Takeda (United Kingdom)

Abstract Background We aimed to develop and validate a transcriptomic signature that correlates with clinical disease activity and therapy response using the Inflammatory Bowel Disease (IBD) Plexus® real-world data platform (Crohn’s & Colitis Foundation), CytoReason Disease Model based on published ulcerative colitis (UC) molecular studies, and a large prospective randomized clinical trial (VARSITY1). Methods A molecular disease activity score was built by identifying shared differential expression signals in transcriptomics data from inflamed v healthy control UC samples using an elastic net regression model trained against disease activity scores.2 The resulting model assigned a continuous molecular activity score per sample based on expression of the selected genes, with interpretability supported by feature importance and downstream biological evaluation. Signature module involvement was assessed using disease model data from 1985 mucosal biopsies from 18 UC clinical studies, including pts treated with golimumab, infliximab or vedolizumab. Pathway differential expression analysis was performed using gene set variation analysis (GSVA) with validation using molecular data from VARSITY.1 Results An 85 gene signature was identified, which represents enrichment of endothelial cells, alpha-beta T cells, epithelial, fibroblasts, and plasma cells (Figure). In contrast, published molecular inflammation gene sets (400–600 genes) 3, 4 are primarily enriched for immune and epithelial cells.3, 4 Our molecular activity signature also captured tertiary lymphoid structure, vascular, connective tissue, and hematopoiesis signaling—processes implicated in severe UC—thus demonstrating broader representation of disease mechanisms. Our molecular signature correlated with Mayo total/endoscopic scores across multiple IBD cohorts, and real-world registries eg., IBD Plexus. Assessment of our gene signature in VARSITY data revealed a significant correlation with therapy response: ie.,change in endoscopic and histological activity at week 52 (Table). Conclusion We developed and validated a refined molecular signature of UC disease activity encompassing diverse cellular populations which correlated with change in endoscopic and histologic disease severity in a prospective centrally read clinical trial. Validation across multiple real-world registries and clinical trials highlights its potential as a biomarker for clinical evaluation and the gene panel size relative to prior work offers enhanced feasibility for use to define residual disease burden in pts with endoscopic and histologic improvements in disease activity. This is an important step towards precision medicine in IBD using a molecular endotype-based classification of UC.

ObjectivesThe use of cost-effectiveness methods to support policy decisions has become well established, but difficulties can arise when evaluating a new treatment that is indicated to be used in combination with an established backbone treatment. If the latter has been priced close to the decision maker’s willingness-to-pay threshold, this may mean that there is no headroom for the new treatment to demonstrate value, at any price, even if the combination is clinically effective. Without a mechanism for attributing value to component treatments within a combination therapy, the health system risks generating negative funding decisions for combinations of proven clinical benefit to patients. The aim of this work was to define a value attribution methodology, which could be used to allocate value between the components of any combination treatment. MethodsThe framework is grounded in the standard decision rules of cost-effectiveness analysis and provides solutions according to key features of the problem: perfect/imperfect information about component treatment monotherapy effects and balanced/unbalanced market power between their manufacturers. ResultsThe share of incremental value varies depending on whether there is perfect/imperfect information and balance/imbalance of market power, with some scenarios requiring the manufacturers to negotiate a share of the incremental value within a range defined by the framework. ConclusionsIt is possible to define a framework that is independent of price and focuses on benefits expressed as quality-adjusted life-year gains (and/or quality-adjusted life-year equivalents for cost savings), a standard metric used by many health technology assessment agencies to evaluate novel treatments.

The impact of health technologies may extend beyond the patient and affect the health of people in their network, like their informal carers. The National Institute for Health and Care Excellence (NICE) methods guide explicitly allows the inclusion of health-related quality of life (HRQoL) effects on carers in economic evaluations when these effects are substantial, but the proportion of NICE appraisals that includes carer HRQoL remains small. This paper discusses when inclusion of carer HRQoL is justified, how inclusion can be substantiated, and how carer HRQoL can be measured and included in health economic models. Inclusion of HRQoL in economic evaluations can best be substantiated by data collected in (carers for) patients eligible for receiving the intervention. To facilitate combining patient and carer utilities on the benefit side of economic evaluations, using EQ-5D to measure impacts on carers seems the most successful strategy in the UK context. Alternatives to primary data collection of EQ-5D include vignette studies, using existing values, and mapping algorithms. Carer HRQoL was most often incorporated in economic models in NICE appraisals by employing (dis)utilities as a function of the patient's health state or disease severity. For consistency and comparability, economic evaluations including carer HRQoL should present analyses with and without carer HRQoL.

Abstract BackgroundCardiovascular risk factors (CVRFs) increase the risk of cerebrovascular disease and AD, and over 30% of the patients with AD coincident cerebrovascular pathology. We previously found that FMNL2 interacts with CVRFs (p = 6.6e‐07) by altering the normal astroglial‐vascular mechanisms that underly amyloid clearance. The goal here was to identify additional genes that contribute to the interaction between CVRFs and AD.MethodA collection of eight multi‐ethnic cohorts was explored to study genome‐wide gene‐CVRF score interaction analysis for AD, in 7,441 AD patients and 10,453 controls. The cardiovascular risk factors score (CVRF score) was created from a first principal component of the four vascular risk factors; self‐reported history of hypertension, diabetes, and heart disease, and measured body mass index. Gene‐based interaction test was performed using the adaptive gene‐environment interaction (aGE) test. Results were summarized using a meta‐analysis. We investigated the association of gene expression with pathological AD and AD phenotype (amyloid‐β, tau, or brain infarcts) in 1,092 samples from the frontal cortex in ROSMAP. The pathway enrichment analysis was performed on the differentially expressed genes. Age and sex were adjusted in the models.ResultThe previous interaction of CVRF score with FMNL2 (p = 3.64e‐07) was strengthened and additional genes were identified including BRINP1 (p = 2.45e‐06), CFAP99 (p = 3.3e‐06), and PRG3 (p = 3.71e‐06). FMNL2 encodes a formin‐related protein important in regulating actin and microtubules. FMNL2 and BRINP1 expressions were higher in the brains of patients with brain infarcts (p = 0.025 and p = 0.006, respectively). The expression level of BRINP1 interacted with brain infarcts on pathological AD (p = 0.02) and with amyloid‐β or tau on brain infarcts (p = 0.02 and p = 0.01, respectively). The pathways were relevant to cellular interactions between astrocytes and endothelia as well as the immune system reaction in the glio‐vascular niche.ConclusionThe four novel genes are likely to be involved in the complex interaction between Alzheimer’s disease pathologies (amyloid and phosphorylated tau deposition) and cerebrovascular pathology, for example, at the glia‐vascular interface during AD progression. Understanding how these genes interfere with the mechanisms underlying the clearance of amyloid and tau increasing their deposition in brain will be essential.

The aims of this study were to test a noninvasive self-management intervention supported by specialist nurses versus intervention alone in patients with inflammatory bowel disease (IBD) experiencing fecal incontinence and to conduct a qualitative evaluation of the trial. Multicenter, parallel-group, open-label, mixed-methods randomized controlled trial (RCT). The sample comprised patients from a preceding case-finding study who reported fecal incontinence and met study requirements; the RCT was delivered via IBD outpatient clinics in 6 hospitals (5 in major UK cities, 1 rural) between September 2015 and August 2017. Sixteen participants and 11 staff members were interviewed for qualitative evaluation. Adults with IBD completed the study activities over a 3-month period following randomization. Each participant received either four 30-minute structured sessions with an IBD clinical nurse specialist and a self-management booklet or the booklet alone. Low retention numbers precluded statistical analysis; individual face-to-face or telephone interviews, recorded digitally and transcribed professionally, were conducted to evaluate the RCT. Transcripts were analyzed thematically using an inductive method. Sixty-seven participants (36%) of the targeted 186 participants were recruited. The groups comprised 32 participants (17% of targeted participants) allocated to the nurse + booklet intervention and 35 (18.8% of targeted participants) allocated to the booklet alone. Less than one-third (n = 21, 31.3%) completed the study. Given the low recruitment and high attrition, statistical analysis of quantitative data was considered futile. Participant interviews were conducted concerning study participation and 4 themes emerged that described experiences of patients and staff. These data provided insights into reasons for low recruitment and high attrition, as well as challenges of delivering resource-heavy studies in busy health service environments. Alternative approaches to trials of nurse-led interventions in hospital settings are needed as many interfering factors may prevent successful completion.

<div>Abstract<p>CHR-2797 is a novel metalloenzyme inhibitor that is converted into a pharmacologically active acid product (CHR-79888) inside cells. CHR-79888 is a potent inhibitor of a number of intracellular aminopeptidases, including leucine aminopeptidase. CHR-2797 exerts antiproliferative effects against a range of tumor cell lines <i>in vitro</i> and <i>in vivo</i> and shows selectivity for transformed over nontransformed cells. Its antiproliferative effects are at least 300 times more potent than the prototypical aminopeptidase inhibitor, bestatin. However, the mechanism by which inhibition of these enzymes leads to proliferative changes is not understood. Gene expression microarrays were used to profile changes in mRNA expression levels in the human promyelocytic leukemia cell line HL-60 treated with CHR-2797. This analysis showed that CHR-2797 treatment induced a transcriptional response indicative of amino acid depletion, the amino acid deprivation response, which involves up-regulation of amino acid synthetic genes, transporters, and tRNA synthetases. These changes were confirmed in other leukemic cell lines sensitive to the antiproliferative effects of CHR-2797. Furthermore, CHR-2797 treatment inhibited phosphorylation of mTOR substrates and reduced protein synthesis in HL-60 cells, both also indicative of amino acid depletion. Treatment with CHR-2797 led to an increase in the concentration of intracellular small peptides, the substrates of aminopeptidases. It is suggested that aminopeptidase inhibitors, such as CHR-2797 and bestatin, deplete sensitive tumor cells of amino acids by blocking protein recycling, and this generates an antiproliferative effect. CHR-2797 is orally bioavailable and currently undergoing phase II clinical investigation in the treatment of myeloid leukemia. [Cancer Res 2008;68(16):6669–79]</p></div>

Tumor-associated macrophages (TAM) play an important role in maintaining the immunosuppressive state of the tumor microenvironment (TME). High levels of CD163+ TAMs specifically are associated with poor prognosis in many solid tumor types. Targeting TAMs may represent a key approach in development of the next generation of cancer immune therapeutics. Members of the leukocyte immunoglobulin-like receptor B (LILRB) family, including LILRB2 (ILT4), are known to transmit inhibitory signals in macrophages and other myeloid cells. Leveraging bulk and single cell RNA-sequencing datasets, as well as extensive immunophenotyping of human tumors, we found that LILRB2 is highly expressed on CD163+ CD11b+ cells in the TME and that LILRB2 expression correlates with CD163 expression across many tumor types. To target LILRB2, we have developed JTX-8064, a highly potent and selective antagonistic mAb. JTX-8064 blocks LILRB2 binding to its cognate ligands, including classical and nonclassical MHC molecules. In vitro, JTX-8064 drives the polarization of human macrophages and dendritic cells toward an immunostimulatory phenotype. As a result, human macrophages treated with a LILRB2 blocker are reprogrammed to increase the activation of autologous T cells in co-culture systems. Furthermore, JTX-8064 significantly potentiates the activity of anti-PD-1 in allogeneic mixed lymphocyte reaction. In a human tumor explant culture, pharmacodynamic activity of JTX-8064 was observed in monotherapy and in combination with anti-PD-1. Collectively, our work provides strong translational and preclinical rationale to target LILRB2 in cancer.

Abstract Background Vedolizumab (VDZ) is a gut-selective humanised monoclonal anti-α4β7 integrin antibody for treatment of UC and CD. This post-authorization safety study (PASS) compared long-term safety in patients (pts) treated with VDZ or other biologics for UC or CD. Methods This was a prospective, observational, multicentre, cohort study in pts with UC or CD starting treatment with VDZ or other biologics (NCT02674308, EUPAS6469). Pts were biologic naïve (VDZ=35%, Other biologic=65%) or had prior exposure to biologics other than VDZ and were followed for up to 7 yrs. Pts were treated under usual standard of care as directed by their physician with no discontinuation from the study due to physician-directed treatment changes. The primary safety outcome was serious infections and was compared between cohorts using a Cox proportional hazards model adjusted by propensity score (with other biologics as reference). Secondary safety outcomes were adverse events (AE) of special interest (AESI) as listed in Tables 2 and 3. Results In total, 5208 patients were enrolled across 21 countries between Mar 2015 and Jul 2019. The full analysis set comprised 5008 pts (VDZ=2502; other biologic=2506) and mean (SD) study duration was 37.4 (14.1) months. Consistent with the observational nature of the study and the current standard of care, the baseline characteristics in the two cohorts were imbalanced (Table 1). The overall treatment-emergent Adverse Event (AE) rate was 61.3% (VDZ) and 59.5% (other biologic), with serious AEs in 27.5% (VDZ) and 25.7% (other biologic), respectively. In UC pts, the incidence rate (IR) of serious infections were: 0.014 (95% CI: 0.010, 0.019) [VDZ] and 0.015 (0.010, 0.023) [other biologic], with a hazard ratio (HR) of 1.018 (0.931, 1.114), p=0.70 (Table 2). In CD pts, corresponding findings were 0.012 (95% CI: 0.008, 0.017) [VDZ] and 0.006 (95% CI: 0.004, 0.009) [other biologic] with HR of 1.035 (0.959, 1.117), p=0.38 (Table 3). The incidence of primary and secondary safety outcomes is reported in Table 2 for UC and Table 3 for CD. There were no safety issues relating to pregnancy and no cases of PML observed. There were 19 deaths in the VDZ cohort (1 case of pneumonia deemed as treatment-related); and 13 deaths in the other biologic cohort, 2 cases deemed treatment-related (one case septic shock and pneumonia; one case non-small cell lung cancer). Clinical outcomes and quality of life (QoL) measures were comparable between cohorts. Conclusion In this long-term, prospective, real-world observational study of a large multinational population under routine standard of care there was no new safety signal identified in relation to VDZ. Results are consistent with the known safety profile of VDZ.