13 research outputs found
Pharmacokinetics and pharmacodynamics of itepekimab in adults with moderateâtoâsevere atopic dermatitis: Results from two terminated phase II trials
Interleukin-33 (IL-33) is a proinflammatory alarmin cytokine released by damaged epithelial tissue cells that initiates and amplifies both type 1 and type 2 inflammatory cascades. A role for IL-33 in atopic dermatitis (AD; a chronic, relapsing type 2 inflammatory disease of the skin) has been proposed. Itepekimab is a novel human IgG4P monoclonal antibody against IL-33, currently in clinical development for chronic obstructive pulmonary disease (COPD). Two global phase II studiesâa dose-ranging itepekimab monotherapy study (NCT03738423) and a proof-of-concept study of itepekimab alone and in combination with dupilumab (NCT03736967)âwere conducted in patients with moderate-to-severe AD to assess safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy; both studies were terminated following an interim analysis of the proof-of-concept study, which failed to demonstrate the efficacy of itepekimab. In these two studies, itepekimab exhibited linear and dose-proportional pharmacokinetics. Pharmacodynamics of total IL-33 indicated that itepekimab saturated binding to the target in serum at 300âmg q2w and q4w doses, and decreased blood eosinophil counts. Concentrationâtime profiles of itepekimab and total IL-33 were similar for itepekimab with or without dupilumab, and between East Asian and non-East Asian subgroups. Itepekimab was generally well tolerated, both alone and in combination with dupilumab. The lack of clinical efficacy for itepekimab observed in these studies suggests that IL-33 may not be a key pathogenic driver in moderate-to-severe AD
A genome-wide gene-environment interaction study of breast cancer risk for women of European ancestry
Background
Genome-wide studies of geneâenvironment interactions (GĂE) may identify variants associated with disease risk in conjunction with lifestyle/environmental exposures. We conducted a genome-wide GĂE analysis ofâ~â7.6 million common variants and seven lifestyle/environmental risk factors for breast cancer risk overall and for estrogen receptor positive (ERâ+) breast cancer.
Methods
Analyses were conducted using 72,285 breast cancer cases and 80,354 controls of European ancestry from the Breast Cancer Association Consortium. Geneâenvironment interactions were evaluated using standard unconditional logistic regression models and likelihood ratio tests for breast cancer risk overall and for ERâ+âbreast cancer. Bayesian False Discovery Probability was employed to assess the noteworthiness of each SNP-risk factor pairs.
Results
Assuming a 1âĂâ10â5 prior probability of a true association for each SNP-risk factor pairs and a Bayesian False Discovery Probabilityâ<â15%, we identified two independent SNP-risk factor pairs: rs80018847(9p13)-LINGO2 and adult height in association with overall breast cancer risk (ORintâ=â0.94, 95% CI 0.92â0.96), and rs4770552(13q12)-SPATA13 and age at menarche for ERâ+âbreast cancer risk (ORintâ=â0.91, 95% CI 0.88â0.94).
Conclusions
Overall, the contribution of GĂE interactions to the heritability of breast cancer is very small. At the population level, multiplicative GĂE interactions do not make an important contribution to risk prediction in breast cancer