Early Dose Optimisation of Golimumab in Nonresponders to Induction Treatment for Ulcerative Colitis Is Effective and Supported by Pharmacokinetic Data

2019 ◽  
Vol 13 (10) ◽  
pp. 1257-1264 ◽  
Author(s):  
George Philip ◽  
Freddy Cornillie ◽  
J Omoniyi Adedokun ◽  
Richard Melsheimer ◽  
Paul Rutgeerts ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Body Weight ◽  
Clinical Response ◽  
Clinical Outcomes ◽  
Maintenance Dose ◽  
Mucosal Healing ◽  
Induction Treatment ◽  
Pharmacokinetic Data ◽  
Dose Optimisation ◽  
Post Hoc

Abstract Background and Aims In nonresponders to golimumab induction for ulcerative colitis, we assessed clinical response rates and golimumab serum concentrations when the 100-mg dose was used early in the course of maintenance. Methods This post-hoc analysis of golimumab maintenance dosing [in the PURSUIT-M study] examined clinical outcomes and golimumab concentrations in early [Week 6] responders and nonresponders to induction, including subgroups based on body weight. Results In nonresponders to golimumab induction [assessed at Week 6], the 100-mg maintenance dose [starting at Week 6] resulted in a meaningful proportion [28.1%] of patients achieving a partial Mayo response at Week 14. After 1 year of maintenance, clinical outcome [response, remission, mucosal healing, corticosteroid-free state] rates in these “late” [Week 14] responders were similar to those in early [Week 6] responders. Golimumab concentrations in early nonresponders were approximately half those of early responders, suggesting that early nonresponders had more rapid golimumab clearance. Examined by body weight, the early nonresponders weighing <80 kg and receiving 100 mg had golimumab concentrations similar to the early responders [weighing <80 kg or ≥80 kg and receiving 50 mg or 100 mg, respectively]. Conclusions Early use of the 100-mg maintenance dose leads to positive clinical outcomes in a meaningful proportion of patients who did not respond to golimumab at Week 6. Early nonresponders <80 kg who received the 100-mg maintenance dose achieved adequate golimumab concentrations and a clinically meaningful proportion of these patients had a late clinical response. PURSUIT-M protocol number C0524T18; ClinicalTrials.gov, NCT00488631; EudraCT, 2006-003399-37.

scholarly journals Clinical Outcomes and Predictors of Response for Adalimumab in Patients with Moderately to Severely Active Ulcerative Colitis: A KASID Prospective Multicenter Cohort Study

2020 ◽  
Author(s):  
Seung Yong Shin ◽  
Soo Jung Park ◽  
Young Kim ◽  
Jong Pil Im ◽  
Hyo Jong Kim ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Clinical Response ◽  
Clinical Outcomes ◽  
Response Rate ◽  
Drug Level ◽  
Mucosal Healing ◽  
Clinical Response Rate ◽  
Active Ulcerative Colitis ◽  
Multicenter Cohort Study ◽  
Tnf Α

Abstract A prospective, observational, multicenter study was conducted over 56 weeks in 146 adult patients with moderately to severely active ulcerative colitis (UC) who received adalimumab (ADA) at 17 Korean academic hospitals. Clinical response rates were 52.1% and 37.7% and clinical remission rates were 24.0% and 21.9% at weeks 8 and 56, respectively. Mucosal healing rates were 39.0% and 30.1% at weeks 8 and 56, respectively. Prior use of anti-tumor necrosis factor-α (anti-TNF-α) did not affect clinical outcomes. The ADA drug level was significantly higher in patients with better outcomes at week 8. In patients with lower endoscopic activity, higher body mass index, and higher serum albumin levels at baseline, the clinical response rate was higher at week 8. In patients with lower Mayo scores and C-reactive protein levels, clinical responses, and mucosal healing at week 8, the clinical response rate was higher at week 56. Serious adverse drug reactions were identified in 2.7% of patients. ADA is effective and safe for induction and maintenance in Korean patients with UC, regardless of prior anti-TNF-α therapy. The ADA drug level is associated with the efficacy of induction therapy. Patients with better short-term outcomes were predictive of those with an improved long-term response

scholarly journals Effect of disease duration on the association between serum albumin and mucosal healing in patients with ulcerative colitis

2021 ◽  
Vol 8 (1) ◽  
pp. e000662
Author(s):  
Sen Yagi ◽  
Shinya Furukawa ◽  
Kana Shiraishi ◽  
Yu Hashimoto ◽  
Kazuhiro Tange ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Serum Albumin ◽  
Clinical Outcomes ◽  
Clinical Remission ◽  
Acute Inflammation ◽  
Japanese Patients ◽  
Cross Sectional Study ◽  
Mucosal Healing ◽  
High Serum ◽  
Cross Sectional

ObjectiveSerum albumin is used as a marker of acute inflammation. Several studies have addressed the association between serum albumin and clinical outcome in patients with ulcerative colitis (UC). While mucosal healing (MH) has been indicated as the therapeutic goal for UC, the association between serum albumin and MH remains unclear. We evaluated this issue in patients with UC overall and explored whether duration of UC affected this association.DesignThis cross-sectional study recruited consecutive patients with UC. Study subjects consisted of 273 Japanese patients with UC. Serum albumin was divided into tertiles based on its distribution in all study subjects. One endoscopy specialist was responsible for measuring partial MH and MH, which were defined as a Mayo endoscopic subscore of 0–1 and 0, respectively. The association between serum albumin and clinical outcomes was assessed by multivariate logistic regression.ResultsRates of clinical remission, partial MH and MH were 57.9%, 63% and 26%, respectively. Only high serum albumin (>4.4 mg/dL) was significantly positively associated with MH (OR 2.29 (95% CI: 1.03 to 5.29), p for trend=0.043). In patients with short UC duration (<7 years) only, high serum albumin was significantly positively associated with MH and clinical remission. In patients with long UC duration (≥7 years), in contrast, no association between serum albumin and clinical outcomes was found.ConclusionIn Japanese patients with UC, serum albumin was significantly positively associated with MH. In patients with short UC duration, serum albumin might be a useful complementary marker for MH.

scholarly journals EXPERIENCE OF TOFACITINIB USING IN THERAPY OF ULCERATIVE COLITIS IN REAL CLINICAL PRACTICE

2019 ◽  
Vol 18 (4) ◽  
pp. 86-99
Author(s):  
E. A. Belousova ◽  
Вю I. Abdulganieva ◽  
O. P. Alekseeva ◽  
I. G. Bakulin ◽  
O. V. Vasilyeva ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Clinical Response ◽  
Clinical Improvement ◽  
Clinical Remission ◽  
Therapeutic Option ◽  
Mucosal Healing ◽  
Induction Treatment ◽  
Extraintestinal Manifestations ◽  
Biological Drugs ◽  
Real Clinical Practice

AIM: to demonstrate the first Russian experience with the use of tofaciminib (TOFA) for the treatment of moderate and severe UC in real clinical practice.PATIENTS AND METHODS: eighty-five patients with UC (aged 41.38±14.69 years, average disease duration 9.55±5.27 years, mild UC – 3.5%, moderate UC – 41.2%, severe – 52.9%, acute severe UC – 2.6%), resistant to corticosteroid therapy (36.5%) and biological agents (61.2%), were prescribed with TOFA at an induction dose of 10 mg 2 times a day, followed by a decrease in the dose to a maintenance dose (5 mg 2 times a day). Early clinical response, clinical and endoscopic remission, prevalence and dynamic of extraintestinal manifestations were assessed at 8 and 12 weeks of treatment, as well as safety and tolerability.RESULTS: Sixty-eight (80.0%) patients completed induction treatment with TOFA for 8 weeks, other patients continue to receive TOFA. A quick response within one week was detected in 41 (50.6%) patients, on average, on the 5th day of therapy. At the end of induction, 52 (76.5%) patients achieved clinical remission, 3 (4.4%) achieved a clinical response, 13 (19.1%) patients showed no positive changes. Of the 53 patients observed over 12 weeks, 41 (77.4%) had clinical remission, 6 (11.3%) had clinical improvement, and 6 (11.3%) patients had no response to the treatment. The changes of extraintestinal manifestations were positive: 55.2% of patients at week 8 and 77.8% of patients at week 12 showed clinical improvement, mainly in relation to the joint syndrome. One episode of herpes zoster infection, one case of anemia, were identified dur-ing 12 weeks of follow-up.CONCLUSION: TOFA in UC is effective in achieving a rapid clinical response, clinical remission and mucosal healing in patients who do not adequately respond to therapy with basic as well as biological drugs. Tofacitinib is an effective and safe therapeutic option for this challenging patient population.

scholarly journals Long-term, Real-life, Observational Study in Treating Outpatient Ulcerative Colitis with Golimumab

2021 ◽  
Author(s):  
Antonio Tursi ◽  
Giammarco Mocci ◽  
Walter Elisei ◽  
Leonardo Allegretta ◽  
Raffaele Colucci ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Clinical Response ◽  
Clinical Remission ◽  
Real Life ◽  
Mucosal Healing ◽  
Term Treatment ◽  
Short Term Treatment ◽  
Mayo Score

Background and Aims: Several studies have found Golimumab (GOL) effective and safe in the short-term treatment of ulcerative colitis (UC), but few long-term data are currently available from real world. Our aim was to assess the long-term real-life efficacy and safety of GOL in managing UC outpatients in Italy. Methods: A retrospective multicenter study assessing consecutive UC outpatients treated with GOL for at least 3-month of follow-up was made. Primary endpoints were the induction and maintenance of remission in UC, defined as Mayo score ≤2. Several secondary endpoints, including clinical response, colectomy rate, steroid free remission and mucosal healing, were also assessed during the follow-up. Results: One hundred and seventy-eight patients were enrolled and followed up for a median (IQR) time of 9 (3-18) months (mean time follow-up: 33.1±13 months). Clinical remission was achieved in 57 (32.1%) patients: these patients continued with GOL, but only 6 patients (3.4%) were still under clinical remission with GOL at the 42nd month of follow-up. Clinical response occurred in 64 (36.4%) patients; colectomy was performed in 8 (7.8%) patients, all of them having primary failure. Steroid-free remission occurred in 23 (12.9%) patients, and mucosal healing was achieved in 29/89 (32.6%) patients. Adverse events occurred in 14 (7.9%) patients. Conclusions: Golimumab does not seem able to maintain long-term remission in UC in real life. The safety profile was good.

scholarly journals DOP55 A real-world comparison of the effectiveness and safety of vedolizumab and anti-TNF therapies in early treatment initiation with first-line biologic therapy in ulcerative colitis: Results from EVOLVE

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S092-S094
Author(s):  
G Mantzaris ◽  
B Bressler ◽  
U Kopylov ◽  
M Bassel ◽  
N Brett ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Clinical Response ◽  
Real World ◽  
Early Treatment ◽  
Clinical Remission ◽  
Treatment Initiation ◽  
Clinical Effectiveness ◽  
Mucosal Healing ◽  
First Line

Abstract Background Evidence suggests that early treatment (Tx) with biologic agents in Crohn’s disease improves long-term clinical outcomes. However, there is less evidence in ulcerative colitis (UC), and data comparing early Tx with first-line biologic vedolizumab (VDZ) to anti-tumour necrosis factor (anti-TNF) in real-world settings is needed. This study compared the clinical effectiveness and safety of UC patients who initiated VDZ or an anti-TNF as a first-line biologic within 2 years following diagnosis. Methods This was a real-world, multi-country, retrospective chart review study in Canada, Greece and the United States where biologic-naïve UC patients (≥18 years old) were treated with VDZ or an anti-TNF (adalimumab, infliximab, golimumab) agent within 2 years following diagnosis (initiated Tx May 2014–March 2018). Clinical effectiveness and safety data were collected from Tx initiation to earliest of chart abstraction date, death, or 6 months post-Tx discontinuation (Canada only). Tx persistence was defined as the duration of time from treatment initiation to discontinuation. Analyses of cumulative rates of Tx persistence, clinical response, clinical remission and mucosal healing over 24 months were estimated using Kaplan–Meier analyses. Clinical response, remission and mucosal healing were assessed using pre-defined hierarchical algorithms of standard disease measures reported in the medical records. Analyses of incidence rates (per 100 person-years [PYs]) of disease exacerbations, disease-related surgeries, serious adverse events (SAEs) and serious infections (SIs) were performed. Adjusted analyses used inverse probability weighting to balance cohorts. Results This analysis included 176 UC patients (VDZ: 86; anti-TNF: 90) from 37 sites. Mean (SD) age at index date: VDZ, 41.4 (18.9); anti-TNF, 36.8 (15.6) years (p = 0.20) and the proportion male: VDZ, 58.1%; anti-TNF, 56.7% (p = 0.84). At 12 months, 72.9% and 58.1% continued VDZ and anti-TNF respectively (p = 0.03) (Figure 1A). Though there were no differences in clinical response, clinical remission or mucosal healing between VDZ and anti-TNF groups; VDZ patients were significantly less likely to experience disease exacerbations (HR = 0.47 [95% CI: 0.32–0.69]) and SAEs (HR = 0.37 [95% CI: 0.19–0.72]) (Figure 2). Adjusted outcomes (Figures 1C and D, and 2B) were similar to unadjusted outcomes. Conclusion EVOLVE is one of the first studies that compared early VDZ Tx to early anti-TNF Tx in biologic-naïve UC patients. Results showed VDZ was associated with higher persistence, lower likelihood of experiencing disease exacerbations and a more favourable safety profile. Thus, in early UC, Tx with VDZ may improve long-term clinical outcomes. Sample size limitations warrant further study.

P069 ONTAMALIMAB, A FULLY HUMAN MONOCLONAL ANTIBODY AGAINST MUCOSAL ADDRESSIN CELL ADHESION MOLECULE-1, PROVIDES SUSTAINED EXPOSURE FOLLOWING LONG-TERM TREATMENT IN PATIENTS WITH ULCERATIVE COLITIS

2020 ◽  
Vol 26 (Supplement_1) ◽  
pp. S11-S11
Author(s):  
Yi Wang ◽  
J F Marier ◽  
Leila Kheibarshekan ◽  
Nastya Kassir ◽  
Patrick Martin
Keyword(s):  
Ulcerative Colitis ◽  
Monoclonal Antibody ◽  
Clinical Response ◽  
Clinical Remission ◽  
Cell Adhesion Molecule ◽  
Mucosal Healing ◽  
Efficacy And Safety ◽  
Induction Study ◽  
Cell Adhesion Molecule 1

Abstract Introduction Ontamalimab is a fully human immunoglobulin G2 monoclonal antibody against mucosal addressin cell adhesion molecule-1 in development for the induction and maintenance of clinical remission in patients with ulcerative colitis (UC). This study aimed to assess the long-term pharmacokinetics (PK) of ontamalimab in patients with UC, and the effects of concomitant medications on PK parameters. Methods A 12-week induction study (TURANDOT; NCT01620255) was performed to assess the PK, efficacy and safety of ontamalimab (7.5, 22.5, 75 and 225 mg subcutaneous [s.c.] every four weeks [Q4W]) in patients with UC. Individuals who completed the induction study were eligible for enrollment in an open-label extension (OLE) study (TURANDOT II; NCT01771809) to assess the long-term PK, efficacy and safety of ontamalimab (75 or 225 mg s.c. Q4W up to week 72). Population PK analyses were performed using nonlinear mixed-effects modelling. Exposure-response analyses were performed to assess the relationships between minimum concentration (Cmin,ss) of ontamalimab and clinical response, clinical remission and mucosal healing. The effect of concomitant treatments (used for ≥20% of treatment duration) on PK parameters was also evaluated. Results The PK population included 130 (39.8%) women and 197 (60.2%) men, of median age of 40 years. A 1-compartment model with linear elimination adequately described the PK of ontamalimab. Population estimates of apparent clearance (CL/F) and volume of distribution (V/F) were 0.00917 L/h (0.22 L/day) and 7.44 L, respectively. Albumin had a significant effect on the variability of CL/F. Individuals with albumin levels of 30 g/L and 47 g/L are expected to have CL/F values 44% higher and 23% lower, respectively, than a typical patient with an albumin level of 39 g/L. Anti-inflammatory agents affected CL/F, such that CL/F is expected to be 14% higher in patients receiving than not receiving these agents. Other medications including immunosuppressants, steroids and treatments for peptic ulcers and gastroesophageal reflux disease had no effect on CL/F. Weight was the only covariate that significantly affected V/F. The half-life of ontamalimab was 23.4 days. Concentrations of ontamalimab over 72 weeks in the OLE study were consistent with those observed in the 12-week induction study. Ontamalimab Cmin,ss was related to efficacy, such that at week 16 (week 28 in total including induction), patients with higher Cmin,ss values were more likely to have clinical response, clinical remission and mucosal healing than those with lower Cmin,ss. Conclusion The exposure to ontamalimab was sustained following prolonged treatment in patients with UC for up to 72 weeks. Higher ontamalimab exposure was associated with a higher probability of clinical response.

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