The primary purpose of this study was to determine the effect of vedolizumab induction treatment on clinical response and remission at 6 weeks and to determine the effect of vedolizumab maintenance treatment on clinical remission at 52 weeks.
BACKGROUND: Vedolizumab è un umanizzato immunoglobulina G1 anticorpo monoclonale che ha come bersaglio esclusivamente il linfocita integrina [alpha] 4 [beta] 7. Questa interazione impedisce il legame di gut-homing linfociti T di mucosa di adesione delle cellule vascolari addressin molecola-1 (MAdCAM-1), riducendo in tal modo l'infiammazione gastrointestinale. Vedolizumab è attualmente in sviluppo per il trattamento della colite ulcerosa (CU) e malattia di Crohn (MC). Vedolizumab farmacocinetica (PK) i dati di fase 3 studi (GEMINI 1 e 2) profili farmacocinetici simili sono stati precedentemente pubblicati e mostrare in UC e CD populations.1,2 paziente Qui l'/ farmacodinamica (PD) rapporto PK e l'immunogenicità del vedolizumab nel GEMINI 1 e 2 studi sono descritti. METODI: La GEMINI 1 e 2 studi hanno incluso una fase di induzione di 6 settimane, durante il quale i pazienti hanno ricevuto Vedolizumab 300 mg o placebo per via endovenosa alle settimane 0 e 2 e sono stati valutati a 6 settimane. Pazienti Vedolizumab trattati che hanno avuto una risposta clinica alla settimana 6 sono stati assegnati in modo casuale a ricevere 300 mg vedolizumab (vedolizumab intention-to-treat [ITT] popolazione) o placebo (placebo popolazione ITT) ogni 4 settimane (Q4W) o ogni 8 settimane ( Q8W) durante la successiva fase di mantenimento di 46 settimane. Non responder ad induzione Vedolizumab (non-ITT popolazione) hanno ricevuto in aperto vedolizumab Q4W, ed i pazienti randomizzati a placebo durante la fase di induzione continuato a ricevere placebo fino alla settimana 52. I campioni di sangue per la determinazione delle concentrazioni Vedolizumab, valutazione PD ([alpha] 4 [beta] 7 [recettore] saturazione tramite MAdCAM-1-Fc vincolanti test di interferenza), e la valutazione di anticorpi anti-Vedolizumab sono stati raccolti in momenti pre-specificati. Le statistiche descrittive sono stati usati per riassumere Vedolizumab PK e dati di immunogenicità. Appezzamenti di saturazione dei recettori sono stati generati. RISULTATI: La somministrazione di 300 mg vedolizumab Q4W o Q8W provocato concentrazioni sieriche medie,> = 10 [micro] g / ml a tutti i tempi in entrambe le pazienti UC e CD (ITT e non ITT). In un'analisi aggregata di UC e CD pazienti (ITT e non ITT), la saturazione dei recettori completo è stato osservato alla settimana 6 e mantenuta fino alla settimana 52 sia nel Q8W vedolizumab e gruppi Q4W. Nel complesso, il 4% (56/1434) dei pazienti risultati positivi per gli anticorpi anti-vedolizumab in qualsiasi momento durante il trattamento vedolizumab. Frequenza di sviluppo di anticorpi anti-Vedolizumab off droga (settimana 66) era ~ 10% (32/320) nel pool UC e CD pazienti (ITT e non ITT). Tra i pazienti che hanno avuto una reazione correlata investigatore-definito, 5% (3/61) testato persistentemente (a> = 2 visite consecutive) positivi per gli anticorpi anti-vedolizumab. Rispetto alla popolazione generale di studio, i pazienti che sono risultati costantemente positivi per gli anticorpi anti-vedolizumab avevano generalmente concentrazioni sieriche vedolizumab valle più basse. Nel gruppo placebo ITT, l'uso di immunomodulatori concomitanti è stato associato ad un più basso tasso di anti-vedolizumab positività anticorpale (3%, 1/32) che visto senza uso di immunomodulatori concomitanti (18%, 44/247). CONCLUSIONI: Conclusioni Durante la somministrazione di vedolizumab sia Q8W o Q4W in pazienti con UC e CD, le concentrazioni sieriche vedolizumab sono stati mantenuti a> = 10 [micro] g / ml, un livello che ha provocato la saturazione dei recettori completo.
BACKGROUND: The efficacy of vedolizumab, an α4β7 integrin antibody, in Crohn's disease is unknown.
METHODS: In an integrated study with separate induction and maintenance trials, we assessed intravenous vedolizumab therapy (300 mg) in adults with active Crohn's disease. In the induction trial, 368 patients were randomly assigned to receive vedolizumab or placebo at weeks 0 and 2 (cohort 1), and 747 patients received open-label vedolizumab at weeks 0 and 2 (cohort 2); disease status was assessed at week 6. In the maintenance trial, 461 patients who had had a response to vedolizumab were randomly assigned to receive placebo or vedolizumab every 8 or 4 weeks until week 52.
RESULTS: At week 6, a total of 14.5% of the patients in cohort 1 who received vedolizumab and 6.8% who received placebo were in clinical remission (i.e., had a score on the Crohn's Disease Activity Index [CDAI] of ≤150, with scores ranging from 0 to approximately 600 and higher scores indicating greater disease activity) (P=0.02); a total of 31.4% and 25.7% of the patients, respectively, had a CDAI-100 response (≥100-point decrease in the CDAI score) (P=0.23). Among patients in cohorts 1 and 2 who had a response to induction therapy, 39.0% and 36.4% of those assigned to vedolizumab every 8 weeks and every 4 weeks, respectively, were in clinical remission at week 52, as compared with 21.6% assigned to placebo (P<0.001 and P=0.004 for the two vedolizumab groups, respectively, vs. placebo). Antibodies against vedolizumab developed in 4.0% of the patients. Nasopharyngitis occurred more frequently, and headache and abdominal pain less frequently, in patients receiving vedolizumab than in patients receiving placebo. Vedolizumab, as compared with placebo, was associated with a higher rate of serious adverse events (24.4% vs. 15.3%), infections (44.1% vs. 40.2%), and serious infections (5.5% vs. 3.0%).
CONCLUSIONS: Vedolizumab-treated patients with active Crohn's disease were more likely than patients receiving placebo to have a remission, but not a CDAI-100 response, at week 6; patients with a response to induction therapy who continued to receive vedolizumab (rather than switching to placebo) were more likely to be in remission at week 52. Adverse events were more common with vedolizumab. (Funded by Millennium Pharmaceuticals; GEMINI 2 ClinicalTrials.gov number, NCT00783692.).
Vedolizumab (VDZ) is a selective antibody against α4β7‐integrin, which targets leukocyte trafficking in the gastrointestinal tract. The GEMINI studies are Phase 3, randomized, placebo‐controlled trials to assess the efficacy of VDZ in induction and maintenance of moderately to severely active ulcerative colitis (GEMINI 1) and Crohn's disease (GEMINI 2). Included in these studies are patients who have failed TNF‐α antagonist therapy. GEMINI 1 showed that VDZ is an effective agent in induction and maintenance of ulcerative colitis. GEMINI 2 met one of two primary end points in the induction phase showing that VDZ is more likely to induce clinical remission compared with placebo. VDZ is an effective agent in the maintenance of Crohn's disease. These studies pave the way to a new class of medications for treatment of inflammatory bowel disease.
Background: Vedolizumab (VDZ) is a gut-selective α4β7 integrin antagonist with demonstrated efficacy and safety in patients with moderately to severely active Crohn's disease (CD).1 In post hoc analyses of data from the double-blind (DB) placebo (PBO)- controlled GEMINI 2 study (NCT00783692), we investigated the effect of VDZ on extraintestinal manifestations (EIMs) in the subpopulation of patients who had EIMs at baseline. Methods: Patients received DB PBO, DB VDZ, or open-label VDZ induction. At week 6, VDZ responders were re-randomized to DB PBO (VDZ/PBO) or VDZ every 8 weeks (Q8W) or every 4 weeks (Q4W) for the 46-week maintenance phase. VDZ nonresponders continued on VDZ Q4W and patients who received PBO continued on PBO (PBO/PBO). EIMs were evaluated post hoc from the CD Activity Index (CDAI) complications component. Patients with EIMs were defined as those with (1) any CDAI complication, (2) CDAI complications excluding anal disease-related complications (ie, arthritis/arthralgia, iritis/uveitis, erythema nodosum, pyoderma gangrenosum, aphthous stomatitis, or fever >37.8°C during the past week), (3) any anal disease-related complication (abscess, anal fissure, anal fistula, or other fistula), and (4) arthritis/arthralgia. Kaplan-Meier (KM) estimates for the time to resolution of EIMs were evaluated in patients with baseline EIMs from the PBO/PBO population and all patients receiving VDZ during maintenance (ie, week 6 responders and nonresponders combined). Resolution of EIMs was defined as absence of CDAI complications at each postbaseline study visit until week 52; patients who discontinued the study were counted as not resolved. Hazard ratios (HRs) were calculated over 52 weeks. Results: In total, 494 combined VDZ and 107 PBO/PBO patients had EIM(s) at baseline. KM estimates for resolution of any EIM with VDZ were 13% at week 26 and 32% at week 52 (versus 4% and 23% with PBO, respectively); the HR was 1.4 (95% CI, 0.7-2.79). When excluding anal disease-related complications, KM estimates with VDZ were 18% at week 26 and 43% at week 52 (versus 6% and 23% with PBO, respectively); the HR was 1.87 (95% CI, 0.96-3.64). For resolution of anal disease-related complications, KM estimates with VDZ were 10% at week 26 and 22% at week 52 (versus 6% and 25% with PBO, respectively); the HR was 0.8 (95% CI, 0.18-3.49). KM estimates for resolution of arthritis/ arthralgia with VDZ were 19% at week 26 and 42% at week 52 (versus 7% and 26% with PBO, respectively); the HR was 1.84 (95% CI, 0.91-3.71). Conclusions: This post hoc analysis did not show statistically significant benefit of vedolizumab over placebo for the treatment of EIMs in CD. However, within the limitations of the data collection and the fact that the study was not powered to assess EIMs, there was a trend toward benefit. Further study is needed regarding which patients may benefit.
Introduction In GEMINI 1 and GEMINI 2, vedolizumab (VDZ) was safe and effective in patients (pts) with ulcerative colitis (UC) or Crohn's disease (CD), respectively, on stable doses of immunosuppressants (IS).1,2 The effect of discontinuing IS in pts who responded to VDZ induction therapy in these studies has not been characterised. Methods Pts who responded to VDZ at week (wk) 6 were rerandomised to placebo (VDZ/PBO) or VDZ every 4 or 8 wks (VDZ/VDZ Q4W or Q8W) for 46 wks. At United States (US) sites, re-randomised pts discontinued IS use at wk 6. At non- US sites, pts could continue IS use. Efficacy, VDZ serum concentration, and immunogenicity data (via an enzyme-linked immunosorbent assay) were evaluated post hoc in pts with baseline IS use stratified by region. Results At wk 52, rates of clinical remission and response (Table), mucosal healing (UC), durable clinical remission, and corticosteroid-free remission were numerically higher with VDZ, mostly irrespective of IS use. The US and non-US sites had similar numbers of patients who were positive for anti- VDZ antibodies during VD maintenance therapy (Table). Mean trough concentrations were similar between US and non- US pts at wk 46. [TABLE PRESENTED] Conclusion Discontinuing IS did not appear to substantially affect efficacy of VDZ maintenance therapy. Interpretation of these post hoc analyses is limited by potential IS discontinuation in non-US pts and the relatively small sample sizes.
INTRODUCTION: The efficacy and safety of vedolizumab, a gut‐selective α4β7 integrin antibody, were demonstrated in the GEMINI 1 and GEMINI 2 clinical trials of adults aged 18‐80 years. We investigated the efficacy and safety of vedolizumab in patients stratified by age from the GEMINI trials. METHODS: Safety and efficacy, including clinical response, clinical remission, and corticosteroid‐free remission, at week 6 and/or 52 were determined post hoc in patients aged <35, 35 to <55, and ≥55 years. RESULTS: At baseline, 353, 412, and 130 ulcerative colitis (UC) and 582, 443, and 90 Crohn's disease (CD) patients were aged <35, 35 to <55, and ≥55. Of these patients, 56 were aged ≥65 years (UC: 33, CD: 23). Trends favoring vedolizumab over placebo were observed for most efficacy endpoints irrespective of patient age; some variability between subgroups was observed. Safety profiles of vedolizumab and placebo were similar in all age groups. Vedolizumab‐treated patients aged ≥55 had the lowest incidence of serious infections (0.9 per 100 person‐years) and adverse events leading to hospitalization (14.8 per 100 person‐years). There were no age‐related differences in the incidence of adverse hematological events, malignancy, or death. CONCLUSIONS: The safety and efficacy of vedolizumab in patients with UC or CD were similar for all age groups. The number of patients in the oldest age group in these analyses was small; thus further studies of vedolizumab in larger cohorts of elderly patients are warranted. FUNDING: Millennium Pharmaceuticals, Inc. (d/b/a Takeda Pharmaceuticals International Co.).
BACKGROUND: Vedolizumab is a gut-selective α4β7 integrin antagonist for the treatment of moderately to severely active Crohn's disease (CD). Aims of this study were to characterize the efficacy and safety of vedolizumab induction and maintenance therapy in patients who were naïve to tumor necrosis factor-alpha (TNF-α) antagonist therapy (TNF-naïve) or who had discontinued TNF-α antagonist therapy because of inadequate response (i.e., primary nonresponse), loss of response, or intolerance (collectively classified as the TNF-failure population).
METHODS: Post hoc analyses of the efficacy data for 516 TNF-naïve and 960 TNF-failure patients from the GEMINI 2 and GEMINI 3 trials were evaluated at weeks 6, 10, and 52 and included clinical remission (CD Activity Index [CDAI] score ≤150), enhanced clinical response (≥100-point decrease from baseline in CDAI score), durable clinical remission (remission at ≥80% of visits), and corticosteroid-free remission. Adverse events were summarized for the TNF-naïve and TNF-failure subgroups by treatment received.
RESULTS: Among patients who responded to vedolizumab induction at week 6, 48.9% of TNF-naïve and 27.7% of TNF-failure patients were in remission with vedolizumab at week 52 (versus 26.8% and 12.8% with placebo). Clinical efficacy was similar between the different types of TNF-α antagonist failure or the number of prior TNF-α antagonists failed. Safety profiles were similar in both subpopulations.
CONCLUSIONS: Vedolizumab had increased efficacy over placebo in CD patients irrespective of TNF-α antagonist treatment history. Overall, rates of response and remission were numerically higher in patients receiving vedolizumab as a first biologic than in patients who had experienced TNF failure.
ABSTRACT
Background and Aims
Vedolizumab, a humanised monoclonal antibody for the treatment of inflammatory bowel disease, selectively blocks gut lymphocyte trafficking. This may reduce the risk of respiratory tract infections [RTIs] compared with systemic immunosuppressive therapies. To assess this possibility, we evaluated the rates of RTIs in clinical trials of vedolizumab.
METHODS
Patient-level data from Phase 3 randomised controlled trials [RCTs] of vedolizumab in ulcerative colitis [UC; GEMINI 1] and Crohn’s disease [CD; GEMINI 2], and a long-term safety study [UC and CD] were pooled. Cox proportional hazards models were used to estimate the incidence of upper RTIs [URTIs] and lower RTIs [LRTIs] with adjustment for significant covariates.
RESULTS
In the RCTs [n = 1731 patients], the incidence of URTIs was numerically higher in patients receiving vedolizumab compared with those receiving placebo, although this difference was not statistically significant (38.7 vs 33.0 patients per 100 patient-years; hazard ratio [HR] 1.12; 95% confidence interval [CI]: 0.83–1.51; p = 0.463). The rate of LRTIs, including pneumonia, was numerically lower in the vedolizumab versus the placebo group: this difference was not statistically significant (7.7 vs 8.5 per 100 patient-years [HR 0.85; 95% CI: 0.48–1.52; p = 0.585]). Both URTIs and LRTIs were more frequent in patients with CD compared with UC. Most RTIs in patients receiving vedolizumab were not serious and did not require treatment discontinuation.
CONCLUSIONS
Vedolizumab therapy was not associated with an increased incidence of respiratory tract infection compared with placebo.
Background: Vedolizumab (VDZ) is a safe and effective treatment for moderately to severely active ulcerative colitis and Crohn's disease; however, effects on surgical rates have not yet been evaluated. This study aimed (1) to compare the surgical incidence rates of VDZ and placebo in GEMINI I (ulcerative colitis; NCT00783718) and II (Crohn's disease; NCT00783692) and (2) to describe the surgical incidence rates through year 5 from the GEMINI LTS trial (ulcerative colitis and Crohn's disease; NCT00790933). Methods: Data were pooled from week 6 induction VDZ responders who were randomized to VDZ or placebo maintenance (intent-to-treat maintenance populations) from GEMINI I1 and II,2 and from patients receiving VDZ in the GEMINI LTS trial.3,4 Using the Kaplan-Meier product-limit method, we estimated “time to first surgery” through 1 year (VDZ and placebo groups from GEMINI I and II) and 5 years (VDZ1 and VDZ2 groups from GEMINI LTS [VDZ1=VDZ throughout; VDZ2=placebo from week 6 to 1 year, then VDZ for the LTS study]). Patients without surgery were censored at the last follow-up date through 1 year and 5 years. The log-rank test was used for comparisons between groups. Results: The analysis included 834 patients in total. Mean ages were 40.0 and 35.7 years for patients with ulcerative colitis and Crohn's disease, respectively; proportions of prior tumor necrosis factor antagonist failure were 39.9% and 54.9%, and mean disease duration times were 7.2 and 8.6 years. Figure 1 shows cumulative surgical incidence rates for the study groups, as well as the log-rank comparisons at 1 year (VDZ and placebo groups) and 5 years (VDZ1 and VDZ2 groups). Conclusion: In this population of patients with moderately to severely active ulcerative colitis or Crohn's disease, surgery rates within the first year of observation were lower in patients assigned to VDZ than in those who received placebo, with a significant difference observed in ulcerative colitis. For patients who continued treatment for up to 5 years, VDZ provided long-term benefit in both diseases with low rates of surgical intervention. The post hoc nature of the analysis and the small number of surgical events require further real-world evaluation of the ability of VDZ to reduce surgical rates in patients with ulcerative colitis and Crohn's disease. References 1Feagan BG, et al. N Engl J Med. 2013;369:699-710 2Sandborn WJ, et al. N Engl J Med. 2013;369:711-21 3Loftus EV Jr, et al. J Crohns Colitis. 2017;11:400-11 4Vermeire S, et al. J Crohns Colitis. 2017;11:412-24 [Figure presented]
BACKGROUND & AIMS: Vedolizumab, a humanized monoclonal antibody against α4β7 integrin, is used to treat adults with moderately to severely active ulcerative colitis (UC) and Crohn's disease (CD). We investigated the time course of clinical response to vedolizumab in patients who were and were not previously treated with tumor necrosis factor (TNF) antagonists.
METHODS: We performed a post-hoc analysis of data from phase 3, randomized, controlled trials of vedolizumab vs placebo in adult patients with UC (N = 374) or CD (N = 784). We collected data on patient-reported symptoms (rectal bleeding and stool frequency for patients with UC, abdominal pain and loose stool frequency for patients with CD) reported at weeks 2, 4, and 6 of treatment. We reported mean percentage score changes from baseline and proportions of patients who achieved predefined scores. We performed multivariate logistic regression analysis to identify factors associated with an early response (at week 2).
RESULTS: In patients with UC (overall or naive to TNF antagonist therapy), a significantly greater percentage of patients given vedolizumab achieved the predefined composite symptom score at weeks 2, 4, and 6 compared to those given placebo. In patients with CD who were naive to TNF antagonists, a significantly greater percentage of patients given vedolizumab achieved the predefined score at weeks 2 and 4 compared to those given placebo. Among patients with UC given vedolizumab, 19.1% (overall) and 22.3% (TNF antagonist naive) achieved a composite score of rectal bleeding of 0 and stool frequency ≤1 at week 2 compared to 10% (overall) and 6.6% (TNF antagonist naive) of those receiving placebo. Among TNF antagonist-naive patients with CD, 15.0% of those given vedolizumab achieved an average daily composite score of abdominal pain ≤1 and loose stool frequency ≤3 at week 2 (compared to 7.9% given placebo), and 23.8% of those given vedolizumab achieved these by week 4 (compared to 10.3% given placebo).
CONCLUSIONS: In a post-hoc analysis of data from phase 3 clinical trials, vedolizumab significantly improved patient-reported symptoms of UC and CD as early as week 2 of treatment, continuing through the first 6 weeks-especially when given as first-line biologic therapy. ClinicalTrials.gov no: NCT00783718, NCT00783692, NCT01224171.
Introduction: Vedolizumab, A Gut‐Selective Monoclonal Antibody Against Α4β7 Integrin, Is Used To Treat Adults With Moderately‐To‐Severely Active Ulcerative Colitis And Crohn’S Disease (Cd). We Investigated Symptomatic Improvement, Including Onset Of Action, Across Disease Activity And Prior Tumor Necrosis Factor Antagonist Α (Anti‐Tnfα) Status In Patients With Cd. Methods: This Was A Post Hoc Exploratory Analysis Of Data From Gemini 2, The Phase 3, Randomized, Placebo (Pbo)‐Controlled Trial Of Vedolizumab Treatment For Moderate‐To‐Severe Cd. Early Onset Efficacy For Abdominal Pain And Stool Frequency At Weeks 2, 4, And 6 Of Treatment Was Stratified By Baseline Moderate Disease Activity (Defined As Crohn’S Disease Activity Index [Cdai] ≤330), Prior Anti‐Tnfα Failure Status, And Also By A Composite Of Prior Anti‐Tnfα Failure And Baseline Disease Activity. Efficacy At Week 52 Was Stratified In A Similar Manner For Clinical Remission, Enhanced Clinical Response (≥100‐Point Reduction In Cdai Score From Baseline), Corticosteroid‐Free Remission, And Durable Clinical Remission (Cdai Score ≤150 Points At ≥80% Of Study Visits, Including The Final Visit [Week 52]). We Report Mean Adjusted Percentage Score Changes From Baseline At Weeks 2, 4, 6, And Percentages Of Patients Who Achieved Predefined Scores At Week 52. Results: Subgroup Analysis (Figure) Showed That Vedolizumab‐Treated Patients With Moderate Disease (Cdai ≤330) And No Prior Anti‐Tnfα Failure Achieved Significant Differences Vs Pbo Recipients In Abdominal Pain At Weeks 2, 4 And 6, And In Stool Frequency At Weeks 2 And 6. At Week 52 (Table), The Overall Population Treated With Vedolizumab Vs Pbo Had More Clinical Remission, Enhanced Clinical Response, And Corticosteroid‐Free Remission. Clinical Remission And Enhanced Clinical Response Rate With Vedolizumab Was Significantly Greater Than Pbo Regardless Of Baseline Disease Activity Or Anti‐Tnfα Exposure. Discussion: In This Post Hoc Analysis, Vedolizumab‐Treated Patients With Moderate Disease Activity (Defined As Cdai ≤330) And No Prior Anti‐Tnfα Failure Achieved Better Clinical Outcomes, Especially At Earlier Time Points, Than Patients With More Severe Disease Activity And Prior Anti‐Tnfα Failure. Funded By Takeda Pharmaceuticals U.S.A., Inc (Figure Presented) (Table Presented)
The primary purpose of this study was to determine the effect of vedolizumab induction treatment on clinical response and remission at 6 weeks and to determine the effect of vedolizumab maintenance treatment on clinical remission at 52 weeks.
