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Purpose To explore symptoms and disease impacts of Crohn’s disease and to develop a new patient-reported outcomes (PRO) measure according to industry best practices. Methods A conceptual model of relevant symptoms experienced by patients with Crohn’s disease was developed following a literature review. Three rounds of combined qualitative semi-structured concept elicitation and cognitive debriefing interviews with 36 patients (≥ 16 years) with Crohn’s disease and 4 clinicians were conducted to further explore the most commonly reported and most bothersome symptoms to patients. Interview results were used to update the conceptual model as well as items and response options included in The Crohn’s Disease Diary, a new PRO measure. Results All patients (N = 36) reported abdominal pain, loose or liquid bowel movements, and high or increased frequency of bowel movements, with most reporting these symptoms spontaneously (100%, 92%, and 75%, respectively). All patients reported bowel movement urgency, but 61% reported this symptom only when probed. Most also reported that symptoms impacted activities of daily living, work/school, and emotional, social, and physical functioning (overall, 78%–100%; spontaneously, 79% – 92%). Data regarding core symptoms of Crohn’s disease from clinician concept elicitation interviews supported patient data. The 17-item Crohn’s Disease Diary assesses core symptoms and impacts of Crohn’s disease over 24 h, and extraintestinal manifestations over 7 days. The content validity of the diary was confirmed during cognitive debriefing interviews. Conclusion The Crohn’s Disease Diary is a new PRO measure for the assessment of Crohn’s disease symptoms and impacts, developed according to industry best practices.

Evaluation of FRalpha expression by tumor cell lines

Table of Patient Characteristics

IgE antibodies are key mediators of antiparasitic immune responses, but their potential for cancer treatment via antibody-dependent cell-mediated cytotoxicity (ADCC) has been little studied. Recently, tumor antigen–specific IgEs were reported to restrict cancer cell growth by engaging high-affinity Fc receptors on monocytes and macrophages; however, the underlying therapeutic mechanisms were undefined and in vivo proof of concept was limited. Here, an immunocompetent rat model was designed to recapitulate the human IgE-Fcϵ receptor system for cancer studies. We also generated rat IgE and IgG mAbs specific for the folate receptor (FRα), which is expressed widely on human ovarian tumors, along with a syngeneic rat tumor model expressing human FRα. Compared with IgG, anti-FRα IgE reduced lung metastases. This effect was associated with increased intratumoral infiltration by TNFα+ and CD80+ macrophages plus elevated TNFα and the macrophage chemoattractant MCP-1 in lung bronchoalveolar lavage fluid. Increased levels of TNFα and MCP-1 correlated with IgE-mediated tumor cytotoxicity by human monocytes and with longer patient survival in clinical specimens of ovarian cancer. Monocytes responded to IgE but not IgG exposure by upregulating TNFα, which in turn induced MCP-1 production by monocytes and tumor cells to promote a monocyte chemotactic response. Conversely, blocking TNFα receptor signaling abrogated induction of MCP-1, implicating it in the antitumor effects of IgE. Overall, these findings show how antitumor IgE reprograms monocytes and macrophages in the tumor microenvironment, encouraging the clinical use of IgE antibody technology to attack cancer beyond the present exclusive reliance on IgG. Cancer Res; 77(5); 1127–41. ©2017 AACR.

Description of additional experiments and procedures carried out in this study

Using a novel physiologically relevant in vitro human whole blood neutrophil shape change assay, an aminopyrazine series of selective PI3Kγ inhibitors was identified and prioritized for further optimization. Severe solubility limitations associated with the series leading to low oral bioavailability and poor exposures, especially at higher doses, were overcome by moving to an aminopyridine core. Compound 33, with the optimal balance of on-target activity, selectivity, and pharmacokinetic parameters, progressed into in vivo studies and demonstrated good efficacy (10 mg/kg) in a rat model of airway inflammation. Sufficient exposures were achieved at high doses to support toxicological studies, where unexpected inflammatory cell infiltrates in cardiovascular tissue prevented further compound development.

Introduction: COVID-19 is a pulmonary disease associated with fever and dyspnea, affecting all age groups. Older patients, however, have a higher likelihood of adverse outcomes including death. Severe disease is associated with hyperinflammation and differential expression of inflammatory mediators has been demonstrated for patients aged ≥70 years. Aim: To evaluate the impact of level of care on length of hospital stay (LOS) and costs for COVID-19 patients stratified by age. Methods: We conducted a cohort study of patient data from the Premier Health Database comprising healthcare and billing information for a geographically diverse selection of hospitals in the United States from April 2020 through March 2021. Results: We identified over 162,000 hospitalized COVID-19 patients requiring respiratory support; approximately 68,000 (42%) were aged ≥70 years, 66,000 (41%) were aged 50–69 years, and 28,000 (17%) were aged Conclusion: Higher levels of care for patients with COVID-19 are associated with LOS and costs. Funded by GSK: medical writing support provided by Fishawack Indicia Ltd, funded by GSK.

Background: COVID-19, due to its deadly nature and rapid spread, is causing significant global economic burden. Aim: To summarize emerging data on direct costs associated with disease management of COVID-19. Methods: A targeted review of the literature published before 21 August 2020 reporting direct costs associated with COVID-19 was undertaken using the PubMed/MEDLINE database. Results were compared by country, study type and disease severity. Results: Retrospective studies in China reported an average total hospitalization cost per case of $3,027 (regardless of severity) to $16,652 for critical patients early in the pandemic, with higher costs observed for females and patients with more severe disease and comorbidities. In the US, simulation studies estimated that median medical costs were $57-$96 per patient for mild cases not requiring hospitalization, and from $11,367 (aged 0-17 years) to $88,114 (requiring ventilation for ≥4 days) per case in hospitalized patients. Older age, more severe disease, major complications or comorbidities, and longer requirement for ventilation were predicted to increase medical costs. The total out-of-pocket costs in the US were estimated as $1,300-$10,560 per hospitalized case depending on complications, comorbidities and length of hospital stay. No studies were identified that reported direct costs of COVID-19 in other countries. Conclusions: Direct costs associated with clinical management of COVID-19 were significant for both the health systems and patients, and varied by country, disease severity, age, sex, comorbidities, and ventilation status. Data from observational studies are needed for countries other than China. Funding: GSK [study 214627]

We describe the discovery, engineering and characterisation of a highly potent anti-human interleukin (IL)-13 Fab fragment designed for administration by inhalation. The lead candidate molecule was generated via a novel antibody discovery process, and the selected IgG variable region genes were successfully humanised and reformatted as a human IgG γ1 Fab fragment. Evaluation of the biophysical properties of a selection of humanised Fab fragments in a number of assays allowed us to select the molecule with the optimal stability profile. The resulting lead candidate, CA652.g2 Fab, was shown to have comparable activity to the parental IgG molecule in a range of in vitro assays and was highly stable. Following nebulisation using a mesh nebuliser, CA652.g2 Fab retained full binding affinity, functional neutralisation potency and structural integrity. Epitope mapping using solution nuclear magnetic resonance confirmed that the antibody bound to the region of human IL-13 implicated in the interaction with IL-13Rα1 and IL-13Rα2. The work described here resulted in the discovery and design of CA652.g2 human γ1 Fab, a highly stable and potent anti-IL-13 molecule suitable for delivery via inhalation.