First-in-human, randomized dose-escalation study of the safety, tolerability, pharmacokinetics, pharmacodynamics and immunogenicity of PF-06480605 in healthy subjects.

AIMS: Human genetic, tissue expression, proteomics, transcriptomics and nonclinical studies implicate tumour necrosis factor α-like ligand 1A (TL1A) as a novel target in inflammatory bowel disease (IBD). PF-06480605, a fully human immunoglobulin G1 monoclonal antibody, targets TL1A. This first-in-human, Phase 1, dose-escalation study assessed safety, tolerability, pharmacokinetics, pharmacodynamics and immunogenicity of intravenous (IV) and subcutaneous (SC) PF-06480605 in healthy subjects (NCT01989143). METHODS: Ninety-two subjects were randomized to single ascending doses (SAD), PF-06480605 1 mg, 3 mg, 10 mg, 30 mg, 100 mg, 300 mg, 600 mg or 800 mg IV, or multiple ascending doses (MAD), PF-06480605 3 × 500 mg IV, or 3 × 30 mg, 3 × 100 mg, or 3 × 300 mg SC every 2 weeks for three doses, or placebo. Safety, tolerability, pharmacokinetics, immunogenicity profiles and total TL1A, anti-drug antibody (ADA) and neutralizing antibody (NAb) levels were assessed at pre-determined times. RESULTS: PF-06480605 SAD up to 800 mg IV and MAD up to 300 mg ×3 SC and 500 mg ×3 IV were well tolerated. Overall, there were 45 and 44 treatment-emergent adverse events in SAD and MAD cohorts, respectively, and no deaths or serious adverse events. PF-06480605 exposure generally increased dose-dependently. ADA and NAb levels did not impact safety, pharmacokinetics, or pharmacodynamics at higher doses. Target engagement was demonstrated through dose-dependent differences in serum total soluble TL1A concentrations for PF-06480605 vs placebo cohorts. CONCLUSIONS: PF-06480605 was generally well tolerated, and binding of soluble TL1A was maintained throughout the dose interval, supporting further study of PF-06480605 in patients with IBD and other inflammatory conditions.

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 ß7+ 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 ß7+ central memory T cells. TRIAL REGISTRATION NUMBER: NCT01276509; Results.

Dietary Patterns and Colorectal Cancer Risk: A Review of 17 Years of Evidence (2000-2016).

PURPOSE OF REVIEW: Colorectal cancer (CRC) is a global public health problem, with an estimated 1.4 million cases diagnosed worldwide in 2012. Evidence suggests that diet may be important for primary prevention. RECENT FINDINGS: The 2017 WCRF/AICR Continuous Update Project on colorectal cancer concluded that there is convincing evidence linking several individual dietary factors with CRC risk but the evidence for dietary patterns was limited and inconclusive. Also, previous reviews and meta-analyses have not critically synthesized various dietary patterns. This review synthesized data from dietary patterns studies over a 17-year period from 2000 to 2016. SUMMARY: We included 49 studies (28 cohort and 21 case-control) that examined the association of index-based and empirically-derived dietary patterns and CRC risk. A synthesis of food group components comprising the different index-based and empirically-derived patterns revealed two distinct dietary patterns associated with CRC risk. A "healthy" pattern, generally characterized by high intake of fruits and vegetables, wholegrains, nuts and legumes, fish and other seafood, milk and other dairy products, was associated with lower CRC risk. In contrast, the "unhealthy" pattern, characterized by high intakes of red meat, processed meat, sugar-sweetened beverages, refined grains, desserts and potatoes was associated with higher CRC risk. It is notable that the number of food groups, the intake quantity, the exact types of foods in each food group, differed between populations, yet the two dietary patterns remained consistent across regions, especially in empirically-derived patterns, an indication of the high reproducibility of these patterns. However, findings for CRC risk in both index-based and empirically-derived patterns, differed by sex, with stronger associations among men than women; study design, a higher proportion of case-control studies reported significant findings compared to prospective studies. Consuming a dietary pattern high in fruits and vegetables and low in meats and sweets is protective against CRC risk. However, important questions remain about mechanisms underlying differences by sex; life-course timing of exposure to dietary patterns; interaction of dietary patterns with the microbiome or with lifestyle factors including physical activity; and elucidation of subsite differences.

Dietary Patterns and the Risk of Colorectal Cancer.

Diet and lifestyle play a significant role in the development of colorectal cancer, but the full complexity of the association is not yet understood. Dietary pattern analysis is an important new technique that may help to elucidate the relationship. This review examines the most common techniques for extrapolating dietary patterns and reviews dietary pattern/colorectal cancer studies published between September 2011 and August 2012. The studies reviewed are consistent with prior research but include a more diverse international population. Results from investigations using a priori dietary patterns (i.e., diet quality scores) and a posteriori methods, which identify existing eating patterns (i.e., principal component analysis), continue to support the benefits of a plant-based diet with some dairy as a means to lower the risk of colorectal cancer, whereas a diet high in meats, refined grains, and added sugar appears to increase risk. The association between colorectal cancer and alcohol remains unclear.

Dietary patterns of women are associated with incident abdominal obesity but not metabolic syndrome.

Data on the relationship between empirical dietary patterns and metabolic syndrome (MetS) and its components in prospective study designs are limited. In addition, demographic and lifestyle determinants of MetS may modify the association between dietary patterns and the syndrome. We prospectively examined the relationship between empirically derived patterns and MetS and MetS components among 1146 women in the Framingham Offspring/Spouse cohort. They were aged 25-77 y with BMI ≥18.5 kg/m(2) and free of cardiovascular disease, diabetes, cancer, and MetS at baseline, and followed for a mean of 7 y. Five dietary patterns, Heart Healthier, Lighter Eating, Wine and Moderate Eating, Higher Fat, and Empty Calorie, were previously identified using cluster analysis from food intake collected using a FFQ. After adjusting for potential confounders, we observed lower odds for abdominal obesity for Higher Fat [OR = 0.48 (95% CI: 0.25, 0.91)] and Wine and Moderate Eating clusters [OR = 0.28 (95% CI: 0.11, 0.72)] compared with the Empty Calorie cluster. Additional adjustment for BMI somewhat attenuated these OR [Higher Fat OR = 0.52 (95% CI: 0.27, 1.00); Wine and Moderate Eating OR = 0.34 (95% CI: 0.13, 0.89)]. None of the clusters was associated with MetS or other MetS components. Baseline smoking status and age did not modify the relation between dietary patterns and MetS. The Higher Fat and Wine and Moderate Eating patterns showed an inverse association with abdominal obesity; certain foods might be targeted in these habitual patterns to achieve optimal dietary patterns for MetS prevention.

Associations of carotid artery intima-media thickness (IMT) with risk factors and prevalent cardiovascular disease: comparison of mean common carotid artery IMT with maximum internal carotid artery IMT.

OBJECTIVE: The goal of this study was to compare internal carotid artery (ICA) intima-media thickness (IMT) with common carotid artery (CCA) IMT as global markers of cardiovascular disease (CVD). METHODS: Cross-sectional measurements of the mean CCA IMT and maximum ICA IMT were made on ultrasound images acquired from the Framingham Offspring cohort (n = 3316; mean age, 58 years; 52.7% women). Linear regression models were used to study the associations of the Framingham risk factors with CCA and ICA IMT. Multivariate logistic regression models and receiver operating characteristic (ROC) curve analysis were used to compare the associations of prevalent CVD with CCA and ICA IMT and determine sensitivity and specificity. RESULTS: The association between age and the mean CCA IMT corresponded to an increase of 0.007 mm/y; the increase was 0.037 mm/y for the ICA IMT. Framingham risk factors accounted for 28.6% and 27.5% of the variability in the CCA and ICA IMT, respectively. Age and gender contributed 23.5% to the variability of the CCA IMT and 22.5% to that of the ICA IMT, with the next most important factor being systolic blood pressure (1.9%) for the CCA IMT and smoking (1.6%) for the ICA IMT. The CCA IMT and ICA IMT were statistically significant predictors of prevalent CVD, with the ICA IMT having a larger area under the ROC curve (0.756 versus 0.695). CONCLUSIONS: Associations of risk factors with CCA and ICA IMT are slightly different, and both are independently associated with prevalent CVD. Their value for predicting incident cardiovascular events needs to be compared in outcome studies.