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Importance: The clinical effects of risankizumab (a monoclonal antibody that selectively targets the p19 subunit of IL-23) for the treatment of ulcerative colitis are unknown. Objective: To evaluate the efficacy and safety of risankizumab when administered as an induction and a maintenance therapy for patients with ulcerative colitis. Design, Setting, and Participants: Two phase 3 randomized clinical trials were conducted. The induction trial was conducted at 261 clinical centers (in 41 countries) and enrolled 977 patients from November 5, 2020, to August 4, 2022 (final follow-up on May 16, 2023). The maintenance trial was conducted at 238 clinical centers (in 37 countries) and enrolled 754 patients from August 28, 2018, to March 30, 2022 (final follow-up on April 11, 2023). Eligible patients had moderately to severely active ulcerative colitis; a history of intolerance or inadequate response to 1 or more conventional therapies, advanced therapies, or both types of therapies; and no prior exposure to risankizumab. Interventions: For the induction trial, patients were randomized 2:1 to receive 1200 mg of risankizumab or placebo administered intravenously at weeks 0, 4, and 8. For the maintenance trial, patients with a clinical response (determined using the adapted Mayo score) after intravenous treatment with risankizumab were randomized 1:1:1 to receive subcutaneous treatment with 180 mg or 360 mg of risankizumab or placebo (no longer receiving risankizumab) every 8 weeks for 52 weeks. Main Outcomes and Measures: The primary outcome was clinical remission (stool frequency score ≤1 and not greater than baseline, rectal bleeding score of 0, and endoscopic subscore ≤1 without friability) at week 12 for the induction trial and at week 52 for the maintenance trial. Results: Among the 975 patients analyzed in the induction trial (aged 42.1 [SD, 13.8] years; 586/973 [60.1%] were male; and 677 [69.6%] were White), the clinical remission rates at week 12 were 132/650 (20.3%) for 1200 mg of risankizumab and 20/325 (6.2%) for placebo (adjusted between-group difference, 14.0% [95% CI, 10.0%-18.0%], P < .001). Among the 548 patients analyzed in the maintenance trial (aged 40.9 [SD, 14.0] years; 313 [57.1%] were male; and 407 [74.3%] were White), the clinical remission rates at week 52 were 72/179 (40.2%) for 180 mg of risankizumab, 70/186 (37.6%) for 360 mg of risankizumab, and 46/183 (25.1%) for placebo (adjusted between-group difference for 180 mg of risankizumab vs placebo, 16.3% [97.5% CI, 6.1%-26.6%], P < .001; adjusted between-group difference for 360 mg of risankizumab vs placebo, 14.2% [97.5% CI, 4.0%-24.5%], P = .002). No adverse event signals were detected in the treatment groups. Conclusion and Relevance: Compared with placebo, risankizumab improved clinical remission rates in an induction trial and in a maintenance trial for patients with moderately to severely active ulcerative colitis. Further study is needed to identify benefits beyond the 52-week follow-up. Trial Registration: ClinicalTrials.gov Identifiers: NCT03398148 and NCT03398135.
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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.
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Enfermedad de Crohn , Dolor Abdominal , Anticuerpos Monoclonales/efectos adversos , Enfermedad de Crohn/tratamiento farmacológico , Método Doble Ciego , HumanosRESUMEN
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.
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Productos Biológicos , Enfermedad de Crohn , Dolor Abdominal , Anticuerpos Monoclonales , Productos Biológicos/uso terapéutico , Enfermedad de Crohn/tratamiento farmacológico , Humanos , Quimioterapia de InducciónRESUMEN
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.
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Colitis Ulcerosa , Adalimumab/uso terapéutico , Protocolos Clínicos , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/diagnóstico , Colitis Ulcerosa/tratamiento farmacológico , Método Doble Ciego , Humanos , Inducción de Remisión , Resultado del TratamientoRESUMEN
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.
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Adalimumab/efectos adversos , Enfermedad de Crohn/tratamiento farmacológico , Inmunosupresores/efectos adversos , Linfoma/epidemiología , Sistema de Registros/estadística & datos numéricos , Adulto , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/inmunología , Enfermedad de Crohn/inmunología , Enfermedad de Crohn/mortalidad , Femenino , Estudios de Seguimiento , Humanos , Infecciones/epidemiología , Infecciones/inmunología , Reacción en el Punto de Inyección/epidemiología , Reacción en el Punto de Inyección/inmunología , Linfoma/inmunología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Enfermedades de la Piel/epidemiología , Enfermedades de la Piel/inmunología , Tasa de SupervivenciaRESUMEN
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.
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Adalimumab/administración & dosificación , Artritis Juvenil/tratamiento farmacológico , Enfermedad de Crohn/tratamiento farmacológico , Psoriasis/tratamiento farmacológico , Adolescente , Antiinflamatorios/administración & dosificación , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Humanos , Masculino , Estudios Retrospectivos , Estudios de Tiempo y Movimiento , Resultado del TratamientoRESUMEN
SERENE UC (NCT02065622) evaluated whether a higher adalimumab induction regimen improved patients with ulcerative colitis (UC) response, but a flat dose-response relationship was found in the induction study. We investigated exposure-response (ER) relationships in induction and maintenance studies considering patients' baseline characteristics. Adalimumab exposures were simulated using the established population pharmacokinetic model. Multivariable logistic regressions were used to assess the efficacy endpoints (clinical remission, endoscopic remission, endoscopic improvement) at weeks 8 and 52. In the induction study, an increasing ER trend with heterogeneity between induction regimens was shown, suggesting average concentration (Cavg) had a significant impact on primary efficacy endpoints within each group. However, data were not described by a single ER curve. Using inverse effective clearance as the exposure metric described trends across induction regimens with a single curve. Patients with inherently lower effective adalimumab clearance responded better. The patient response rates at week 52 showed no heterogeneity. A short-term increase in adalimumab dose did not drive better responses for induction, and apparent ER relationships were better explained by patient-inherent lower clearance. Conversely, during maintenance up to week 52, increasing the concentration via dose translated to better responses more robustly. The ER findings for SERENE UC were consistent with SERENE CD.
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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.
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Enfermedad de Crohn , Humanos , Enfermedad de Crohn/tratamiento farmacológico , Jeringas , Inyecciones Subcutáneas , Anticuerpos Monoclonales/uso terapéuticoRESUMEN
BACKGROUND: Risankizumab is efficacious and well tolerated in adults with moderately to severely active Crohn's disease (CD). AIM: To evaluate the corticosteroid-sparing effect of risankizumab in CD. METHODS: During the 12-week induction period, patients maintained stable baseline corticosteroid doses, up to 20 mg/day prednisone or equivalent. At week 0 of maintenance, a mandatory corticosteroid taper was started. This post hoc analysis evaluated corticosteroid-free clinical and endoscopic outcomes at week 52 of maintenance; safety was also assessed. RESULTS: Of 889 patients randomised to induction with risankizumab 600 mg or placebo, 285 (32.1%) were taking baseline concomitant corticosteroids. Week 12 clinical remission and endoscopic response rates were greater for risankizumab 600 mg versus placebo, regardless of concomitant corticosteroid use. At week 52, 66.7%, 50.0% and 41.2% of patients taking risankizumab 180 mg, risankizumab 360 mg and (withdrawal) placebo, respectively, discontinued corticosteroids. Week 52 corticosteroid-free clinical remission per stool frequency/abdominal pain score (risankizumab 180 mg [42.7%] or 360 mg [49.8%]; [withdrawal] placebo [39.0%]), corticosteroid-free clinical remission per Crohn's Disease Activity Index (risankizumab 180 mg [51.0%] or 360 mg [49.5%]; [withdrawal] placebo [40.2%]), and corticosteroid-free endoscopic response (risankizumab 180 mg [44.6%] or 360 mg [44.7%]; [withdrawal] placebo [20.7%]) rates were greater for risankizumab than placebo. Adverse event rates were generally similar, regardless of baseline corticosteroid use. CONCLUSIONS: Efficacy of risankizumab 600 mg induction therapy was independent of concomitant corticosteroid use. Risankizumab 180 and 360 mg maintenance therapy yielded high rates of corticosteroid-free clinical and endoscopic outcomes at week 52.
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Background and Aims: Early biologic therapy treatment has demonstrated better outcomes in Crohn's disease (CD). We evaluated the impact of CD duration in patients with moderately to severely active CD treated with risankizumab therapy. Methods: This post hoc analysis evaluated clinical, endoscopic, and safety outcomes by baseline CD duration (<2, 2-5, >5-10, and >10 years) in patients from ADVANCE, MOTIVATE, and FORTIFY. Pooled induction analyses included patients who received intravenous 600-mg dose of risankizumab or placebo for 12 weeks. Maintenance analyses included patients who responded to induction risankizumab and received subcutaneous 180-mg or 360-mg dose of risankizumab for 52 weeks. Duration subgroups were compared using Cochrane-Armitage trend tests with nominal P values. Results: Among 527 patients who received risankizumab 600-mg induction therapy, higher outcome rates were observed at week 12 among patients with shorter vs longer baseline disease duration (for <2, 2-5, >5-10, and >10 years, clinical remission: 42.7%, 46.9%, 43.5%, and 33.2% [P = .046]; endoscopic response: 48.3%, 36.3%, 32.0%, and 33.4% [P = .025]). Among 298 patients receiving risankizumab (180 mg or 360 mg) maintenance therapy, shorter vs longer baseline disease duration was generally associated with numerically higher endoscopic outcome rates at week 52. Higher clinical remission and endoscopic outcome rates were generally observed with shorter disease duration with 180-mg risankizumab dose only. Adverse event rates were generally similar across duration subgroups. Conclusion: Clinical benefits of risankizumab are observed across disease duration subgroups; clinical and endoscopic outcome rates are higher with risankizumab initiation earlier in the disease course (ClinicalTrials.gov numbers: NCT03105128, NCT03104413, and NCT03105102).
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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%; pâ <â 0.05], stool frequency/abdominal pain remission [69.2%, 64.1%, vs 50.5%; pâ <â 0.01], endoscopic response [70.2%, 68.2%, vs 38.4%; pâ <â 0.001], endoscopic remission [74.4%, 45.5%, vs 23.9%; pâ <â 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.
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Anticuerpos Monoclonales , Enfermedad de Crohn , Humanos , Enfermedad de Crohn/tratamiento farmacológico , Dolor Abdominal , Administración Intravenosa , BiomarcadoresRESUMEN
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).
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Enfermedad de Crohn , Humanos , Anticuerpos Monoclonales/uso terapéutico , Enfermedad de Crohn/tratamiento farmacológico , Inyecciones , Evaluación del Resultado de la Atención al Paciente , Resultado del TratamientoRESUMEN
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.
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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.
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Adalimumab , Enfermedad de Crohn , Efectos Tardíos de la Exposición Prenatal , Adalimumab/efectos adversos , Enfermedad de Crohn/tratamiento farmacológico , Enfermedad de Crohn/epidemiología , Femenino , Humanos , Recién Nacido , Embarazo , Efectos Tardíos de la Exposición Prenatal/epidemiología , Vigilancia de Productos Comercializados , Sistema de Registros , Estudios RetrospectivosRESUMEN
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.
Asunto(s)
Anticuerpos Monoclonales/farmacología , Psoriasis , Jeringas , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Humanos , Inyecciones Subcutáneas , Psoriasis/tratamiento farmacológicoRESUMEN
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.
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Anticuerpos Monoclonales/uso terapéutico , Enfermedad de Crohn/tratamiento farmacológico , Fármacos Gastrointestinales/uso terapéutico , Infecciones Oportunistas/etiología , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/farmacocinética , Femenino , Fármacos Gastrointestinales/administración & dosificación , Fármacos Gastrointestinales/farmacocinética , Humanos , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto JovenRESUMEN
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.
RESUMEN
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.
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Adalimumab/uso terapéutico , Antirreumáticos/uso terapéutico , Artritis Juvenil/tratamiento farmacológico , Sistema de Registros , Adolescente , Artritis Juvenil/complicaciones , Niño , Preescolar , Quimioterapia Combinada , Femenino , Humanos , Masculino , Metotrexato/uso terapéutico , Uveítis/tratamiento farmacológico , Uveítis/etiologíaRESUMEN
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.
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Adalimumab/uso terapéutico , Antiinflamatorios/uso terapéutico , Enfermedad de Crohn/tratamiento farmacológico , Sistema de Registros/estadística & datos numéricos , Índice de Severidad de la Enfermedad , Adulto , Enfermedad de Crohn/patología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Inducción de Remisión , Resultado del TratamientoRESUMEN
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.