Randomised clinical trial: a phase 1b study of GB004, an oral HIF-1α stabiliser, for treatment of ulcerative colitis.

Background: Epithelial barrier dysfunction contributes to a dysregulated intestinal immune response in ulcerative colitis (UC). GB004 is an orally administered, small molecule, gut-targeted stabiliser of hypoxia-inducible factor-1α, a transcription factor with protective roles at the epithelial layer of the inflamed gut.

Aims: To evaluate safety, pharmacokinetics, pharmacodynamics and efficacy of GB004 in patients with active UC.

Ozanimod induction therapy for patients with moderate to severe Crohn's disease: a single-arm, phase 2, prospective observer-blinded endpoint study.

Background: Although treatment of Crohn's disease has improved with development of tumour necrosis factor antagonists, fewer than 50% of patients have sustained benefit. Durable maintenance therapy with orally administered alternative treatments remains an unmet need. We aimed to evaluate the effects of ozanimod, an oral agent selectively targeting sphingosine-1-phosphate receptor subtypes 1 and 5, on endoscopic disease activity in Crohn's disease.

RPC4046, a Monoclonal Antibody Against IL13, Reduces Histologic and Endoscopic Activity in Patients With Eosinophilic Esophagitis.

Background & Aims: Eosinophilic esophagitis (EoE) is a chronic, esophageal, type 2 inflammatory response associated with increased serum levels of interleukin 13 (IL13), which might contribute to its pathogenesis. RPC4046, a recombinant humanized monoclonal antibody against IL13, prevents its binding to the receptor subunits IL13RA1 and IL13RA2. We performed a phase 2 trial to evaluate the efficacy and safety of RPC4046 in patients with EoE.

A composite disease activity index for early drug development in ulcerative colitis: development and validation of the UC-100 score.

Background: Combining clinical, endoscopic, and histological data associated with ulcerative colitis disease activity in a composite index could be a more sensitive way to detect efficacy in small numbers of patients during early drug development. Our aim was to derive and externally validate a novel index for this purpose.

Methods: Index development was done with data from a phase 2 placebo-controlled trial of ozanimod in patients with moderate-to-severe ulcerative colitis (n=179).

Responsiveness of histological disease activity indices in ulcerative colitis: a post hoc analysis using data from the TOUCHSTONE randomised controlled trial.

Objective: We evaluated the reliability and responsiveness of available but incompletely validated UC histological disease activity indices using standardised rules for centralised assessment.

Design: Disease activity was assessed in biopsies collected in a phase II placebo-controlled ozanimod trial by four blinded pathologists using the Geboes (GS) and modified Riley (MRS) scores, the Robarts Histopathology (RHI) and Nancy Histological (NHI) indices and a Visual Analogue Scale. Reliability was assessed with intraclass correlation coefficients (ICCs).

Cardiac Safety of Ozanimod, a Novel Sphingosine-1-Phosphate Receptor Modulator: Results of a Thorough QT/QTc Study.

Ozanimod is a novel, selective, oral sphingosine-1-phosphate (1 and 5) receptor modulator in development for multiple sclerosis and inflammatory bowel disease. This randomized, double-blind, placebo-controlled, positive-controlled, parallel-group thorough QT study characterized the effects of ozanimod on cardiac repolarization in healthy subjects. Eligible subjects were randomized to 1 of 2 groups: ozanimod (escalated from 0.

Results From the First-in-Human Study With Ozanimod, a Novel, Selective Sphingosine-1-Phosphate Receptor Modulator.

The sphingosine-1-phosphate 1 receptor (S1P ) is expressed by lymphocytes, dendritic cells, and vascular endothelial cells and plays a role in the regulation of chronic inflammation and lymphocyte egress from peripheral lymphoid organs. Ozanimod is an oral selective modulator of S1P and S1P receptors in clinical development for the treatment of chronic immune-mediated, inflammatory diseases. This first-in-human study characterized the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of ozanimod in 88 healthy volunteers using a range of single and multiple doses (7 and 28 days) and a dose-escalation regimen.

Ozanimod Induction and Maintenance Treatment for Ulcerative Colitis.

Background: Ozanimod (RPC1063) is an oral agonist of the sphingosine-1-phosphate receptor subtypes 1 and 5 that induces peripheral lymphocyte sequestration, potentially decreasing the number of activated lymphocytes circulating to the gastrointestinal tract.

Methods: We conducted a double-blind, placebo-controlled phase 2 trial of ozanimod in 197 adults with moderate-to-severe ulcerative colitis. Patients were randomly assigned, in a 1:1:1 ratio, to receive ozanimod at a dose of 0.

Safety and efficacy of the selective sphingosine 1-phosphate receptor modulator ozanimod in relapsing multiple sclerosis (RADIANCE): a randomised, placebo-controlled, phase 2 trial.

Background: Modulation of sphingosine 1-phosphate (S1P) receptors in a non-selective manner decreases disease activity in patients with multiple sclerosis but has potential safety concerns. We assessed the safety and efficacy of the oral selective S1P receptor modulator ozanimod in patients with relapsing multiple sclerosis.

Methods: RADIANCE is a combined phase 2/3 trial.

Haemodynamic effects, safety, and pharmacokinetics of human stresscopin in heart failure with reduced ejection fraction.

Aims: Human stresscopin is a corticotropin-releasing factor (CRF) type 2 receptor (CRFR2) selective agonist and a member of the CRF peptide family. Stimulation of CRFR2 improves cardiac output and left ventricular ejection fraction (LVEF) in patients with stable heart failure (HF) with reduced LVEF. We examined the safety, pharmacokinetics, and effects on haemodynamics and serum biomarkers of intravenous human stresscopin acetate (JNJ-39588146) in patients with stable HF with LVEF ≤ 35% and cardiac index (CI) ≤ 2.

Colectomy rate comparison after treatment of ulcerative colitis with placebo or infliximab.

Background & Aims: The efficacy of infliximab for treating patients with ulcerative colitis has been established.

Methods: The Active Ulcerative Colitis Trial (ACT)-1 and ACT-2 randomized, double-blind, placebo-controlled studies evaluated infliximab induction and maintenance therapy in moderately to severely active ulcerative colitis. Overall, 728 patients received placebo or infliximab (5 or 10 mg/kg) intravenously at weeks 0, 2, and 6, then every 8 weeks through week 46 (ACT-1) or 22 (ACT-2).

Infliximab therapy in children with concurrent perianal Crohn disease: observations from REACH.

Objective: Post hoc analyses evaluated the effect of infliximab upon concurrent perianal Crohn disease (CD) in a subpopulation of 31 patients from REACH, a randomized trial of 112 children with moderately to severely active luminal CD.

Materials And Methods: The Pediatric Crohn Disease Activity Index perirectal subscore was used to assess perianal symptom activity and therapeutic response. Patients with no symptoms or asymptomatic tags received a score of 0; those with "1-2 indolent fistula, scant drainage, no tenderness" received a score of 5; and those with "active fistula, drainage, tenderness or abscess" received a score of 10.

Improvement in biomarkers of bone formation during infliximab therapy in pediatric Crohn's disease: results of the REACH study.

Background & Aims: Crohn's disease (CD) is associated with altered bone metabolism. This study examined changes in bone formation and resorption after infliximab induction and associations between bone biomarkers, linear growth, and disease activity (Pediatric Crohn's Disease Activity Index [PCDAI]) after 54 weeks of infliximab therapy.

Methods: One hundred twelve subjects ages 6-17 years with moderate to severe CD received infliximab induction (5 mg/kg/dose) at weeks 0, 2, and 6; week-10 responders were randomized to infliximab every 8 or every 12 weeks maintenance therapy.

Response and remission are associated with improved quality of life, employment and disability status, hours worked, and productivity of patients with ulcerative colitis.

Background: Impairment of health-related quality of life, employment, and productivity has been documented in patients with moderate to severe ulcerative colitis.

Methods: Using prospectively collected data from the Active Ulcerative Colitis Trials 1 and 2, we examined the impact of clinical response or remission, as defined using the Mayo score, on health-related quality of life, employment, disability, productivity, and hours worked per week. These analyses were based on observed data and included all 728 patients, regardless of their randomized treatment group (i.

Induction and maintenance infliximab therapy for the treatment of moderate-to-severe Crohn's disease in children.

Background And Aims: The REACH study evaluated the safety and efficacy of infliximab in children with moderately to severely active Crohn's disease.

Methods: Patients (n = 112) with a Pediatric Crohn's Disease Activity Index (PCDAI) score >30 received infliximab 5 mg/kg at weeks 0, 2, and 6. Patients responding to treatment at week 10 were randomized to infliximab 5 mg/kg every 8 or 12 weeks through week 46.

The effects of infliximab therapy on health-related quality of life in ulcerative colitis patients.

Objectives: The impact of infliximab induction and maintenance therapy on health-related quality of life (HRQL) was evaluated in patients with ulcerative colitis (UC).

Methods: In two placebo-controlled, double-blind studies (the Active Ulcerative Colitis Trials 1 and 2 [ACT 1 and 2]), 728 patients were randomized to placebo or infliximab 5 mg/kg or 10 mg/kg. Infusions were administered at weeks 0, 2, 6, and every 8 wk thereafter, up to week 22 (ACT 2) or 46 (ACT 1).

Polymorphism in IgG Fc receptor gene FCGR3A and response to infliximab in Crohn's disease: a subanalysis of the ACCENT I study.

Recently, it has been shown that FCGR3A-158 gene polymorphism is associated with biological and possibly clinical response to infliximab in Crohn's disease. We further assessed this association in a subset of 344 patients from the large and well-defined cohort of 573 patients with Crohn's disease from the ACCENT I study. No association could be observed between FCGR3A-158 gene polymorphism and the clinical response to infliximab, which was primarily defined as a decrease of >or=70 points in the Crohn's disease activity index or clinical remission (Crohn's disease activity index <150).

Factors associated with the development of intestinal strictures or obstructions in patients with Crohn's disease.

Objective: Theoretical concern exists that rapid luminal healing in Crohn's disease (CD) with therapies like infliximab increases the risk of intestinal stenosis, stricture, or obstruction (SSOs).

Methods: Data were analyzed from the ongoing observational TREAT (the Crohn's Therapy, Resource, Evaluation, and Assessment Tool) Registry and ACCENT I (A Crohn's Disease Clinical Trial Evaluating Infliximab in a New Long-Term Treatment Regimen) study. Investigators reported SSOs as adverse events or serious adverse events.

Scheduled maintenance treatment with infliximab is superior to episodic treatment for the healing of mucosal ulceration associated with Crohn's disease.

Background: The endoscopic substudy of the ACCENT I (A Crohn's Disease Clinical Trial Evaluating Infliximab in a New Long-term Treatment Regimen) Crohn's disease trial examined the effects of infliximab on mucosal inflammation and mucosal healing, and assessed their impact on outcomes.

Design: ACCENT I was a randomized, double-blind, parallel group study.

Setting: This study took place at multiple centers in North America, Europe, and Israel.

Infliximab for induction and maintenance therapy for ulcerative colitis.

Background: Infliximab, a chimeric monoclonal antibody directed against tumor necrosis factor alpha, is an established treatment for Crohn's disease but not ulcerative colitis.

Methods: Two randomized, double-blind, placebo-controlled studies--the Active Ulcerative Colitis Trials 1 and 2 (ACT 1 and ACT 2, respectively)--evaluated the efficacy of infliximab for induction and maintenance therapy in adults with ulcerative colitis. In each study, 364 patients with moderate-to-severe active ulcerative colitis despite treatment with concurrent medications received placebo or infliximab (5 mg or 10 mg per kilogram of body weight) intravenously at weeks 0, 2, and 6 and then every eight weeks through week 46 (in ACT 1) or week 22 (in ACT 2).

Endoscopic and histologic evidence of persistent mucosal healing and correlation with clinical improvement following sustained infliximab treatment for Crohn's disease.

Objectives: The long-term effect of infliximab on endoscopic and histologic disease activity and expression of inflammatory markers was assessed in Crohn's disease patients who received infliximab as episodic or scheduled maintenance therapy therapy over 54 weeks (ACCENT 1).

Methods: All patients received Infliximab 5 mg/kg at week 0 and at week 2 were then randomized as responders or nonresponders to placebo or infliximab (5 or 10mg/kg). Patients received placebo or infliximab 5 mg/kg at weeks 2 and 6 followed by placebo or infliximab (5 or 10mg/kg) every 8 weeks or episodically on loss of response.

Unemployment and disability in patients with moderately to severely active Crohn's disease.

Goals: Unemployment and disability rates in Crohn's disease patients from the ACCENT I trial were assessed. Factors associated with employment and disability status were explored.

Background: Limited data regarding unemployment and disability status in patients with active Crohn's disease are available.

Incidence and importance of antibody responses to infliximab after maintenance or episodic treatment in Crohn's disease.

Background & Aims: The effect of different treatment regimens on antibody responses to infliximab and their clinical significance was examined by using data from ACCENT I.

Methods: Patients with Crohn's disease (n = 573) received 5 mg/kg infliximab (week 0) and then were randomly assigned to blinded infusions at weeks 2 and 6 and every 8 weeks until week 46 of placebo (group I), 5 mg/kg infliximab (group II), or 5 mg/kg infliximab at weeks 2 and 6, followed by 10 mg/kg thereafter (group III). At week 14 or later, patients losing response could cross over to episodic infliximab treatment increased by 5 mg/kg.