Tim Wyant

Vedolizumab as Induction and Maintenance Therapy for Ulcerative Colitis

BACKGROUND Gut-selective blockade of lymphocyte trafficking by vedolizumab may constitute effective treatment for ulcerative colitis. METHODS We conducted two integrated randomized, double-blind, placebo-controlled trials of vedolizumab in patients with active disease. In the trial of induction therapy, 374 patients (cohort 1) received vedolizumab (at a dose of 300 mg) or placebo intravenously at weeks 0 and 2, and 521 patients (cohort 2) received open-label vedolizumab at weeks 0 and 2, with disease evaluation at week 6. In the trial of maintenance therapy, patients in either cohort who had a response to vedolizumab at week 6 were randomly assigned to continue receiving vedolizumab every 8 or 4 weeks or to switch to placebo for up to 52 weeks. A response was defined as a reduction in the Mayo Clinic score (range, 0 to 12, with higher scores indicating more active disease) of at least 3 points and a decrease of at least 30% from baseline, with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1. RESULTS Response rates at week 6 were 47.1% and 25.5% among patients in the vedolizumab group and placebo group, respectively (difference with adjustment for stratification factors, 21.7 percentage points; 95% confidence interval [CI], 11.6 to 31.7; P<0.001). At week 52, 41.8% of patients who continued to receive vedolizumab every 8 weeks and 44.8% of patients who continued to receive vedolizumab every 4 weeks were in clinical remission (Mayo Clinic score ≤2 and no subscore >1), as compared with 15.9% of patients who switched to placebo (adjusted difference, 26.1 percentage points for vedolizumab every 8 weeks vs. placebo [95% CI, 14.9 to 37.2; P<0.001] and 29.1 percentage points for vedolizumab every 4 weeks vs. placebo [95% CI, 17.9 to 40.4; P<0.001]). The frequency of adverse events was similar in the vedolizumab and placebo groups. CONCLUSIONS Vedolizumab was more effective than placebo as induction and maintenance therapy for ulcerative colitis. (Funded by Millennium Pharmaceuticals; GEMINI 1 ClinicalTrials.gov number, NCT00783718.).

The Binding Specificity and Selective Antagonism of Vedolizumab, an Anti-α4β7 Integrin Therapeutic Antibody in Development for Inflammatory Bowel Diseases

Vedolizumab is a humanized monoclonal antibody that targets the α4β7 integrin exclusively, and modulates inflammation in the gastrointestinal tract without inducing the systemic immunosuppression that characterizes anti-α4 chain monoclonal antibodies, such as natalizumab. This unique pharmacologic profile is largely attributable to four determinants. The first determinant is the restriction of the expression of the α4β7 integrin to subsets of leukocytes. Vedolizumab does not bind to the majority of memory CD4+ T lymphocytes (60%), neutrophils, and most monocytes. The highest level of vedolizumab binding is to a subset (∼25%) of human peripheral blood memory CD4+ T lymphocytes that include gut-homing interleukin 17 T-helper lymphocytes. Vedolizumab also binds to eosinophils at high levels, and to naive T-helper lymphocytes, naive and memory cytotoxic T lymphocytes, B lymphocytes, natural killer cells, and basophils at lower levels; vedolizumab binds to memory CD4+ T and B lymphocytes with subnanomolar potency (EC50 = 0.3–0.4 nM). The second determinant is binding specificity; vedolizumab binds exclusively to the α4β7 integrin, and not to the α4β1 and αEβ7 integrins. The third determinant is selective antagonism; vedolizumab selectively inhibits adhesion of α4β7-expressing cells to mucosal addressin cell adhesion molecule 1 (median inhibition concentration [IC50] = 0.02–0.06 μg/ml) and fibronectin (IC50 = 0.02 μg/ml), but not vascular cell adhesion molecule 1. The fourth determinant is the gastrointestinal-specific tropism of the α4β7 integrin function. These pharmacologic properties of vedolizumab, in conjunction with the gastrointestinal tropism of α4β7 integrin function, may ultimately confer an improved risk-to-benefit profile for patients with inflammatory bowel diseases.

Vedolizumab for the treatment of active ulcerative colitis: A randomized controlled phase 2 dose‐ranging study

Background: Vedolizumab is a gut‐selective biologic that has shown efficacy in ulcerative colitis (UC) and Crohns disease (CD). We studied the pharmacokinetics, pharmacodynamics, safety, tolerability, and efficacy of a new formulation of vedolizumab produced by an improved manufacturing process. Methods: UC patients were randomized to receive vedolizumab (2, 6, or 10 mg/kg) or placebo on days 1, 15, 29, and 85. Safety, pharmacokinetics, pharmacodynamics, and immunogenicity evaluations were performed at multiple timepoints through day 253. Partial Mayo Scores and fecal calprotectin levels were used to assess efficacy. Results: In all, 46 patients (9 placebo, 37 vedolizumab) received at least one dose of study medication. The vedolizumab serum concentration declined monoexponentially until concentrations reached 1–10 &mgr;g/mL, and then fell nonlinearly. Vedolizumab maximum serum concentration (Cmax) and area under the curve (AUC) increased approximately proportionally as a function of dose. Vedolizumab maximally saturated &agr;4&bgr;7 receptors on peripheral serum lymphocytes at all measurable serum concentrations. Vedolizumab was well tolerated, with no deaths and no adverse events leading to discontinuation. At every assessment from day 29 through day 253, over 50% of vedolizumab‐treated patients were in clinical response, while placebo response rates generally ranged between 22% and 33%. Vedolizumab treatment reduced fecal calprotectin levels compared with placebo. Conclusions: Vedolizumab demonstrated dose‐proportional pharmacokinetics and maximally saturated &agr;4&bgr;7 receptors over the tested dose range. Multiple dosing up to 10 mg/kg was well tolerated. Over the course of follow‐up a greater proportion of patients treated with vedolizumab were in clinical response than those who were assigned to placebo. (Inflamm Bowel Dis 2012)

Population pharmacokinetics‐pharmacodynamics of vedolizumab in patients with ulcerative colitis and Crohn's disease

Vedolizumab, an anti‐α4β7 integrin monoclonal antibody (mAb), is indicated for treating patients with moderately to severely active ulcerative colitis (UC) and Crohns disease (CD). As higher therapeutic mAb concentrations have been associated with greater efficacy in inflammatory bowel disease, understanding determinants of vedolizumab clearance may help to optimise dosing.

Effect of CC chemokine receptor 2 CCR2 blockade on serum C-reactive protein in individuals at atherosclerotic risk and with a single nucleotide polymorphism of the monocyte chemoattractant protein-1 promoter region.

CC chemokine receptor 2 (CCR2), expressed on the surface of circulating monocytes, and its ligand monocyte chemoattractant protein-1 (MCP-1; also known as CC-chemokine ligand 2) are present in atherosclerotic plaques and may have important roles in endothelial monocyte recruitment and activation. MLN1202 is a highly specific humanized monoclonal antibody that interacts with CCR2 and inhibits MCP-1 binding. The aim of this randomized, double-blind, placebo-controlled study was to measure reductions in circulating levels of high-sensitivity C-reactive protein, an established biomarker of inflammation associated with coronary artery disease, on MLN1202 treatment in patients at risk for atherosclerotic cardiovascular disease (≥2 risk factors for atherosclerotic cardiovascular disease and circulating high-sensitivity C-reactive protein >3 mg/L). Additionally, patients were genotyped for the 2518 A→G polymorphism in the promoter of the MCP-1 gene to investigate the correlation between this polymorphism and reduced C-reactive protein levels with MLN1202 treatment. Patients who received MLN1202 exhibited significant decreases in high-sensitivity C-reactive protein levels, beginning at 4 weeks and continuing through 12 weeks after dosing. Patients with A/G or G/G genotypes in the MCP-1 promoter had significantly greater reductions in high-sensitivity C-reactive protein levels than patients with the wild-type A/A genotype. In conclusion, MLN1202 treatment was well tolerated in this patient population and resulted in significant reductions in high-sensitivity C-reactive protein levels.

Exclusive antagonism of the α4β7 integrin by vedolizumab confirms the gut-selectivity of this pathway in primates†

Background: Biological therapies that antagonize specific molecules have demonstrated efficacy in inflammatory bowel diseases, but infections resulting from systemic immunosuppression underscore the need for safer therapies. The objective of this investigation was to determine if antagonism of the &agr;4&bgr;7 integrin would exclusively yield gut‐selective antiinflammatory activity in primates. Methods: A series of experiments were conducted to investigate potential intra‐ and extraintestinal effects in healthy nonhuman primates dosed repeatedly with the &agr;4&bgr;7‐exclusive antagonist vedolizumab (former versions: MLN0002, MLN02, LDP‐02) for 4, 13, and 26 weeks. Results: No adverse clinical effects of vedolizumab were observed in healthy cynomolgus monkeys up to the highest doses tested (100 mg/kg). Histomorphologic analyses indicated a reduction in the frequency of leukocytes in gastrointestinal tissue, but not other organs. A significant (P < 0.05) decrease in the frequency of &bgr;Symbol lymphocytes in gastrointestinal tissues corresponded to a significant (P < 0.05) increase in &agr;4&bgr;Symbol memory helper T lymphocytes in peripheral blood. This elevation was specific to &agr;4&bgr;Symbol memory helper T lymphocytes; levels of other leukocyte subsets remained unaffected. Systemic opportunistic infections were not observed, and vedolizumab did not inhibit adaptive or innate immune responses systemically. Symbol. No caption available. Symbol. No caption available. Symbol. No caption available. Conclusions: These data demonstrate that blocking the &agr;4&bgr;7 integrin exclusively yields gut‐selective antiinflammatory activity in primates. (Inflamm Bowel Dis 2012;)

Vedolizumab affects antibody responses to immunisation selectively in the gastrointestinal tract: randomised controlled trial results.

Objective The α4β7 integrin monoclonal antibody vedolizumab is hypothesised to be gut selective. Effects of vedolizumab on immune responses to parenterally or enterally administered antigens were investigated. Design In this randomised, double-blind, placebo-controlled, phase I trial, healthy participants received a single intravenous dose of vedolizumab 750 mg (n=64) or placebo (n=63). After 4 days, participants began intramuscular hepatitis B vaccine (HBV; days 4, 32, 60) and oral cholera vaccine (OCV; days 4, 18) regimens. The study was designed to demonstrate a 15% non-inferiority margin for the between-group difference in the primary end point: percentage of participants with HBV seroconversion at day 74 (serum hepatitis B surface antigen (HBs) antibody titre ≥10 IU/L). OCV seroconversion at day 74 (>4-fold increase in serum cholera toxin (CT) antibodies) was a secondary end point. Results A total of 56 (90.3%) placebo-treated and 54 (88.5%) vedolizumab-treated participants responded to HBV. Geometric mean anti-HBs titres were similar for placebo (114.4 IU/L) and vedolizumab (129.6 IU/L) at day 74. A total of 60 (96.8%) placebo-treated and 52 (82.5%) vedolizumab-treated participants responded to OCV at day 74. Geometric mean anti-CT IgG levels were higher for placebo than for vedolizumab at day 74 (9210.08 vs 3007.8 ELISA Units (EU)/mL) and day 32 (11629.3 vs 1575.4 EU/mL). Anti-CT IgA results were similar. Adverse events were consistent with previous experience. One serious adverse event (spontaneous abortion) was reported for placebo. Conclusions Vedolizumab did not alter the response to parenterally administered antigens but reduced the response to oral antigens, demonstrating its gut-selective mechanism of action. Trial registration number NCT Number: 01981616; EudraCT Number: 2011-001874-24.

Vedolizumab, a monoclonal antibody to the gut homing α4β7 integrin, does not affect cerebrospinal fluid T-lymphocyte immunophenotype

Vedolizumab, a gut-homing α4β7 integrin antagonist, has demonstrated efficacy in ulcerative colitis and Crohns disease. Development of progressive multifocal leukoencephalopathy, a serious brain infection associated with natalizumab (an α4β7 and α4β1 integrin antagonist), has raised concern that vedolizumab may convey a similar risk. Natalizumab is believed to impair central nervous system immune surveillance by affecting cerebrospinal fluid (CSF) lymphocyte counts and the CD4:CD8 ratio. To determine if vedolizumab elicits similar effects, we examined CSF of healthy volunteers by flow cytometry for T-lymphocyte surface markers 5 weeks after administration of intravenous vedolizumab 450 mg. No significant changes were observed in CSF T-lymphocyte populations.

Antagonizing the α4β1 Integrin, but Not α4β7, Inhibits Leukocytic Infiltration of the Central Nervous System in Rhesus Monkey Experimental Autoimmune Encephalomyelitis

The immune system is characterized by the preferential migration of lymphocytes through specific tissues (i.e., tissue tropism). Tissue tropism is mediated, in part, by the α4 integrins expressed by T lymphocytes. The α4β1 integrin mediates migration of memory T lymphocytes into the CNS, whereas the α4β7 integrin mediates migration preferentially into gastrointestinal tissue. This paradigm was established primarily from investigations in rodents; thus, the objective of this investigation was to determine if blocking the α4β7 integrin exclusively would affect migration of T lymphocytes into the CNS of primates. The effects of the dual α4β1 and α4β7 antagonist natalizumab were compared with those of the α4β7 antagonist vedolizumab on experimental autoimmune encephalomyelitis in the rhesus monkey. Animals received an initial i.v. bolus of placebo, natalizumab (30 mg/kg), or vedolizumab (30 mg/kg) before intracutaneous immunization with recombinant human myelin oligodendrocyte glycoprotein and then Ab once weekly thereafter. Natalizumab prevented CNS inflammation and demyelination significantly (p < 0.05), compared with time-matched placebo control animals, whereas vedolizumab did not inhibit these effects, despite saturating the α4β7 integrin in each animal for the duration of the investigation. These results demonstrate that blocking α4β7 exclusively does not inhibit immune surveillance of the CNS in primates.

Why CCR2 and CCR5 blockade failed and why CCR1 blockade might still be effective in the treatment of rheumatoid arthritis

Background The aim of this study was to provide more insight into the question as to why blockade of CCR1, CCR2, and CCR5 may have failed in clinical trials in rheumatoid arthritis (RA) patients, using an in vitro monocyte migration system model. Methodology/Principal Findings Monocytes from healthy donors (HD; n = 8) or from RA patients (for CCR2 and CCR5 antibody n = 8; for CCR1 blockade n = 13) were isolated from peripheral blood and pre-incubated with different concentrations of either anti-CCR1, anti-CCR2, or anti-CCR5 blocking antibodies (or medium or isotype controls). In addition, a small molecule CCR1 antagonist (BX471) was tested. Chemotaxis was induced by CCL2/MCP-1 (CCR2 ligand), CCL5/RANTES (CCR1 and CCR5 ligand), or by a mix of 5 RA synovial fluids (SFs), and cellular responses compared to chemotaxis in the presence of medium alone. Anti-CCR2 antibody treatment blocked CCL2/MCP-1-induced chemotaxis of both HD and RA monocytes compared to isotype control. Similarly, anti-CCR5 antibody treatment blocked CCL5/RANTES-induced chemotaxis of RA monocytes. While neither CCR2 nor CCR5 blocking antibodies were able to inhibit SF-induced monocyte chemotaxis, even when both receptors were blocked simultaneously, both anti-CCR1 antibodies and the CCR1 antagonist were able to inhibit SF-induced monocyte chemotaxis. Conclusions/Significance The RA synovial compartment contains several ligands for CCR1, CCR2, and CCR5 as well as other chemokines and receptors involved in monocyte recruitment to the site of inflammation. The results suggest that CCR2 and CCR5 are not critical for the migration of monocytes towards the synovial compartment in RA. In contrast, blockade of CCR1 may be effective. Conceivably, CCR1 blockade failed in clinical trials, not because CCR1 is not a good target, but because very high levels of receptor occupancy at all times may be needed to inhibit monocyte migration in vivo.