A Programme for Risk Assessment and Minimisation of Progressive Multifocal Leukoencephalopathy Developed for Vedolizumab Clinical Trials.

INTRODUCTION: Over the past decade, the potential for drug-associated progressive multifocal leukoencephalopathy (PML) has become an increasingly important consideration in certain drug development programmes, particularly those of immunomodulatory biologics. Whether the risk of PML with an investigational agent is proven (e.g. extrapolated from relevant experience, such as a class effect) or merely theoretical, the serious consequences of acquiring PML require careful risk minimisation and assessment. No single standard for such risk minimisation exists. Vedolizumab is a recently developed monoclonal antibody to α4ß7 integrin. Its clinical development necessitated a dedicated PML risk minimisation assessment as part of a global preapproval regulatory requirement. OBJECTIVE: The aim of this study was to describe the multiple risk minimisation elements that were incorporated in vedolizumab clinical trials in inflammatory bowel disease patients as part of the risk assessment and minimisation of PML programme for vedolizumab. METHODS: A case evaluation algorithm was developed for sequential screening and diagnostic evaluation of subjects who met criteria that indicated a clinical suspicion of PML. An Independent Adjudication Committee provided an independent, unbiased opinion regarding the likelihood of PML. RESULTS: Although no cases were detected, all suspected PML events were thoroughly reviewed and successfully adjudicated, making it unlikely that cases were missed. CONCLUSION: We suggest that this programme could serve as a model for pragmatic screening for PML during the clinical development of new drugs.

A Review of the Clinical Pharmacokinetics, Pharmacodynamics, and Immunogenicity of Vedolizumab.

Vedolizumab is a humanized anti-α4ß7 integrin monoclonal antibody that selectively blocks trafficking of memory T cells to inflamed gut tissue by inhibiting the α4ß7-mucosal addressin cell adhesion molecule-1 (MAdCAM-1) interaction. Approved for treating patients with moderately to severely active ulcerative colitis (UC) or Crohn's disease (CD), vedolizumab is administered as a 300 mg intravenous infusion. Vedolizumab undergoes a rapid, saturable, non-linear, target-mediated elimination process at low concentrations and a slower, linear, non-specific elimination process at higher concentrations. At therapeutic concentrations, vedolizumab primarily undergoes linear elimination. From population pharmacokinetic modeling, the vedolizumab terminal elimination half-life (t ½ ß) was estimated to be 25.5 days; linear clearance (CLL) was similar for patients with UC (0.159 L/day) and CD (0.155 L/day). Extreme low albumin concentrations and extreme high body weight values were potentially clinically important predictors of vedolizumab CLL. Other factors, including concomitant therapy use (methotrexate, azathioprine, mercaptopurine, or aminosalicylates) or prior tumor necrosis factor-α (TNF-α) antagonist use, had no clinically relevant effects on CLL. A positive exposure-efficacy relationship for clinical remission and clinical response was apparent for vedolizumab induction therapy in patients with UC or CD. On average, patients with higher albumin, lower fecal calprotectin (UC only), lower C-reactive protein (CD only), and no prior TNF-α antagonist use had a higher probability of remission. Off drug, 10% of patients with UC or CD were positive for anti-drug antibodies. This article provides a comprehensive review of the clinical pharmacokinetics, pharmacodynamics, exposure-efficacy relationships, and immunogenicity of vedolizumab.

Exposure-efficacy Relationships for Vedolizumab Induction Therapy in Patients with Ulcerative Colitis or Crohn's Disease.

BACKGROUND AND AIMS: A positive relationship between vedolizumab trough serum concentrations and clinical outcomes in patients with ulcerative colitis [UC] or Crohn's disease [CD] has been reported. Here we further explore exposure-efficacy relationships for vedolizumab induction therapy in post hoc analyses of GEMINI study data. METHODS: Vedolizumab trough concentrations at Week 6 or 10 were grouped in quartiles and clinical outcome rates calculated. Exposure-efficacy relationships at Week 6 and potential baseline covariate effects were explored using logistic regression and individual predicted cumulative average concentration through Week 6 [Caverage] as exposure measure. RESULTS: Higher vedolizumab concentrations were associated with higher clinical remission rates; the exposure-efficacy relationship was steeper for UC than CD. Unadjusted analyses overestimated the relationship, more so for CD. From covariate-adjusted models, average probability of remission at Week 6 increased by approximately 15% for UC and 10% for CD between Caverage values of 35 and 84 µg/ml [5th and 95th percentiles, respectively]. On average, patients with higher albumin, lower faecal calprotectin [UC only], lower C-reactive protein [CD only], and no previous tumour necrosis factor-α [TNFα] antagonist use had a higher remission probability. Previous TNFα antagonist use had the greatest impact; remission probability was approximately 10% higher in treatment-naïve patients. CONCLUSIONS: Higher vedolizumab serum concentrations were associated with higher remission rates after induction therapy in patients with moderately to severely active UC or CD. This relationship is affected by several factors, including previous TNFα antagonist use. Prospective studies are needed to assess vedolizumab dose individualisation and optimisation.

HER2-positive breast cancer targeting and treatment by a peptide-conjugated mini nanodrug.

HER2+ breast cancer is one of the most aggressive forms of breast cancer. The new polymalic acid-based mini nanodrug copolymers are synthesized and specifically characterized to inhibit growth of HER2+ breast cancer. These mini nanodrugs are highly effective and in the clinic may substitute for trastuzumab (the marketed therapeutic antibody) and antibody-targeted nanobioconjugates. Novel mini nanodrugs are designed to have slender shape and small size. HER2+ cells were recognized by the polymer-attached trastuzumab-mimetic 12-mer peptide. Synthesis of the nascent cell-transmembrane HER2/neu receptors by HER2+ cells was inhibited by antisense oligonucleotides that prevented cancer cell proliferation and significantly reduced tumor size by more than 15 times vs. untreated control or PBS-treated group. We emphasize that the shape and size of mini nanodrugs can enhance penetration of multiple bio-barriers to facilitate highly effective treatment. Replacement of trastuzumab by the mimetic peptide favors reduced production costs and technical efforts, and a negligible immune response.

The safety of vedolizumab for ulcerative colitis and Crohn's disease.

OBJECTIVE: Vedolizumab is a gut-selective antibody to α4ß7 integrin for the treatment of ulcerative colitis (UC) and Crohn's disease (CD). We report an integrated summary of the safety of vedolizumab. DESIGN: Safety data (May 2009-June 2013) from six trials of vedolizumab were integrated. Adverse events were evaluated in patients who received ≥1 dose of vedolizumab or placebo and were reported as exposure-adjusted incidence rates as the number of patients experiencing the event per 100 person-years (PYs) of exposure. Predictors of serious infection were assessed using a Cox proportional hazards model. RESULTS: In total, 2830 patients had 4811 PYs of vedolizumab exposure (median exposure range, 1-1977 days). No increased risk of any infection or serious infection was associated with vedolizumab exposure. Serious clostridial infections, sepsis and tuberculosis were reported infrequently (≤0.6% of patients). No cases of progressive multifocal leucoencephalopathy were observed. Independent risk factors for serious infection in UC were prior failure of a tumour necrosis factor α antagonist (HR, 1.99; 95% CIs 1.16 to 3.42; p=0.0122) and narcotic analgesic use (HR, 2.68; 95% CI 1.57 to 4.58; p=0.0003), and in CD were younger age (HR, 0.97; 95% CI 0.95 to 0.98; p<0.0001), corticosteroid (HR, 1.88; 95% CI 1.35 to 2.63; p=0.0002) or narcotic analgesic use (HR, 2.72; 95% CI 1.90 to 3.89; p<0.0001). Investigator-defined infusion-related reactions were reported for ≤5% of patients in each study. Eighteen vedolizumab-exposed patients (<1%) were diagnosed with a malignancy. CONCLUSIONS: Vedolizumab has a favourable safety profile with low incidence rates of serious infections, infusion-related reactions and malignancies over an extended treatment period. TRIAL REGISTRATION NUMBER: NCT01177228, NCT00619489, NCT00783718, NCT00783692, NCT01224171, NCT00790933.

Simultaneous blockade of interacting CK2 and EGFR pathways by tumor-targeting nanobioconjugates increases therapeutic efficacy against glioblastoma multiforme.

Glioblastoma multiforme (GBM) remains the deadliest brain tumor in adults. GBM tumors are also notorious for drug and radiation resistance. To inhibit GBMs more effectively, polymalic acid-based blood-brain barrier crossing nanobioconjugates were synthesized that are delivered to the cytoplasm of cancer cells and specifically inhibit the master regulator serine/threonine protein kinase CK2 and the wild-type/mutated epidermal growth factor receptor (EGFR/EGFRvIII), which are overexpressed in gliomas according to The Cancer Genome Atlas (TCGA) GBM database. Two xenogeneic mouse models bearing intracranial human GBMs from cell lines LN229 and U87MG that expressed both CK2 and EGFR at different levels were used. Simultaneous knockdown of CK2α and EGFR/EGFRvIII suppressed their downstream prosurvival signaling. Treatment also markedly reduced the expression of programmed death-ligand 1 (PD-L1), a negative regulator of cytotoxic lymphocytes. Downregulation of CK2 and EGFR also caused deactivation of heat shock protein 90 (Hsp90) co-chaperone Cdc37, which may suppress the activity of key cellular kinases. Inhibition of either target was associated with downregulation of the other target as well, which may underlie the increased efficacy of the dual nanobioconjugate that is directed against both CK2 and EGFR. Importantly, the single nanodrugs, and especially the dual nanodrug, markedly suppressed the expression of the cancer stem cell markers c-Myc, CD133, and nestin, which could contribute to the efficacy of the treatments. In both tumor models, the nanobioconjugates significantly increased (up to 2-fold) animal survival compared with the PBS-treated control group. The versatile nanobioconjugates developed in this study, with the abilities of anti-cancer drug delivery across biobarriers and the inhibition of key tumor regulators, offer a promising nanotherapeutic approach to treat GBMs, and to potentially prevent drug resistance and retard the recurrence of brain tumors.

Vedolizumab Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability Following Administration of a Single, Ascending, Intravenous Dose to Healthy Volunteers.

BACKGROUND AND OBJECTIVES: Vedolizumab, a humanized monoclonal antibody against the α4ß7 integrin, is indicated for treatment of moderately to severely active ulcerative colitis or Crohn's disease. In this placebo-controlled, double-blind, randomized, single ascending-dose study, the pharmacokinetics, pharmacodynamics, safety, and tolerability of vedolizumab were evaluated in healthy volunteers. METHODS: Forty-nine participants (in five cohorts) were randomly assigned in a 4:1 ratio to receive a single intravenous infusion of either vedolizumab (0.2, 0.5, 2.0, 6.0, or 10.0 mg/kg) or placebo. Blood samples were collected for measurement of vedolizumab serum concentrations and α4ß7 saturation on peripheral blood lymphocytes by vedolizumab. Pharmacokinetic parameters were computed using a non-compartmental approach. Adverse events were monitored. RESULTS: Vedolizumab maximum observed serum concentration (C max) demonstrated dose proportionality over the dose range tested. Greater than dose-proportional increases in area under the serum concentration-time curve from time 0 to infinity (AUC0-inf) and shorter terminal elimination half-life (t 1/2) were observed from 0.2 to 2.0 mg/kg, suggestive of nonlinear pharmacokinetics at lower doses. At doses higher than 2.0 mg/kg, these parameters increased dose proportionally. Saturation of α4ß7 was at or near maximal levels (>90 %) at all doses and time points when vedolizumab was measurable in serum. A total of 21 of 39 (54 %) vedolizumab-treated participants were anti-drug antibody (ADA) positive, and 11 (28 %) were persistently ADA positive. Overall, no adverse event signals, including serious infections or malignancies, were apparent. CONCLUSIONS: Vedolizumab exhibited target-mediated disposition, characterized by a rapid, saturable, nonlinear elimination process at low concentrations and a slower linear elimination process at higher concentrations. Nearly complete α4ß7 saturation was observed at all doses. A single intravenous infusion of vedolizumab was well tolerated by healthy volunteers.

Occurrence of adverse events among patients with inflammatory bowel disease in the HealthCore Integrated Research Database.

OBJECTIVES: Inflammatory bowel disease (IBD) is a chronic condition commonly requiring lifelong care. Both IBD and IBD-related treatments can cause significant morbidity, and it is often difficult to differentiate their relative etiologic contribution to adverse events (AEs). The objectives of this study were to assess the rates of select AEs among patients with IBD as a function of disease severity and of the use of anti-tumor necrosis factor alpha (anti-TNFα) medications. METHODS: We conducted a retrospective cohort study of IBD patients in the HealthCore Integrated Research Database (HIRD(TM)) between January 2004 and January 2011 to determine rates of AEs in patients with mild and moderate to severe IBD. Key study endpoints were select prespecified malignant neoplasms, infections, and other AEs of interest. RESULTS: A total of 33,386 IBD patients (52.7% ulcerative colitis; 47.3% Crohn's disease) met the inclusion criteria, and 60% had been followed for ≥1 year. Patients with moderate to severe IBD had increased rates of infections, lymphatic and digestive tract cancers, gastrointestinal (GI) perforations, and myocardial infarctions versus patients with mild IBD. Patients with IBD who used anti-TNFα therapies during the study had increased incidence of many types of infections, certain GI cancers (including rectal and anal cancer), intestinal perforations, and kidney stones compared with patients who had never used anti-TNFα therapies. CONCLUSIONS: Results from this large US cohort provide descriptive information on AE rates in a population of IBD patients undergoing routine care, estimating background incidence rates of AEs that are not readily available in the published literature. Our study findings may be limited owing to a lack of generalizability and potential for misclassification due to reliance on medical diagnosis and treatment and procedure codes to identify disease, comorbidities, and treatments. Further research and validation of our findings in other populations and databases are needed.

Effects of vedolizumab induction therapy for patients with Crohn's disease in whom tumor necrosis factor antagonist treatment failed.

BACKGROUND & AIMS: There is an increasing need for new treatments for patients with Crohn's disease (CD) in whom previous therapy with tumor necrosis factor (TNF) antagonists has failed. We performed a placebo-controlled, phase 3, double-blind trial to evaluate the efficacy and safety of vedolizumab, an antibody against the integrin α4ß7, as induction therapy. METHODS: Patients with moderately to severely active CD (CD activity index [CDAI] score, 220-400 points) were assigned randomly to groups given vedolizumab (300 mg) or placebo intravenously at weeks 0, 2, and 6. The primary analysis involved 315 patients with previous TNF antagonist failure (ie, an inadequate response to, loss of response to, or intolerance of ≥1 TNF antagonists); we determined the proportion of patients in clinical remission (CDAI, ≤150 points) at week 6. Secondary analyses evaluated outcomes at weeks 6 and 10 in this population and in the overall population (N = 416), which included patients naive to TNF antagonist therapy (n = 101). RESULTS: Among patients who had experienced previous TNF antagonist failure, 15.2% of those given vedolizumab and 12.1% of those given placebo were in remission at week 6 (P = .433). At week 10, a higher proportion of this population given vedolizumab was in remission (26.6%) than those given placebo (12.1%) (nominal P = .001; relative risk, 2.2; 95% confidence interval, 1.3-3.6). A higher proportion of patients with previous TNF antagonist failure given vedolizumab also had a CDAI-100 response (≥100-point decrease in CDAI score from baseline) at week 6 than those given placebo (39.2% vs 22.3%; nominal P = .001; relative risk, 1.8; 95% confidence interval, 1.2-2.5). Adverse event results were similar among all groups. CONCLUSIONS: Vedolizumab was not more effective than placebo in inducing clinical remission at week 6 among patients with CD in whom previous treatment with TNF antagonists had failed. The therapeutic benefits of vedolizumab in these patients were detectable at week 10. ClinicalTrials.gov number: NCT01224171.

Vedolizumab as induction and maintenance therapy for Crohn's disease.

BACKGROUND: The efficacy of vedolizumab, an α4ß7 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.).

Long-term clinical experience with vedolizumab in patients with inflammatory bowel disease.

BACKGROUND: Vedolizumab, a gut-selective, anti-inflammatory monoclonal antibody, has shown preliminary efficacy in ulcerative colitis (UC) and Crohn's disease (CD). We report long-term experience with vedolizumab for active UC and CD. METHODS: After a placebo-controlled study, 38 patients with UC were randomized to a loading regimen of vedolizumab 2, 6, or 10 mg/kg on days 1, 15, and 43, followed by maintenance dosing every 8 weeks. Thirty-four vedolizumab-naive patients (15 UC; 19 CD) were randomized to vedolizumab 2, 6, or 10 mg/kg on the same schedule. Rollover patients were treated up to 630 days and treatment-naive patients were treated up to 547 days. RESULTS: Seventy-two patients were dosed; 52 (72%) completed the study. In exploratory analyses, 28 of 72 (39%; UC: 21 of 53, CD: 7 of 19) achieved clinical response and 42 of 72 (58.3%; UC: 38 of 53, CD: 4 of 19) achieved clinical remission. Mean partial Mayo scores declined from baseline through day 155 in both treatment-naive patients with UC (5.4 to 1.7, respectively) and rollover patients with UC (2.3 to 1.4, respectively), leveling off thereafter. Mean Crohn's Disease Activity Index scores decreased from 295 (baseline) to 238 at day 43, continued to trend downward through day 155, and remained below baseline through day 491. Mean Inflammatory Bowel Disease Questionnaire scores increased in all treatment groups. No deaths or systemic opportunistic infections were reported. CONCLUSION: Vedolizumab every 8 weeks for up to 78 weeks had an adverse event profile similar to that previously observed. Mean disease activity indices (partial Mayo score and Crohn's Disease Activity Index score) improved with all 3 doses investigated.