of 32.9 (9.9) years and CD duration of 2.7 (3.0) years. At week 4, 38/102 patients (37%) receiving adalimumab and 7/103 (7%) receiving placebo (p < 0.001) achieved clinical remission. Among week-8 responders, 93/144 (65%) achieved clinical remission at week 26 (p < 0.001). No unexpected AEs and no malignancies, active tuberculosis, or deaths were reported. CONCLUSIONS: Adalimumab induced and maintained remission in Chinese patients with CD. Safety results were consistent with the known safety profile of adalimumab. CLINICALTRIALSGOV IDENTIFIER: NCT02499783.

Safety and Effectiveness of Adalimumab in Patients With Polyarticular Course of Juvenile Idiopathic Arthritis: STRIVE Registry Seven-Year Interim Results.

OBJECTIVE: To evaluate safety and effectiveness of adalimumab (ADA) in polyarticular-course juvenile idiopathic arthritis (JIA) in the STRIVE registry. METHODS: STRIVE enrolled patients with polyarticular-course JIA into 2 arms based on treatment with methotrexate (MTX) alone or ADA with/without MTX (ADA ± MTX). Adverse events (AEs) per 100 patient-years of observation time were analyzed by registry arm. Patients who entered the registry within 4 weeks of starting MTX or ADA ± MTX, defined as new users, were evaluated for change in disease activity assessed by the 27-joint Juvenile Arthritis Disease Activity Score with the C-reactive protein level (JADAS-27CRP ). RESULTS: At the 7-year cutoff date (June 1, 2016), data from 838 patients were available (MTX arm n = 301, ADA ± MTX arm n = 537). The most common AEs were nausea (10.3%), sinusitis (4.7%), and vomiting (4.3%) in the MTX arm and arthritis (3.9%), upper respiratory tract infection (3.5%), sinusitis, tonsillitis, and injection site pain (3.0% each) in the ADA ± MTX arm. Rates of serious infection were 1.5 events/100 patient-years in the MTX arm and 2.0 events/100 patient-years in the ADA ± MTX arm. AE and serious AE rates were similar in patients receiving ADA with versus without MTX. No deaths or malignancies were reported. New users in the ADA ± MTX arm showed a trend toward lower mean JADAS-27CRP compared with new users in the MTX arm in the first year of STRIVE. CONCLUSION: The STRIVE registry 7-year interim results support the idea that ADA ± MTX is well tolerated by most children. Registry median ADA exposure was 2.47 (interquartile range 1.0-3.6) years, with 42% of patients continuing ADA at the 7-year cutoff date.

Adalimumab Effectiveness Up to Six Years in Adalimumab-naïve Patients with Crohn's Disease: Results of the PYRAMID Registry.

BACKGROUND: PYRAMID was an international multicenter, noninterventional, postmarketing registry assessing long-term safety and effectiveness of adalimumab (Humira), as used in routine clinical practice. METHODS: Adult patients with moderately to severely active Crohn's disease with or without prior adalimumab experience were enrolled in the registry and followed for up to 6 years. Effectiveness measurements included the Physician's Global Assessment (PGA, a composite of Harvey Bradshaw Index [HBI] and rectal bleeding score), clinical remission (HBI < 5), Short Inflammatory Bowel Disease Questionnaire (SIBDQ), and Work Productivity and Activity Impairment (WPAI) questionnaire. Data were reported for adalimumab-naïve patients and analyzed by baseline immunomodulator use and disease duration. RESULTS: This study evaluated 2057 adalimumab-naïve patients. Mean PGA improved from 7.5 (baseline) to 3.9 (year 1) and 3.3 (year 6). The proportion of patients in HBI remission increased from 29% (573 of 1969; baseline) to 68% (900 of 1331; year 1) and 75% (625 of 831; year 6). Patients stratified by baseline immunomodulator use had similar HBI remission rates; patients with disease duration <2 years achieved numerically higher HBI remission rates than patients with longer disease duration. Patient-reported SIBDQ and WPAI scores improved at year 1; all WPAI subscore improvements were clinically meaningful (≥7% point change) at year 1 and maintained through year 6. Serious infections were reported in 11.1% of patients; incidence rates of malignancies, lymphoma, and demyelinating disorders were low. CONCLUSION: Adalimumab therapy, as used in routine clinical practice, improved physician-reported and patient-reported disease outcomes and remission rates for up to 6 years. No new safety signals were observed.

Clinical Responses and Synovial Vascularity in Obese Rheumatoid Arthritis Patients Treated with Adalimumab and Methotrexate.

OBJECTIVE: Obese patients with rheumatoid arthritis (RA) report more joint swelling and tenderness and often have poorer responses to therapy than nonobese patients. The aim of this posthoc analysis of the MUSICA trial was to compare imaging and clinical disease activity measures in obese and nonobese patients with RA. METHODS: MUSICA evaluated methotrexate (MTX) 20 mg/week versus 7.5 mg/week in combination with adalimumab (ADA) in RA patients with an inadequate response to MTX. Patients were categorized by baseline body mass index as normal (< 25), overweight (≥ 25 to < 30), or obese (≥ 30). Synovial vascularity and hypertrophy, swollen and tender joint counts (SJC and TJC), American College of Rheumatology (ACR) responses, and low disease activity (LDA), defined as Clinical Disease Activity Index < 10 and 28-joint count Disease Activity Score using C-reactive protein (DAS28-CRP) < 3.2, were assessed at weeks 12 and 24. RESULTS: Patient characteristics were similar among groups at baseline. Obese patients had numerically smaller changes from baseline to weeks 12/24 in SJC, TJC, DAS28-CRP, and synovial hypertrophy and vascularity versus nonobese patients. Significantly fewer obese patients reached ACR20/50 at weeks 12 and 24, and LDA at Week 12; this difference was especially apparent in patients receiving 7.5 mg/week MTX but was no longer significant at Week 24. CONCLUSION: Obese patients with RA had worse clinical and ultrasonographic responses than nonobese patients, which were partly overcome with time. Obese patients may experience better and faster clinical improvements if ADA is initiated with high-dose (20 mg/week) rather than low-dose MTX. [ClinicalTrials.gov: NCT01185288].

Systematic review and network meta-analysis: effect of biologics on radiographic progression in rheumatoid arthritis.

AIM: To evaluate the comparative effectiveness of biologics in inhibiting radiographic progression among rheumatoid arthritis (RA) patients. MATERIALS & METHODS: Bayesian network meta-analysis of published trials investigating the USA FDA approved biologics treatment in RA patients, using methotrexate (MTX) as the reference comparator. RESULTS: Nine trials met the inclusion criteria for base case analysis. Compared with MTX, most biologics (except golimumab) + MTX had significantly lower rates of radiographic progression at 1 year. Mean difference in radiographic progression rates between MTX monotherapy and biologics + MTX was highest for adalimumab + MTX (-3.8) and lowest for tocilizumab + MTX (-0.7). Inhibition of radiographic progression was sustained. CONCLUSION: Biologics inhibit radiographic progression in patients with RA at 1 year; however, published evidence beyond 1 year is limited.

Safety of Adalimumab in Pediatric Patients with Polyarticular Juvenile Idiopathic Arthritis, Enthesitis-Related Arthritis, Psoriasis, and Crohn's Disease.

OBJECTIVE: To evaluate the safety of adalimumab in pediatric patients who participated in clinical trials of juvenile idiopathic arthritis (polyarticular juvenile idiopathic arthritis and pediatric enthesitis-related arthritis), psoriasis, and Crohn's disease. STUDY DESIGN: This analysis included data from 7 global, randomized, and open-label AbbVie-sponsored clinical trials of adalimumab and their open-label extensions conducted between September 2002 and December 31, 2015 (cutoff date for ongoing studies). Patients who received ≥1 dose of adalimumab subcutaneously were included. Adverse events that occurred after the first dose of adalimumab and up to 70 days (5 half-lives) after the last dose were reported and events per 100 patient-years were calculated. RESULTS: The analysis included 577 pediatric patients, representing 1440.7 patient-years of adalimumab exposure. Across indications, the most commonly reported adverse events (events/100 patient-years) were upper respiratory tract infections (24.3), nasopharyngitis (17.3), and headache (19.9). Serious infections (4.0 events/100 patient-years) were the most frequent serious adverse events across indications; the most commonly reported was pneumonia (0.6 events/100 patient-years). Serious infection rates were 2.7, 0.8, and 6.6 events/100 patient-years in patients with juvenile idiopathic arthritis, psoriasis, and Crohn's disease, respectively. No events of malignancies were reported. One death (accidental fall) occurred in a patient with psoriasis. CONCLUSIONS: The safety profile of adalimumab in pediatric patients with polyarticular juvenile idiopathic arthritis, enthesitis-related arthritis, psoriasis, and Crohn's disease was generally similar across indications; no new safety signals were identified in the treatment of pediatric patients with adalimumab. TRIAL REGISTRATION: Clinicaltrials.gov: NCT00048542, NCT00775437, NCT00690573, NCT01166282, NCT01251614, NCT00409682, and NCT00686374.

Lymphoma Risk and Overall Safety Profile of Adalimumab in Patients With Crohn's Disease With up to 6 Years of Follow-Up in the Pyramid Registry.

OBJECTIVES: Real-world, prospective, long-term studies in Crohn's disease (CD) characterizing adalimumab safety data and lymphoma risk were lacking. We present the final results from the PYRAMID registry, which was designed to rule out a doubling of lymphoma risk in adalimumab-treated patients with CD. METHODS: Patients with moderately to severely active CD newly prescribed or currently receiving adalimumab according to local product labels were followed for up to 6 years and analyzed for adverse events (AEs). The registry exposure-adjusted observed rate of lymphoma was compared with the estimated background lymphoma rate from a sex-matched general population in the Surveillance, Epidemiology, and End Results 17 Registry database adjusted for anticipated prior or concurrent thiopurine use in a CD population. RESULTS: A total of 5025 patients were evaluated (16680.4 PY of adalimumab registry exposure, ≈3 years/patient mean follow-up). Registry treatment-emergent AEs included 4129 serious AEs (n = 1853 [36.9%]; 24.8 E/100 PY), 792 serious infections (n = 556 [11.1%]; 4.7 E/100 PY), and 134 malignancies (n = 116 [2.3%]; 0.8 E/100 PY), including ten lymphomas. The observed lymphoma rate (0.060 E/100 PY) was lower than the estimated background rate (0.084 E/100 PY), and the upper bound of the one-sided 95% CI of the observed rate (0.102 E/100 PY) was lower than double the estimated rate (0.168 E/100 PY). CONCLUSIONS: PYRAMID is the longest prospective adalimumab study in routine clinical practice, with up to 6 years of follow-up. No new safety signals were reported. The pre-specified registry objective of ruling out a doubling of lymphoma risk with adalimumab was met.

Similar Improvements in Patient-Reported Outcomes Among Rheumatoid Arthritis Patients Treated with Two Different Doses of Methotrexate in Combination with Adalimumab: Results From the MUSICA Trial.

INTRODUCTION: In patients with rheumatoid arthritis (RA), combination treatment with methotrexate (MTX) and adalimumab is more effective than MTX monotherapy. From the patients' perspective, the impact of reduced MTX doses upon initiating adalimumab is not known. The objective was to evaluate the effects of low and high MTX doses in combination with adalimumab initiation on patient-reported outcomes (PROs), in MTX-inadequate responders (MTX-IR) with moderate-to-severe RA. METHODS: MUSICA was a randomized, double-blind, controlled trial evaluating the efficacy of 7.5 or 20 mg/week MTX, in combination with adalimumab for 24 weeks in MTX-IR RA patients receiving prior MTX ≥ 15 mg/week for ≥ 12 weeks. PROs were recorded at each visit, including physical function, health-related quality-of-life, work productivity, quality-of-sleep, satisfaction with treatment medication, sexual impairment due to RA, patient global assessment of disease activity (PGA), and patient pain. Last observation carried forward was used to account for missing values. RESULTS: At baseline, patients in both MTX dosage groups had similar demographics, disease characteristics, and PRO scores. Overall, initiation of adalimumab led to significant improvements from baseline in the PROs assessed for both MTX dosage groups. Improvements in presenteeism from baseline were strongly correlated with corresponding improvements in SF-36 (vitality), pain, and physical function. Physical and mental well-being had a good correlation with improvement in sleep. Overall, improvements in disease activity from baseline were correlated with improvements in several PROs. CONCLUSIONS: The addition of adalimumab to MTX in MTX-IR patients with moderate-to-severe RA led to improvements in physical function, quality-of-life, work productivity, quality of sleep, satisfaction with treatment medication, and sexual impairment due to RA, regardless of the concomitant MTX dosage. FUNDING: AbbVie. TRIAL REGISTRATION: Clinicaltrials.gov identifier, NCT01185288.

Treatment efficacy and methotrexate-related toxicity in patients with rheumatoid arthritis receiving methotrexate in combination with adalimumab.

BACKGROUND: Treatment of rheumatoid arthritis (RA) with a combination of methotrexate (MTX)+adalimumab (ADA) is more effective than ADA monotherapy. We assessed the toxicity of different doses of MTX and treatment efficacy of ADA+MTX in two trials. METHODS: Data originated from CONCERTO, in patients with early RA initiating ADA+ 2.5, 5, 10 or 20 mg/week MTX for 26 weeks; and MUSICA, in patients with an inadequate response to MTX initiating ADA+ 7.5 or 20 mg/week MTX for 24 weeks. Efficacy was assessed by the American College of Rheumatology 50 (ACR50). Patient-reported MTX-related toxicity information was collected at each visit on 18 prespecified MTX-related adverse events (AE) in the MTX label. RESULTS: In CONCERTO, ACR50 rates increased over time, ranging from 54% to 68% at week 26, while AE rates remained steady, ranging from 2.4% to 17.8% at week 26. Of 395 patients, 113 (28.6%) reported 345 MTX-related AEs, including one serious AE (SAE, excessive fatigue and/or malaise); 10 AEs (in two patients) led to study discontinuation. In MUSICA, ACR50 rates increased over time, and were 32.3% and 37.5% at week 24, while MTX-related AE rates remained steady and were 6.5% at week 24. Of 309 patients, 71 (23%) reported 185 MTX-related AEs, including 5 SAEs (four infections and one fever/chills); six AEs (in four patients) led to study discontinuation. CONCLUSION: In patients with RA initiating ADA+MTX combination, treatment efficacy was achieved and increased throughout both trials, while rates of MTX-related AEs remained steady. MTX-related AEs were observed in up to 30% of patients and most were mild. MTX was discontinued by 0.5%-1.3% of patients. TRIAL REGISTRATION NUMBER: MUSICA (NCT01185288), CONCERTO (NCT01185301), Post results.