A mechanistic PK/PD model of AZD0171 (anti-LIF) to support Phase II dose selection.

AZD0171 (INN: Falbikitug) is being developed as a humanized monoclonal antibody (mAb), immunoglobulin G subclass 1 (IgG1), which binds specifically to the immunosuppressive human cytokine leukemia inhibitory factor (LIF) and inhibits downstream signaling by blocking recruitment of glycoprotein 130 (gp130) to the LIF receptor (LIFR) subunit (gp190) and the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and is intended to treat adult participants with advanced solid tumors. LIF is a pleiotropic cytokine (and a member of the IL-6 family of cytokines) involved in many physiological and pathological processes and is highly expressed in a subset of solid tumors, including non-small cell lung cancer (NSCLC), colon, ovarian, prostate, and pancreatic cancer. The aim of this work was to develop a mechanistic PK/PD model to investigate the effect of AZD0171 on tumor LIF levels, predict the level of downstream signaling complex (LIF:LIFR:gp130) inhibition, and examine the dose-response relationship to support dose selection for a Phase II clinical study.

Tools and Techniques to Accelerate Crop Breeding.

As climate changes and a growing global population continue to escalate the need for greater production capabilities of food crops, technological advances in agricultural and crop research will remain a necessity. While great advances in crop improvement over the past century have contributed to massive increases in yield, classic breeding schemes lack the rate of genetic gain needed to meet future demands. In the past decade, new breeding techniques and tools have been developed to aid in crop improvement.

Effect of metformin use on graft and patient survival in kidney transplant recipients with type 2 diabetes: a systematic review protocol.

Introduction: Metformin is a first-line antihyperglycaemic agent for type 2 diabetes (T2DM). In addition to glycaemic control, it offers benefits related to cardiovascular health, weight neutrality and metabolic syndrome. However, its benefits in kidney transplant recipients remain unclear as metformin use is controversial in this population due to a lack of evidence and there are recommendations against its use in patients with poor kidney function.

BiSim Tool: a binding simulation tool to aid and simplify ligand-binding assay design and development.

Ligand-binding assays (LBAs) rely on the reversible, noncovalent binding between the analyte of interest and the assay reagents, and understanding their dynamic equilibrium is key to building robust LBA methods. Although the dynamic interplay of free and bound fractions can be calculated using mathematical models, these are not routinely applied. This approach is costly in terms of both assay development time and reagents, and can result in an under-exploration of the possible parameter combinations.

Robust production of monovalent bispecific IgG antibodies through novel electrostatic steering mutations at the C1-C interface.

Bispecific antibodies represent an increasingly large fraction of biologics in therapeutic development due to their expanded scope in functional capabilities. Asymmetric monovalent bispecific IgGs (bsIgGs) have the additional advantage of maintaining a native antibody-like structure, which can provide favorable pharmacology and pharmacokinetic profiles. The production of correctly assembled asymmetric monovalent bsIgGs, however, is a complex engineering endeavor due to the propensity for non-cognate heavy and light chains to mis-pair.

Laying the foundation for Real-world evidence studies: a case study from Newfoundland and Labrador.

The Janssen and Newfoundland and Labrador Health Innovation Partnership (JANL-HIP) was established to carry out Real-World Evidence (RWE) projects to generate evidence about disease pathways, healthcare delivery, the effects of clinical interventions. Doing so will support and influence clinical decision-making in Newfoundland and Labrador (NL). This case study describes the foundational elements necessary for a real-world evidence generation project in NL and may provide learning for the effective execution of real-world studies in other jurisdictions.

Tozorakimab (MEDI3506): an anti-IL-33 antibody that inhibits IL-33 signalling via ST2 and RAGE/EGFR to reduce inflammation and epithelial dysfunction.

Interleukin (IL)-33 is a broad-acting alarmin cytokine that can drive inflammatory responses following tissue damage or infection and is a promising target for treatment of inflammatory disease. Here, we describe the identification of tozorakimab (MEDI3506), a potent, human anti-IL-33 monoclonal antibody, which can inhibit reduced IL-33 (IL-33) and oxidized IL-33 (IL-33) activities through distinct serum-stimulated 2 (ST2) and receptor for advanced glycation end products/epidermal growth factor receptor (RAGE/EGFR complex) signalling pathways. We hypothesized that a therapeutic antibody would require an affinity higher than that of ST2 for IL-33, with an association rate greater than 10 M s, to effectively neutralize IL-33 following rapid release from damaged tissue.

Running Marathons in High School: A 5-Year Review of Injury in a Structured Training Program.

Objective: The aim in this study was to quantify the number, nature, and severity of injuries sustained by male and female high school students who took part in a running training program that culminated in the completion of a half or full marathon.

Design: This study is a retrospective clinical audit.

Methods: Injury reports from high school students (grades 9-12) who participated in a half or full marathon 30-week progressive training program comprising four training days per week (three running days and one cross-training day) were reviewed.

Real World Studies of Psoriasis and Mental Illness in Newfoundland and Labrador.

Background: Psoriasis is a chronic, immune-mediated inflammatory disease with an implied connection to psychiatric disorders.

Objective: This study aims to illustrate an association between psoriasis and psychiatric disorders using real world data gathered from the Newfoundland and Labrador population.

Methods: Data on 15,100 patients with psoriasis and 75,500 controls (1:5) was collected from the Newfoundland and Labrador Centre for Health Information's Electronic Health Records.

The Incidence of Cutaneous Malignant Melanoma in Eastern Newfoundland and Labrador, Canada, from 2007 to 2015.

Background: The incidence of cutaneous malignant melanoma continues to increase worldwide and in Canada. It is unclear whether the increase in incidence and clinical characteristic trends of cutaneous malignant melanoma are similar in the province of Newfoundland and Labrador.

Objective: The objective of this study is to examine the incidence and trends of cutaneous malignant melanoma in Eastern Newfoundland and Labrador.

"Hot-spotting" to improve vaccine allocation by harnessing digital contact tracing technology: An application of percolation theory.

Vaccinating individuals with more exposure to others can be disproportionately effective, in theory, but identifying these individuals is difficult and has long prevented implementation of such strategies. Here, we propose how the technology underlying digital contact tracing could be harnessed to boost vaccine coverage among these individuals. In order to assess the impact of this "hot-spotting" proposal we model the spread of disease using percolation theory, a collection of analytical techniques from statistical physics.

Recombinant sclerostin inhibits bone formation and in a mouse model of sclerosteosis.

Background: Sclerosteosis, a severe autosomal recessive sclerosing skeletal dysplasia characterised by excessive bone formation, is caused by absence of sclerostin, a negative regulator of bone formation that binds LRP5/6 Wnt co-receptors. Current treatment is limited to surgical management of symptoms arising from bone overgrowth. This study investigated the effectiveness of sclerostin replacement therapy in a mouse model of sclerosteosis.

Evaluation of In Vitro Models for Assessment of Human Intestinal Metabolism in Drug Discovery.

Although intestinal metabolism plays an important role in drug disposition, early predictions of human outcomes are challenging, in part because of limitations of available in vitro models. To address this, we have evaluated three in vitro models of human intestine (microsomes, permeabilized enterocytes, and cryopreserved intestinal mucosal epithelium) as tools to assess intestinal metabolism and estimate the fraction escaping gut metabolism ( ) in drug discovery. The models were tested with a chemically diverse set of 32 compounds, including substrates for oxidoreductive, hydrolytic, and conjugative enzymes.

Moderate-to-severe plaque psoriasis patients treated with ixekizumab: early real-world outcomes and adverse events.

Introduction: Data on real-world experiences for patients treated with ixekizumab is currently limited.

Objectives: Describe characteristics of ixekizumab-treated psoriasis patients and provide evidence of clinical outcomes using disease severity scores Body Surface Area (BSA) and Psoriasis Area and Severity Index (PASI) in the real world.

Methods: Chart review was performed for adult patients treated with ixekizumab at a single Canadian dermatology clinic (February 2017-August 2018).

Applications of Quantitative Systems Pharmacology in Model-Informed Drug Discovery: Perspective on Impact and Opportunities.

Quantitative systems pharmacology (QSP) approaches have been increasingly applied in the pharmaceutical since the landmark white paper published in 2011 by a National Institutes of Health working group brought attention to the discipline. In this perspective, we discuss QSP in the context of other modeling approaches and highlight the impact of QSP across various stages of drug development and therapeutic areas. We discuss challenges to the field as well as future opportunities.

A genome-wide association study identifies single nucleotide polymorphisms associated with time-to-metastasis in colorectal cancer.

Background: Differentiating between cancer patients who will experience metastasis within a short time and who will be long-term survivors without metastasis is a critical aim in healthcare. The microsatellite instability (MSI)-high tumor phenotype is such a differentiator in colorectal cancer, as patients with these tumors are unlikely to experience metastasis. Our aim in this study was to determine if germline genetic variations could further differentiate colorectal cancer patients based on the long-term risk and timing of metastasis.

Best Practices to Maximize the Use and Reuse of Quantitative and Systems Pharmacology Models: Recommendations From the United Kingdom Quantitative and Systems Pharmacology Network.

The lack of standardization in the way that quantitative and systems pharmacology (QSP) models are developed, tested, and documented hinders their reproducibility, reusability, and expansion or reduction to alternative contexts. This in turn undermines the potential impact of QSP in academic, industrial, and regulatory frameworks. This article presents a minimum set of recommendations from the UK Quantitative and Systems Pharmacology Network (UK QSP Network) to guide QSP practitioners seeking to maximize their impact, and stakeholders considering the use of QSP models in their environment.

Associations of single nucleotide polymorphisms with mucinous colorectal cancer: genome-wide common variant and gene-based rare variant analyses.

Background: Colorectal cancer has significant impact on individuals and healthcare systems. Many genes have been identified to influence its pathogenesis. However, the genetic basis of mucinous tumor histology, an aggressive subtype of colorectal cancer, is currently not well-known.

XRCC3 Thr241Met and TYMS variable number tandem repeat polymorphisms are associated with time-to-metastasis in colorectal cancer.

Background: Metastasis is a major cause of mortality in cancer. Identifying prognostic factors that distinguish patients who will experience metastasis in the short-term and those that will be free of metastasis in the long-term is of particular interest in current medical research. The objective of this study was to examine if select genetic polymorphisms can differentiate colorectal cancer patients based on timing and long-term risk of metastasis.

Preclinical QSP Modeling in the Pharmaceutical Industry: An IQ Consortium Survey Examining the Current Landscape.

A cross-industry survey was conducted to assess the landscape of preclinical quantitative systems pharmacology (QSP) modeling within pharmaceutical companies. This article presents the survey results, which provide insights on the current state of preclinical QSP modeling in addition to future opportunities. Our results call attention to the need for an aligned definition and consistent terminology around QSP, yet highlight the broad applicability and benefits preclinical QSP modeling is currently delivering.

A randomised, placebo-controlled trial of anti-interleukin-1 receptor 1 monoclonal antibody MEDI8968 in chronic obstructive pulmonary disease.

Background: Interleukin-1 receptor 1 (IL-1R1) inhibition is a potential strategy for treating patients with chronic obstructive pulmonary disease (COPD). MEDI8968, a fully human monoclonal antibody, binds selectively to IL-1R1, inhibiting activation by IL-1α and IL-1β. We studied the efficacy and safety/tolerability of MEDI8968 in adults with symptomatic, moderate-to-very severe COPD.

Efficacy and Safety of MEDI2070, an Antibody Against Interleukin 23, in Patients With Moderate to Severe Crohn's Disease: A Phase 2a Study.

Background & Aims: MEDI2070 is a human monoclonal antibody that selectively inhibits interleukin 23 (IL23), a cytokine implicated in the pathogenesis of Crohn's disease (CD). We analyzed its safety and efficacy in treatment of CD in a phase 2a study.

Methods: We conducted a double-blind, placebo-controlled study of 119 adults with moderate to severe CD failed by treatment with tumor necrosis factor antagonists.

Unraveling the pharmacokinetic interaction of ticagrelor and MEDI2452 (Ticagrelor antidote) by mathematical modeling.

The investigational ticagrelor-neutralizing antibody fragment, MEDI2452, is developed to rapidly and specifically reverse the antiplatelet effects of ticagrelor. However, the dynamic interaction of ticagrelor, the ticagrelor active metabolite (TAM), and MEDI2452, makes pharmacokinetic (PK) analysis nontrivial and mathematical modeling becomes essential to unravel the complex behavior of this system. We propose a mechanistic PK model, including a special observation model for post-sampling equilibration, which is validated and refined using mouse in vivo data from four studies of combined ticagrelor-MEDI2452 treatment.