Fabio Cataldi

Anrukinzumab, an anti-interleukin 13 monoclonal antibody, in active UC: efficacy and safety from a phase IIa randomised multicentre study

Objective Interleukin 13 (IL-13) is thought to play a key role as an effector cytokine in UC. Anrukinzumab, a humanised antibody that inhibits human IL-13, was evaluated for the treatment of UC. Design In a multicentre, randomised, double-blind, placebo-controlled study, patients with active UC (Mayo score ≥4 and <10) were randomised to anrukinzumab 200, 400 or 600 mg or placebo. Patients received five intravenous administrations over 14 weeks. The primary endpoint was fold change from baseline in faecal calprotectin (FC) at Week 14. Secondary endpoints included safety, pharmacokinetics and IL-13 levels. Results The modified intention-to-treat population included 84 patients (21 patients/arm). Fold change of FC from baseline at Week 14 was not significantly different for any treatment groups compared with the placebo. The study had a high dropout rate, in part, related to lack of efficacy. The exploratory comparisons of each dose were not significantly different from placebo in terms of change from baseline in total Mayo score, clinical response, clinical remission and proportion of subjects with mucosal healing. An increase in serum total IL-13 (free and bound to anrukinzumab) was observed for all anrukinzumab groups but not with placebo. This suggests significant binding of anrukinzumab to IL-13. The safety profile was not different between the anrukinzumab and placebo groups. Conclusions A statistically significant therapeutic effect of anrukinzumab could not be demonstrated in patients with active UC in spite of binding of anrukinzumab to IL-13. Trial registration number ClinicalTrials.gov number NCT01284062.

Anti-MAdCAM antibody (PF-00547659) for ulcerative colitis (TURANDOT): a phase 2, randomised, double-blind, placebo-controlled trial

BACKGROUND PF-00547659 is a fully human monoclonal antibody that binds to human mucosal addressin cell adhesion molecule-1 (MAdCAM-1) to selectively reduce lymphocyte homing to the intestinal tract. We aimed to assess the efficacy and safety of PF-00547659 in patients with moderate to severe ulcerative colitis. METHODS This phase 2, randomised, double-blind, placebo-controlled clinical trial recruited patients aged 18-65 years from 105 centres in 21 countries, with a history (≥3 months) of active ulcerative colitis extending more than 15 cm beyond the anal verge (with a total Mayo score ≥6 and a Mayo endoscopic subscore ≥2) who had failed or were intolerant to at least one conventional therapy. Patients were stratified by previous anti-TNFα treatment, and randomly assigned by a computer-generated randomisation schedule to receive a subcutaneous injection of 7·5 mg, 22·5 mg, 75 mg, or 225 mg PF-00547659 or placebo at baseline, then every 4 weeks. Patients, investigators, and sponsors were blinded to the treatment. The primary endpoint was the proportion of patients achieving remission (total Mayo score ≤2 with no individual subscore >1 and rectal bleeding subscore ≤1) at week 12. The efficacy analysis included all patients who received at least one dose of the randomised treatment; the safety analysis was done according to treatment received. All p values were one-sided and multiplicity-adjusted. This study is registered with ClinicalTrials.gov, number NCT01620255. FINDINGS Between Nov 2, 2012, and Feb 4, 2016, we screened 587 patients; 357 were eligible and randomly assigned to receive placebo (n=73) or PF-00547659 at doses of 7·5 mg (n=71), 22·5 mg (n=72), 75 mg (n=71), or 225 mg (n=70). Remission rates at week 12 were significantly greater in three of four active-treatment groups than in the placebo group (2·7% [two of 73]): 7·5 mg (11·3% [eight of 71]), 22·5 mg (16·7% [12 of 72]), 75 mg (15·5% [11 of 71]), and 225 mg (5·7% [four of 70]). These rates corresponded to a stratum-adjusted (anti-TNFα-naive and anti-TNFα-experienced) risk difference versus placebo of 8·0% for 7·5 mg (90% CI 1·9 to 14, p=0·0425), 12·8% for 22·5 mg (5·6 to 19·9, p=0·0099), 11·8% for 75 mg (4·8 to 18·8, p=0·0119), and 2·6% for 225 mg (-1·2 to 6·4, p=0·1803). Four of 73 (5·5%) patients had a serious adverse event in the placebo group, ten of 71 (14·1%) in the 7·5 mg group, one of 70 (1·4%) in the 22·5 mg group, three of 73 (4·1%) in the 75 mg group, and three of 70 (4·3%) in the 225 mg group. No safety signal was observed for the study drug. INTERPRETATION PF-00547659 was safe and well tolerated in this patient population, and better than placebo for induction of remission in patients with moderate to severe ulcerative colitis. The greatest clinical effects were observed with the 22·5 mg and 75 mg doses. FUNDING Pfizer.

A pharmacokinetic comparison of anrukinzumab, an anti- IL-13 monoclonal antibody, among healthy volunteers, asthma and ulcerative colitis patients.

AIMS Anrukinzumab is an anti-IL13 monoclonal antibody. The goals of this study are to characterize the pharmacokinetics of anrukinzumab in healthy volunteers and different disease states and to identify covariates. METHODS A population pharmacokinetic (PK) model was developed in NONMEM, using data from five clinical studies including healthy volunteers, asthma and ulcerative colitis (UC) patients. Different dosing regimens including different routes of administration were also included in the data. RESULTS The PK of anrukinzumab were described by a two compartment model with first order absorption and elimination. The population estimates (relative standard error) of the volumes of distribution in the central (Vc ) and peripheral (Vp ) compartments were 3.8 (4.6%) and 2.2 l (8.7%), respectively. In non-UC patients, the population estimate of the systemic clearance (CL) and inter-compartmental CL was 0.00732 l h(-1) (4.9%) and 0.0224 l h(-1) (15.4%). For subcutaneous administration, the absorption rate constant was 0.012 h(-1) (6.6%) and bioavailability was nearly 100% in healthy and mild to moderate asthma patients. Both V and CL increased with body weight. CL (but not V) decreased with increasing baseline albumin concentrations. UC patients had an increased CL of 72.3% (10.5%), after correction for differences in body weight and albumin. Moderate to severe asthma patients had decreased bioavailability compared with other populations. CONCLUSIONS Anrukinzumabs PK behave like a typical antibody. UC patients were identified to have a faster CL of anrukinzumab than healthy volunteers and asthma patients. This finding suggests a higher dose level may be required for this population.

Phase II evaluation of anti-MAdCAM antibody PF-00547659 in the treatment of Crohn's disease: report of the OPERA study.

Objective This phase II, randomised, double-blind, placebo-controlled clinical trial was designed to evaluate the efficacy and safety of PF-00547659, a fully human monoclonal antibody that binds to human mucosal addressin cell adhesion molecule (MAdCAM) to selectively reduce lymphocyte homing to the intestinal tract, in patients with moderate-to-severe Crohn’s disease (CD). Design Eligible adults were aged 18–75 years, with active moderate-to-severe CD (Crohn’s Disease Activity Index (CDAI) 220–450), a history of failure or intolerance to antitumour necrosis factor and/or immunosuppressive agents, high-sensitivity C reactive protein >3.0 mg/L and ulcers on colonoscopy. Patients were randomised to PF-00547659 22.5 mg, 75 mg or 225 mg or placebo. The primary endpoint was CDAI 70-point decrease from baseline (CDAI-70) at week 8 or 12. Results In all, 265 patients were eligible for study entry. Although CDAI-70 response was not significantly different with placebo versus PF-00547659 treatment at weeks 8 or 12, remission rate was greater in patients with higher baseline C reactive protein (>5 mg/L vs >18.8 mg/L, respectively). Soluble MAdCAM decreased significantly from baseline to week 2 in a dose-related manner and remained low during the study in PF-00547659-treated patients. Circulating β7+ CD4+ central memory T-lymphocytes increased at weeks 8 and 12 with PF-00547659 treatment. No safety signal was seen. Conclusions Clinical endpoint differences between PF-00547659 and placebo did not reach statistical significance in patients with moderate-to-severe CD. PF-00547659 was pharmacologically active, as shown by a sustained dose-related decrease in soluble MAdCAM and a dose-related increase in circulating β7+ central memory T cells. Trial registration number NCT01276509; Results.

Blockade of lymphocyte trafficking in inflammatory bowel diseases therapy: importance of specificity of endothelial target

Inflammatory bowel diseases (IBD) are chronic, relapsing to continuously active inflammatory disorders of the gastrointestinal tract, of potentially destructive nature. So far, the excessive and/or unbalanced immune response has been the target of the majority of the IBD treatments. Despite the increasing use of immunosuppressants and anti-TNF-α inhibitors, about 30% of patients with Crohn’s disease and about one-tenth of patients with ulcerative colitis still require major abdominal surgery at 5–10 years. As a result, new therapeutic approaches are urgently needed. The endothelium has a key role in the development of the inflammation, as it selectively governs the leukocyte trafficking and the influx of leukocytes into the intestinal mucosa. Drugs blocking such crossing, specifically at intestinal level, are going to be a new therapeutic option in IBD.

Randomised trial and open-label extension study of an anti-interleukin-6 antibody in Crohn's disease (ANDANTE I and II)

Objective Neutralising pro-inflammatory interleukin-6 (IL-6) may effectively treat Crohn’s disease (CD). Effects of PF-04236921, an anti-IL-6 antibody, in adults with CD are reported. Design Parallel-group, dose-ranging, double-blind trial with 4-week screening and 12-week treatment periods. After induction, patients entered 28-week follow-up or 48-week open-label extension (OLE) with 28-week follow-up. Adults with confirmed CD and inadequate response to anti-tumour necrosis factor (TNF) therapy were included. Induction study: 249 patients randomised 1:1:1:1 to placebo, PF-04236921 10, 50 or 200 mg by subcutaneous injection on days 1 and 28. OLE study: PF-04236921 50 mg every 8 weeks up to six doses followed by 28-week follow-up. Results 247 patients were randomised and received treatment in the induction study. The 200 mg dose was discontinued due to safety findings in another study (NCT01405196) and was not included in the primary efficacy analysis. Crohn’s Disease Activity Index (CDAI)-70 response rates with PF-04236921 50 mg were significantly greater than placebo at weeks 8 (49.3% vs 30.6%, P<0.05) and 12 (47.4% vs 28.6%, P<0.05) and met the primary end point. Week 12 CDAI remission rates with PF-04236921 50 mg and placebo were 27.4% and 10.9%, respectively (16.5% difference; P<0.05). 191 subjects received treatment in the OLE. Common treatment-emergent and serious adverse events in both studies included worsening CD, abdominal pain and nasopharyngitis. Conclusions PF-04236921 50 mg induced clinical response and remission in refractory patients with moderate-to-severe CD following failure of anti-TNF therapy. GI abscess and perforation were observed, a specific focus of attention during future clinical development. Trial registration number NCT01287897 and NCT01345318.

P516 Discrepancy between fecal biomarkers and their intestinal gene expression in ulcerative colitis: Results from an anti-IL-13 antibody study

Methods: A questionnaire about disease (type, localization, diagnosis, treatment and surveillance) was distributed to IBD patients who attended outpatient gastroenterology clinic at our Hospital. The answers were categorized as appropriate or inappropriate. Demographic data, education level and features of the disease were recorded. Results: 73 patients were included (41 females) with a mean age of 44 years-old and a mean duration of IBD of 9.4 years. There were 42 patients with Ulcerative Colitis, 29 with Crohn’s disease and 2 with unclassified IBD. The mean of appropriate answers was 53.6%. The type of IBD was correctly marked in 86% of patients whereas the specific localization of the disease was recognized in only 27%. 95% of the responders considered colonoscopy important in diagnosis. Only 55% of the patients were aware of the increased risk of bowel cancer. A better performance in the questionnaire was associated with: younger patients at diagnosis (r = 0.593; p = 0.000) and at the time of the questionnaire (r = 0.451; p = 0.000), a higher education level (F = 5.976; p = 0.001), presence of Crohn’s Disease (65% versus 46%, F = 6.990; p = 0.000), previous hospitalization (60% versus 42%, t = 4.197; p = 0.000) or surgery related to the disease (66% vs 51%, t = 2.401; p = 0.019) and multiple past medications (including 2 anti-tumor necrosis factor therapy) (F = 4.194; p = 0.000). Conclusions: The age, the educational level of the patient and the severity of the disease requiring hospitalization, surgery or aggressive therapy, were associated with a better knowledge of the disease. The low percentage (marginally positive) of appropriate responses highlights the need for better educational strategies.

Effect of PF-00547659 on Central Nervous System Immune Surveillance and Circulating β7+ T Cells in Crohn’s Disease: Report of the TOSCA Study

Abstract Background and Aims Progressive multifocal leukoencephalopathy [PML], a brain infection associated with anti-integrin drugs that inhibit lymphocyte translocation from bloodstream to tissue, can be fatal. Decreased central nervous system [CNS] immune surveillance leading to this infection has been reported in patients with multiple sclerosis or Crohn’s disease treated with anti-integrin antibody natalizumab. PF-00547659 is an investigational human monoclonal antibody for inflammatory bowel disease, targeted against α4β7-mucosal addressin cell-adhesion molecule-1 [the integrin ligand selectively expressed in the gut]. We hypothesised that this selective agent would not affect central nervous system immune surveillance. Methods Cerebrospinal fluid from five healthy volunteers, and from 10 patients with Crohn’s disease previously treated with immunosuppressants, was evaluated to assess the feasibility of the study. Subsequently, 39 patients with active Crohn’s disease and previous immunosuppression were evaluated over 12 weeks of PF-00547659-induction therapy. We measured total lymphocytes, T cell subsets in cerebrospinal fluid, and circulating β7+ memory cells. Disease activity was assessed using the Harvey–Bradshaw Index. Results Patients treated with PF-00547659 had no reduction of cerebrospinal fluid lymphocytes, T-lymphocyte subsets, or CD4:CD8 ratio, whereas circulating β7+ memory cells increased significantly. A total of 28/35 [80%] patients had a clinical response and 27/34 [79%] had disease remission. Treatment-related adverse events, none serious, were reported in 23/49 [47%] patients. Conclusions In patients with active Crohn’s disease, natalizumab therapy increases the risk for PML, and the increased risk is thought to be associated with iatrogenic leukopenia within the CNS. PML under PF-00547659 may be a lesser concern, as this agent did not reduce lymphocytes or T cell subsets in the cerebrospinal fluid.

Anti-MAdCAM Antibody Increases ß7+ T Cells and CCR9 Gene Expression in the Peripheral Blood of Patients With Crohn’s Disease

Abstract Objective To define pharmacodynamic biomarkers in the peripheral blood of patients with Crohn’s disease [CD] after treatment with PF-00547659, an anti-human mucosal addressin cell adhesion molecule-1 [MAdCAM-1] monoclonal antibody. Methods In this Phase 2, randomised, double-blind, controlled study [OPERA], blood samples were analysed from patients with moderate to severe active CD who received placebo or 22.5 mg, 75 mg, or 225 mg of PF-00547659 subcutaneously at baseline and at Weeks 4 and 8, with follow-up at Week 12. Soluble MAdCAM [sMAdCAM] was measured by mass spectrometry, β7-expressing T cells by flow cytometry, and gene transcriptome by RNA sequencing. Results A slight increase in sMAdCAM was measured in the placebo group from baseline to Week 12 [6%], compared with significant decreases in all PF-00547659 groups [–87% to –98%]. A slight increase from baseline to Week 12 was observed in frequency and molecules of equivalent soluble fluorochrome for β7+ central memory T cells in the placebo group [4%], versus statistically significant increases in the active treatment groups [48% to 81%]. Similar trends were seen for β7+ effector memory T cells [placebo, 8%; PF-00547659, 84–138%] and β7+ naïve T cells [8%; 13–50%]. CCR9 gene expression had statistically significant up-regulation [p = 1.09e-06; false discovery rate < 0.1] with PF-00547659 treatment, and was associated with an increase in β7+ T cells. Conclusions Results of the OPERA study demonstrate positive pharmacology and dose-dependent changes in pharmacodynamic biomarker measurements in blood, including changes in cellular composition of lymphocytes and corresponding CCR9 gene expression changes.

Normal intrathecal leukocyte cell number and composition do not decrease the incidence of post–lumbar puncture headache

The pathogenesis of post-lumbar puncture headache (PLPH) has remained unclear. A beneficial role of CSF cells in the repair of a post-traumatic dural CSF leak has been suggested. The primary purpose of this study was to investigate the effects of 8weeks of induction therapy with high-dose PF-00547659 on the cellular elements of CNS immune surveillance in patients with active Crohns Disease and a history of immunosuppressive therapy (Clinicaltrials.govNCT01387594). PF-00547659 is a human monoclonal antibody that binds to mucosal addressin-cell adhesion molecule 1 (MAdCAM-1) on endothelial cells and blocks its interaction with beta7-integrin expressing lymphocytes. The study was executed in three parts or cohorts under two protocols. The incidence of a PLPH was 35% after the initial lumbar puncture, and 26% following the second lumbar puncture. After initiation of PF-00547659 anti-MAdCAM-1 therapy, there was a small and non-significant increase in the numbers of overall CSF leukocytes, and in lymphocyte subsets (CD3+, CD4+, and CD8+ T cells). The lymphocyte composition was unaltered by PF-00547659 anti-MAdCAM-1 therapy. Our observations suggest that normal numbers and composition of intrathecal leukocytes do not decrease the incidence of PLPH.