Showing papers by "Eli Lilly and Company published in 2016"
Yasser Iturria-Medina, Roberto C. Sotero1, Paule-Joanne Toussaint, José María Mateos-Pérez +311 more•Institutions (60)
TL;DR: Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development, suggesting early memory deficit associated with the primary disease factors.
Abstract: Multifactorial mechanisms underlying late-onset Alzheimer's disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-β deposition, metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD-abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system's integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions.
786 citations
Christian R. Marshall1, Daniel P. Howrigan2, Daniele Merico1, Bhooma Thiruvahindrapuram1 +252 more•Institutions (87)
TL;DR: A collaborative effort in which a centralized analysis pipeline is applied to a SCZ cohort, finding support at a suggestive level for nine additional candidate susceptibility and protective loci, which consist predominantly of CNVs mediated by non-allelic homologous recombination (NAHR).
Abstract: Genomic copy number variants (CNVs) have been strongly implicated in the etiology of schizophrenia (SCZ). However, apart from a small number of risk variants, elucidation of the CNV contribution to risk has been difficult due to the rarity of risk alleles, all occurring in less than 1% of cases. We sought to address this obstacle through a collaborative effort in which we applied a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. We observed a global enrichment of CNV burden in cases (OR=1.11, P=5.7e-15), which persisted after excluding loci implicated in previous studies (OR=1.07, P=1.7e-6). CNV burden is also enriched for genes associated with synaptic function (OR = 1.68, P = 2.8e-11) and neurobehavioral phenotypes in mouse (OR = 1.18, P= 7.3e-5). We identified genome-wide significant support for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. We find support at a suggestive level for nine additional candidate susceptibility and protective loci, which consist predominantly of CNVs mediated by non-allelic homologous recombination (NAHR).
764 citations
TL;DR: In three phase 3 trials involving patients with psoriasis, ixekizumab was effective through 60 weeks of treatment and the benefits need to be weighed against the risks of adverse events.
Abstract: BackgroundTwo phase 3 trials (UNCOVER-2 and UNCOVER-3) showed that at 12 weeks of treatment, ixekizumab, a monoclonal antibody against interleukin-17A, was superior to placebo and etanercept in the treatment of moderate-to-severe psoriasis. We report the 60-week data from the UNCOVER-2 and UNCOVER-3 trials, as well as 12-week and 60-week data from a third phase 3 trial, UNCOVER-1. MethodsWe randomly assigned 1296 patients in the UNCOVER-1 trial, 1224 patients in the UNCOVER-2 trial, and 1346 patients in the UNCOVER-3 trial to receive subcutaneous injections of placebo (placebo group), 80 mg of ixekizumab every 2 weeks after a starting dose of 160 mg (2-wk dosing group), or 80 mg of ixekizumab every 4 weeks after a starting dose of 160 mg (4-wk dosing group). Additional cohorts in the UNCOVER-2 and UNCOVER-3 trials were randomly assigned to receive 50 mg of etanercept twice weekly. At week 12 in the UNCOVER-3 trial, the patients entered a long-term extension period during which they received 80 mg of ixeki...
593 citations
TL;DR: Many of the key and newly identified histone modifications known to be deregulated in cancer and how this impacts function are reviewed.
Abstract: Histone posttranslational modifications represent a versatile set of epigenetic marks involved not only in dynamic cellular processes, such as transcription and DNA repair, but also in the stable maintenance of repressive chromatin. In this article, we review many of the key and newly identified histone modifications known to be deregulated in cancer and how this impacts function. The latter part of the article addresses the challenges and current status of the epigenetic drug development process as it applies to cancer therapeutics.
563 citations
TL;DR: It is reported that TREM2 protects mice from Alzheimer's disease by enabling resident microglia to insulate and alter Aβ plaque structure, thereby limiting neuritic damage.
Abstract: Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial receptor that recognizes changes in the lipid microenvironment, which may occur during amyloid β (Aβ) accumulation and neuronal degeneration in Alzheimer's disease (AD). Rare TREM2 variants that affect TREM2 function lead to an increased risk of developing AD. In murine models of AD, TREM2 deficiency prevents microglial clustering around Aβ deposits. However, the origin of myeloid cells surrounding amyloid and the impact of TREM2 on Aβ accumulation are a matter of debate. Using parabiosis, we found that amyloid-associated myeloid cells derive from brain-resident microglia rather than from recruitment of peripheral blood monocytes. To determine the impact of TREM2 deficiency on Aβ accumulation, we examined Aβ plaques in the 5XFAD model of AD at the onset of Aβ-related pathology. At this early time point, Aβ accumulation was similar in TREM2-deficient and -sufficient 5XFAD mice. However, in the absence of TREM2, Aβ plaques were not fully enclosed by microglia; they were more diffuse, less dense, and were associated with significantly greater neuritic damage. Thus, TREM2 protects from AD by enabling microglia to surround and alter Aβ plaque structure, thereby limiting neuritic damage.
534 citations
TL;DR: Abemaciclib represents the first selective inhibitor of CDK4 and CDK6 with a safety profile allowing continuous dosing to achieve sustained target inhibition, and this first-in-human experience demonstrates single-agent activity for patients with advanced breast cancer, NSCLC, and other solid tumors.
Abstract: We evaluated the safety, pharmacokinetic profile, pharmacodynamic effects, and antitumor activity of abemaciclib, an orally bioavailable inhibitor of cyclin-dependent kinases (CDK) 4 and 6, in a multicenter study including phase I dose escalation followed by tumor-specific cohorts for breast cancer, non–small cell lung cancer (NSCLC), glioblastoma, melanoma, and colorectal cancer. A total of 225 patients were enrolled: 33 in dose escalation and 192 in tumor-specific cohorts. Dose-limiting toxicity was grade 3 fatigue. The maximum tolerated dose was 200 mg every 12 hours. The most common possibly related treatment-emergent adverse events involved fatigue and the gastrointestinal, renal, or hematopoietic systems. Plasma concentrations increased with dose, and pharmacodynamic effects were observed in proliferating keratinocytes and tumors. Radiographic responses were achieved in previously treated patients with breast cancer, NSCLC, and melanoma. For hormone receptor–positive breast cancer, the overall response rate was 31%; moreover, 61% of patients achieved either response or stable disease lasting ≥6 months.
SIGNIFICANCE: Abemaciclib represents the first selective inhibitor of CDK4 and CDK6 with a safety profile allowing continuous dosing to achieve sustained target inhibition. This first-in-human experience demonstrates single-agent activity for patients with advanced breast cancer, NSCLC, and other solid tumors. Cancer Discov; 6(7); 1–14. ©2016 AACR.
525 citations
Memorial Sloan Kettering Cancer Center1, Cornell University2, University of Washington3, The Royal Marsden NHS Foundation Trust4, Washington University in St. Louis5, UCLA Medical Center6, University of Colorado Boulder7, Northwestern University8, Carolinas Healthcare System9, University of Texas MD Anderson Cancer Center10, Novartis11, Eli Lilly and Company12, Columbia University13
TL;DR: An open-label phase 1b and randomised phase 2 study of doxorubicin plus olaratumab treatment in patients with unresectable or metastatic soft-tissue sarcoma at 16 clinical sites in the USA, finding progression-free survival in phase 2 was 6.6 months and the efficacy was assessed.
482 citations
TL;DR: In patients with rheumatoid arthritis and an inadequate response to biologic DMARDs, baricitinib at a daily dose of 4 mg was associated with clinical improvement at 12 weeks and a small reduction in neutrophil levels and increases in serum creatinine and low-density cholesterol levels.
Abstract: BackgroundIn phase 2 studies, baricitinib, an oral Janus kinase 1 and 2 inhibitor, reduced disease activity in patients with rheumatoid arthritis who had not previously received treatment with biologic disease-modifying antirheumatic drugs (DMARDs). MethodsIn this phase 3 study involving 527 patients with an inadequate response to or unacceptable side effects associated with one or more tumor necrosis factor inhibitors, other biologic DMARDs, or both, we randomly assigned the patients in a 1:1:1 ratio to baricitinib at a dose of 2 or 4 mg daily or placebo for 24 weeks. End points, tested hierarchically at week 12 to control type 1 error, were the American College of Rheumatology 20% (ACR20) response (primary end point), the Health Assessment Questionnaire–Disability Index (HAQ-DI) score, the 28-joint Disease Activity Score based on C-reactive protein level (DAS28-CRP), and a Simplified Disease Activity Index (SDAI) score of 3.3 or less (on a scale of 0.1 to 86.0, with a score of 3.3 or less indicating rem...
449 citations
TL;DR: It is found that in primary patient samples, the IL-3 receptor α chain CD123 was highly expressed on leukemia-initiating cells and CD19-negative blasts in bulk B-ALL at baseline and at relapse after CART19 administration, indicating that targeting CD19 and CD123 on leukemic blasts represents an effective strategy for treating and preventing antigen-loss relapses occurring after CD19
Abstract: Potent CD19-directed immunotherapies, such as chimeric antigen receptor T cells (CART) and blinatumomab, have drastically changed the outcome of patients with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL). However, CD19-negative relapses have emerged as a major problem that is observed in approximately 30% of treated patients. Developing approaches to preventing and treating antigen-loss escapes would therefore represent a vertical advance in the field. Here, we found that in primary patient samples, the IL-3 receptor α chain CD123 was highly expressed on leukemia-initiating cells and CD19-negative blasts in bulk B-ALL at baseline and at relapse after CART19 administration. Using intravital imaging in an antigen-loss CD19-negative relapse xenograft model, we determined that CART123, but not CART19, recognized leukemic blasts, established protracted synapses, and eradicated CD19-negative leukemia, leading to prolonged survival. Furthermore, combining CART19 and CART123 prevented antigen-loss relapses in xenograft models. Finally, we devised a dual CAR-expressing construct that combined CD19- and CD123-mediated T cell activation and demonstrated that it provides superior in vivo activity against B-ALL compared with single-expressing CART or pooled combination CART. In conclusion, these findings indicate that targeting CD19 and CD123 on leukemic blasts represents an effective strategy for treating and preventing antigen-loss relapses occurring after CD19-directed therapies.
444 citations
TL;DR: The estimated Braak stage was significantly associated with amyloid status, diagnostic category and measures of global cognition and could be classified into patterns similar to those prescribed by Braak neuropathological staging of tau pathology.
Abstract: SEE THAL AND VANDENBERGHE DOI101093/BRAIN/AWW057 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Post-mortem Braak staging of neurofibrillary tau tangle topographical distribution is one of the core neuropathological criteria for the diagnosis of Alzheimer's disease. The recent development of positron emission tomography tracers targeting neurofibrillary tangles has enabled the distribution of tau pathology to be imaged in living subjects. Methods for extraction of classic Braak staging from in vivo imaging of neurofibrillary tau tangles have not yet been explored. Standardized uptake value ratio images were calculated from 80-100 minute (18)F-AV-1451 (also known as T807) positron emission tomography scans obtained from n = 14 young reference subjects (age 21-39 years, Mini-Mental State Examination 29-30) and n = 173 older test subjects (age 50-95 years) comprising amyloid negative cognitively normal (n = 42), clinically-diagnosed mild cognitive impairment (amyloid positive, n = 47, and amyloid negative, n = 40) and Alzheimer's disease (amyloid positive, n = 28, and amyloid negative, n = 16). We defined seven regions of interest in anterior temporal lobe and occipital lobe sections corresponding closely to those used as decision points in Braak staging. An algorithm based on the Braak histological staging procedure was applied to estimate Braak stages directly from the region of interest profiles in each subject. Quantitative region-based analysis of (18)F-AV-1451 images yielded region of interest and voxel level profiles that mirrored key features of neuropathological tau progression including profiles consistent with Braak stages 0 through VI. A simple set of decision rules enabled plausible Braak stages corresponding to stereotypical progression patterns to be objectively estimated in 149 (86%) of test subjects. An additional 12 (7%) subjects presented with predefined variant profiles (relative sparing of the hippocampus and/or occipital lobe). The estimated Braak stage was significantly associated with amyloid status, diagnostic category and measures of global cognition. In vivo (18)F-AV-1451 positron emission tomography images across the Alzheimer's disease spectrum could be classified into patterns similar to those prescribed by Braak neuropathological staging of tau pathology.
373 citations
VU University Amsterdam1, University of Toronto2, Peking Union Medical College3, Katholieke Universiteit Leuven4, Bosch5, Washington University in St. Louis6, Imperial College Healthcare7, University of California, Davis8, The Chinese University of Hong Kong9, Eli Lilly and Company10, University of Chicago11
TL;DR: Pemetrexed-cisplatin combined with TRT followed by consolidation pemetrexe was not superior to standard chemoradiotherapy for stage III unresectable nonsquamous non-small-cell lung cancer.
Abstract: PurposeThe phase III PROCLAIM study evaluated overall survival (OS) of concurrent pemetrexed-cisplatin and thoracic radiation therapy (TRT) followed by consolidation pemetrexed, versus etoposide-cisplatin and TRT followed by nonpemetrexed doublet consolidation therapy.Patients and MethodsPatients with stage IIIA/B unresectable nonsquamous non–small-cell lung cancer randomly received (1:1) pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 intravenously every 3 weeks for three cycles plus concurrent TRT (60 to 66 Gy) followed by pemetrexed consolidation every 3 weeks for four cycles (arm A), or standard therapy with etoposide 50 mg/m2 and cisplatin 50 mg/m2 intravenously, every 4 weeks for two cycles plus concurrent TRT (60 to 66 Gy) followed by two cycles of consolidation platinum-based doublet chemotherapy (arm B). The primary objective was OS. The study was designed as a superiority trial with 80% power to detect an OS hazard ratio of 0.74 with a type 1 error of .05.ResultsEnrollment was stopped early because ...
TL;DR: Two identically designed placebo‐controlled phase 3 studies assessing effects of solanezumab, an antiamyloid monoclonal antibody binding soluble amyloid‐β peptide, on cognitive and functional decline over 80 weeks in patients with mild‐to‐moderate Alzheimer's disease (AD).
Abstract: Introduction EXPEDITION and EXPEDITION2 were identically designed placebo-controlled phase 3 studies assessing effects of solanezumab, an antiamyloid monoclonal antibody binding soluble amyloid-β peptide, on cognitive and functional decline over 80 weeks in patients with mild-to-moderate Alzheimer's disease (AD). Primary findings for both studies have been published. Methods Secondary analyses of efficacy, biomarker, and safety endpoints in the pooled (EXPEDTION + EXPEDITION2) mild AD population were performed. Results In the mild AD population, less cognitive and functional decline was observed with solanezumab (n = 659) versus placebo (n = 663), measured by Alzheimer's Disease Assessment Scale Cognitive subscale, Mini-Mental State Examination, and Alzheimer's Disease Cooperative Study–Activities of Daily Living functional scale Instrumental ADLs. Baseline-to-endpoint changes did not differ between treatment groups for Alzheimer's Disease Cooperative Study–Activities of Daily Living functional scale, basic items of the ADCS-ADL, and Clinical Dementia Rating Sum of Boxes. Plasma/cerebrospinal fluid biomarker findings indicated target engagement by solanezumab. Solanezumab demonstrated acceptable safety. Efficacy findings for the moderate AD population are also provided. Discussion These findings describe solanezumab effects on efficacy/safety measures in a mild AD population. Another phase 3 study, EXPEDITION3, will investigate solanezumab's effects in a mild AD population.
TL;DR: The path to 2025 is discussed, and what is feasible in this time frame given the realities and challenges of AD drug development, with a focus on disease-modifying therapies (DMTs).
Abstract: The global impact of Alzheimer’s disease (AD) continues to increase, and focused efforts are needed to address this immense public health challenge. National leaders have set a goal to prevent or effectively treat AD by 2025. In this paper, we discuss the path to 2025, and what is feasible in this time frame given the realities and challenges of AD drug development, with a focus on disease-modifying therapies (DMTs). Under the current conditions, only drugs currently in late Phase 1 or later will have a chance of being approved by 2025. If pipeline attrition rates remain high, only a few compounds at best will meet this time frame. There is an opportunity to reduce the time and risk of AD drug development through an improvement in trial design; better trial infrastructure; disease registries of well-characterized participant cohorts to help with more rapid enrollment of appropriate study populations; validated biomarkers to better detect disease, determine risk and monitor disease progression as well as predict disease response; more sensitive clinical assessment tools; and faster regulatory review. To implement change requires efforts to build awareness, educate and foster engagement; increase funding for both basic and clinical research; reduce fragmented environments and systems; increase learning from successes and failures; promote data standardization and increase wider data sharing; understand AD at the basic biology level; and rapidly translate new knowledge into clinical development. Improved mechanistic understanding of disease onset and progression is central to more efficient AD drug development and will lead to improved therapeutic approaches and targets. The opportunity for more than a few new therapies by 2025 is small. Accelerating research and clinical development efforts and bringing DMTs to market sooner would have a significant impact on the future societal burden of AD. As these steps are put in place and plans come to fruition, e.g., approval of a DMT, it can be predicted that momentum will build, the process will be self-sustaining, and the path to 2025, and beyond, becomes clearer.
TL;DR: How TREM2 may control the microglia response to Aβ and its impact on microglial senescence is discussed, as well as the interaction of TREM 2 with other molecules that are encoded by gene variants associated with AD and the hypothetical consequences of the cleavage of T REM2 from the cell surface.
Abstract: Genome-wide association studies have identified rare variants of the gene that encodes triggering receptor expressed on myeloid cells 2 (TREM2) - an immune receptor that is found in brain microglia - as risk factors for non-familial Alzheimer disease (AD). Furthermore, animal studies have indicated that microglia have an important role in the brain response to amyloid-β (Aβ) plaques and that TREM2 variants may have an impact on such a function. We discuss how TREM2 may control the microglial response to Aβ and its impact on microglial senescence, as well as the interaction of TREM2 with other molecules that are encoded by gene variants associated with AD and the hypothetical consequences of the cleavage of TREM2 from the cell surface.
TL;DR: These findings demonstrate that psychological "stress" is sensed by the innate immune system in the brain via the ATP/P2X7R-NLRP3 inflammasome cascade, and they identify novel therapeutic targets for the treatment of stress-related mood disorders and comorbid illnesses.
TL;DR: Modification of existing cisplatin-based treatments can still lead to improvements in patient outcomes and experiences, and better understanding of the molecular mechanisms of cisPlatin resistance, identification of predictive markers and the development of newer, more effective and less toxic platinum agents is required.
University of Exeter1, University of Aberdeen2, University of the Highlands and Islands3, King's College London4, National Institutes of Health5, University of Helsinki6, University of Hong Kong7, Utrecht University8, Karolinska Institutet9, Eli Lilly and Company10, University College London11, University of Essex12, Royal Devon and Exeter Hospital13
TL;DR: This paper performed a multi-stage epigenome-wide association study, quantifying genome-wide patterns of DNA methylation in a total of 1714 individuals from three independent sample cohorts.
Abstract: Schizophrenia is a highly heritable, neuropsychiatric disorder characterized by episodic psychosis and altered cognitive function. Despite success in identifying genetic variants associated with schizophrenia, there remains uncertainty about the causal genes involved in disease pathogenesis and how their function is regulated. We performed a multi-stage epigenome-wide association study, quantifying genome-wide patterns of DNA methylation in a total of 1714 individuals from three independent sample cohorts. We have identified multiple differentially methylated positions and regions consistently associated with schizophrenia across the three cohorts; these effects are independent of important confounders such as smoking. We also show that epigenetic variation at multiple loci across the genome contributes to the polygenic nature of schizophrenia. Finally, we show how DNA methylation quantitative trait loci in combination with Bayesian co-localization analyses can be used to annotate extended genomic regions nominated by studies of schizophrenia, and to identify potential regulatory variation causally involved in disease. This study represents the first systematic integrated analysis of genetic and epigenetic variation in schizophrenia, introducing a methodological approach that can be used to inform epigenome-wide association study analyses of other complex traits and diseases. We demonstrate the utility of using a polygenic risk score to identify molecular variation associated with etiological variation, and of using DNA methylation quantitative trait loci to refine the functional and regulatory variation associated with schizophrenia risk variants. Finally, we present strong evidence for the co-localization of genetic associations for schizophrenia and differential DNA methylation.
TL;DR: The results show that a high-fat diet (HFD; ~16 weeks) causes anxiety and anhedonic behaviors, and pharmacological blockade of the innate immune inflammasome system by repeated administration of an inhibitor of the purinergic P2X7 receptor blocks the anxiety caused by HFD.
Harvard University1, University of Rochester2, University of Washington3, Stanford University4, East Carolina University5, Oslo University Hospital6, Washington University in St. Louis7, French Institute of Health and Medical Research8, University of Kiel9, MetroHealth10, University of Maryland, Baltimore11, Tufts University12, Eli Lilly and Company13, Johnson & Johnson14, University of Florida15, Astellas Pharma16, National Institutes of Health17, Imperial College London18, Pfizer19, Columbia University20, Ceres21, University of Pittsburgh22, Purdue Pharma23, Rambam Health Care Campus24
TL;DR: Evidence is presented on the most promising phenotypic characteristics of patients that are most predictive of individual variation in analgesic treatment outcomes, and the measurement tools that are best suited to evaluate these characteristics.
Abstract: There is tremendous interpatient variability in the response to analgesic therapy (even for efficacious treatments), which can be the source of great frustration in clinical practice This has led to calls for "precision medicine" or personalized pain therapeutics (ie, empirically based algorithms that determine the optimal treatments, or treatment combinations, for individual patients) that would presumably improve both the clinical care of patients with pain and the success rates for putative analgesic drugs in phase 2 and 3 clinical trials However, before implementing this approach, the characteristics of individual patients or subgroups of patients that increase or decrease the response to a specific treatment need to be identified The challenge is to identify the measurable phenotypic characteristics of patients that are most predictive of individual variation in analgesic treatment outcomes, and the measurement tools that are best suited to evaluate these characteristics In this article, we present evidence on the most promising of these phenotypic characteristics for use in future research, including psychosocial factors, symptom characteristics, sleep patterns, responses to noxious stimulation, endogenous pain-modulatory processes, and response to pharmacologic challenge We provide evidence-based recommendations for core phenotyping domains and recommend measures of each domain
University College London1, Newcastle University2, University of Oxford3, Eisai4, Pfizer5, Cardiff University6, University of Cambridge7, University of Birmingham8, University of Leeds9, National Cancer Research Institute10, University of Glasgow11, AstraZeneca12, Merck KGaA13, Astex14, Vertex Pharmaceuticals15, Institute of Cancer Research16, Eli Lilly and Company17, University of Manchester18, Sarah Cannon Research Institute19, Genentech20
TL;DR: The CTRad Working Group's consensus recommendations to increase the number of novel drugs being successfully registered in combination with radiotherapy to improve clinical outcomes for patients with cancer are highlighted.
Abstract: In countries with the best cancer outcomes, approximately 60% of patients receive radiotherapy as part of their treatment, which is one of the most cost-effective cancer treatments. Notably, around 40% of cancer cures include the use of radiotherapy, either as a single modality or combined with other treatments. Radiotherapy can provide enormous benefit to patients with cancer. In the past decade, significant technical advances, such as image-guided radiotherapy, intensity-modulated radiotherapy, stereotactic radiotherapy, and proton therapy enable higher doses of radiotherapy to be delivered to the tumour with significantly lower doses to normal surrounding tissues. However, apart from the combination of traditional cytotoxic chemotherapy with radiotherapy, little progress has been made in identifying and defining optimal targeted therapy and radiotherapy combinations to improve the efficacy of cancer treatment. The National Cancer Research Institute Clinical and Translational Radiotherapy Research Working Group (CTRad) formed a Joint Working Group with representatives from academia, industry, patient groups and regulatory bodies to address this lack of progress and to publish recommendations for future clinical research. Herein, we highlight the Working Group's consensus recommendations to increase the number of novel drugs being successfully registered in combination with radiotherapy to improve clinical outcomes for patients with cancer.
TL;DR: The current understanding of some of the key aspects of biased signaling that are related to these questions are discussed, including mechanistic insights in the nature ofbiased signaling and methods for measuring ligand bias, as well as relevant examples of drug discovery applications and medicinal chemistry strategies that highlight the challenges and opportunities in this rapidly evolving field.
TL;DR: This Review assesses emerging strategies and agents for CKD treatment, highlighting the associated challenges in their clinical development.
Abstract: Chronic kidney disease (CKD) represents a leading cause of death in the United States. There is no cure for this disease, with current treatment strategies relying on blood pressure control through blockade of the renin-angiotensin system. Such approaches only delay the development of end-stage kidney disease and can be associated with serious side effects. Recent identification of several novel mechanisms contributing to CKD development - including vascular changes, loss of podocytes and renal epithelial cells, matrix deposition, inflammation and metabolic dysregulation - has revealed new potential therapeutic approaches for CKD. This Review assesses emerging strategies and agents for CKD treatment, highlighting the associated challenges in their clinical development.
TL;DR: Plaque psoriasis is a chronic and often debilitating skin disorder and proinflammatory cytokines are known to play a key role in the disease process.
Abstract: SummaryBackground
Plaque psoriasis is a chronic and often debilitating skin disorder and proinflammatory cytokines are known to play a key role in the disease process.
Objectives
To evaluate the safety and efficacy of baricitinib, an oral Janus kinase (JAK) 1/JAK2 inhibitor, in patients with moderate-to-severe psoriasis in a randomized, double-blind, placebo-controlled, dose-ranging phase 2b study.
Methods
Patients were randomized (n = 271) to receive placebo or oral baricitinib at 2, 4, 8 or 10 mg once daily for 12 weeks (Part A). Dose adjustment for 12 additional weeks was based on percentage improvement in the Psoriasis Area and Severity Index (PASI) score. The primary end point was Psoriasis Area and Severity Index (PASI) 75% (PASI-75) at 12 weeks for North American patients (n = 238); secondary end points were safety and efficacy measures in the entire population.
Results
At week 12, more North American patients in the 8-mg (43%) and 10-mg (54%) baricitinib groups than in placebo group (17%; P < 0·05) achieved PASI-75. All baricitinib-treated groups had greater mean changes from baseline in their PASI scores (P < 0·05) at 12 weeks and (except 2 mg) had higher rates of PASI-50 than the placebo group; statistically significant PASI-90 responses were achieved in the 8-mg and 10-mg groups at 8 and 12 weeks. More than 81% of PASI-75 responders maintained their scores through 24 weeks. During Part A, study discontinuations due to adverse events (AEs) were 0%, 0%, 2·8%, 6·3% and 5·8% and treatment-emergent AE rates were 44%, 50%, 47%, 58% and 64% for placebo and 2-, 4-, 8- and 10-mg baricitinib groups, respectively. No opportunistic infections were observed in any treatment group. Dose-dependent changes in laboratory values were observed.
Conclusions
Patients with moderate-to-severe psoriasis treated with baricitinib for 12 weeks achieved significant improvements in PASI-75.
TL;DR: Tabalumab had biological activity—changes in anti-dsDNA, complement, B cells and immunoglobulins—consistent with BAFF pathway inhibition; safety profiles were similar with tabalumab and placebo; key clinical efficacy endpoints did not achieve statistical significance.
Abstract: Objectives Evaluate efficacy and safety of tabalumab, a human IgG4 monoclonal antibody that binds and neutralises membrane and soluble B-cell activating factor (BAFF) versus placebo plus standard of care (SoC) in patients with systemic lupus erythematosus (SLE). Methods This phase III, 52-week study randomised 1164 patients with moderate-to-severe SLE (Safety of Estrogens in Lupus Erythematosus National Assessment—SLE Disease Activity Index ≥6 at baseline). Patients received SoC plus subcutaneous injections of tabalumab or placebo, starting with a loading dose (240 mg) at week 0 and followed by 120 mg every two weeks (120 Q2W, n=387), 120 mg every four weeks (120 Q4W, n=389) or placebo Q2W (n=388). Primary endpoint: proportion of patients achieving SLE Responder Index 5 (SRI-5) response at week 52. Results Similar proportions of patients in each group achieved SRI-5 response at week 52 (120 Q2W: 31.8%; 120 Q4W: 35.2% and placebo: 29.3%). Key secondary endpoints were not met. In a sensitivity analysis not excluding patients who decreased antimalarials or immunosuppressants, SRI-5 response was achieved with 120 Q4W (37.0% vs 29.8% placebo; p=0.021), but not 120 Q2W (34.1%; p=0.171). Significant reductions in anti-dsDNA antibodies, increases in C3 and C4, and reductions in total B cells and immunoglobulins were observed with tabalumab. No differences were observed between treatment groups in percentage of deaths (120 Q2W: 0.8%; 120 Q4W: 0.5%; placebo: 0.5%), serious adverse events (AEs) (range 11.1–14.4%) or treatment-emergent AEs (range 81.1–82.3%). Conclusions Tabalumab had biological activity—changes in anti-dsDNA, complement, B cells and immunoglobulins—consistent with BAFF pathway inhibition. Key clinical efficacy endpoints did not achieve statistical significance. Safety profiles were similar with tabalumab and placebo. Trial registration number NCT01196091.
TL;DR: Key mechanistic insights include the observation of electron donor-acceptor complexes in solution as well as a high dependence on photon flux have culminated in the application of this chemistry on a kilogram scale, demonstrating the utility of this reagent combination for preparative applications.
TL;DR: Patients treated with tabalumab had greater SRI-5 response rates in a serologically active subset and improvements in more stringent SRI cut-offs, SELENA-SLEDAI, Physician's Global Assessment, anti-double-stranded DNA antibodies, complement, total B cells and immunoglobulins.
Abstract: Objectives To evaluate the efficacy and safety of tabalumab, a human IgG4 monoclonal antibody that neutralises membrane and soluble B-cell activating factor (BAFF). Methods This randomised, placebo-controlled study enrolled 1124 patients with moderate-to-severe systemic lupus erythematosus (SLE) (Safety of Estrogens in Lupus Erythematosus National Assessment- SLE Disease Activity Index ≥6 at baseline). Patients received standard of care plus subcutaneous study drug, starting with a loading dose (240 mg) at week 0 and followed by 120 mg every 2 weeks (120 Q2W), 120 mg every 4 weeks (120 Q4W) or placebo. Primary endpoint was proportion achieving SLE Responder Index 5 (SRI-5) improvement at week 52. Results Clinical characteristics were balanced across groups. The primary endpoint was met with 120 Q2W (38.4% vs 27.7%, placebo; p=0.002), but not with the less frequent 120 Q4W regimen (34.8%, p=0.051). Although key secondary endpoints (time to severe flare, corticosteroid sparing and fatigue) were not met, patients treated with tabalumab had greater SRI-5 response rates in a serologically active subset and improvements in more stringent SRI cut-offs, SELENA-SLEDAI, Physician9s Global Assessment, anti-double-stranded DNA antibodies, complement, total B cells and immunoglobulins. The incidences of deaths, serious adverse events (AEs), and treatment-emergent AEs were similar in the 120 Q2W, 120 Q4W and placebo groups, but depression and suicidal ideation, albeit rare events, were more commonly reported with tabalumab. Conclusion SRI-5 was met with 120 Q2W and although key secondary endpoints were not met, numerous other secondary endpoints significantly improved in addition to pharmacodynamic evidence of BAFF pathway blockade. The safety profile for tabalumab was similar to placebo, except for depression and suicidality, which were uncommon. Trial registration number NCT01205438.
TL;DR: Galunisertib + lomustine failed to demonstrate improved OS relative to placebo + lmustine, and patients treated with galun isertib alone had fewer drug-related grade 3/4 adverse events compared with lomUSTine-treated patients.
Abstract: Background The combination of galunisertib, a transforming growth factor (TGF)-β receptor (R)1 kinase inhibitor, and lomustine was found to have antitumor activity in murine models of glioblastoma. Methods Galunisertib (300 mg/day) was given orally 14 days on/14 days off (intermittent dosing). Lomustine was given as approved. Patients were randomized in a 2:1:1 ratio to galunisertib + lomustine, galunisertib monotherapy, or placebo + lomustine. The primary objective was overall survival (OS); secondary objectives were safety, pharmacokinetics (PKs), and antitumor activity. Results One hundred fifty-eight patients were randomized: galunisertib + lomustine (N = 79), galunisertib (N = 39), and placebo + lomustine (N = 40). Baseline characteristics were: male (64.6%), white (75.3%), median age 58 years, ECOG performance status (PS) 1 (63.3%), and primary glioblastoma (93.7%). The PKs of galunisertib were not altered with lomustine, and galunisertib had a median half-life of ∼8 hours. Median OS in months (95% credible interval [CrI]) for galunisertib + lomustine was 6.7 (range: 5.3-8.5), 8.0 (range: 5.7-11.7) for galunisertib alone, and 7.5 (range: 5.6-10.3) for placebo + lomustine. There was no difference in OS for patients treated with galunisertib + lomustine compared with placebo + lomustine [P (HR Conclusions Galunisertib + lomustine failed to demonstrate improved OS relative to placebo + lomustine. Efficacy outcomes were similar in all 3 arms. Clinical trial registration NCT01582269, ClinicalTrials.gov.
University of Washington1, Fred Hutchinson Cancer Research Center2, Broad Institute3, Pacific Northwest National Laboratory4, Johns Hopkins University5, Washington University in St. Louis6, Vanderbilt University7, National Institutes of Health8, University of North Carolina at Chapel Hill9, Eli Lilly and Company10, ETH Zurich11, Mayo Clinic12, National Institute of Standards and Technology13, Quest Diagnostics14, Institute for Systems Biology15, University of Utah16, Pfizer17, Thermo Fisher Scientific18, Cedars-Sinai Medical Center19, Wake Forest University20, Baylor College of Medicine21
TL;DR: The Clinical Proteomic Tumor Analysis Consortium of the National Cancer Institute has collaborated with clinical laboratorians, peptide manufacturers, metrologists, representatives of the pharmaceutical industry, and other professionals to develop a consensus set of recommendations for peptide procurement, characterization, storage, and handling.
Abstract: BACKGROUND: For many years, basic and clinical researchers have taken advantage of the analytical sensitivity and specificity afforded by mass spectrometry in the measurement of proteins. Clinical laboratories are now beginning to deploy these work flows as well. For assays that use proteolysis to generate peptides for protein quantification and characterization, synthetic stable isotope–labeled internal standard peptides are of central importance. No general recommendations are currently available surrounding the use of peptides in protein mass spectrometric assays.
CONTENT: The Clinical Proteomic Tumor Analysis Consortium of the National Cancer Institute has collaborated with clinical laboratorians, peptide manufacturers, metrologists, representatives of the pharmaceutical industry, and other professionals to develop a consensus set of recommendations for peptide procurement, characterization, storage, and handling, as well as approaches to the interpretation of the data generated by mass spectrometric protein assays. Additionally, the importance of carefully characterized reference materials—in particular, peptide standards for the improved concordance of amino acid analysis methods across the industry—is highlighted. The alignment of practices around the use of peptides and the transparency of sample preparation protocols should allow for the harmonization of peptide and protein quantification in research and clinical care.
TL;DR: This in vivo dMRI study demonstrates that N ODDI identifies potential tissue sources contributing to DTI indices and NODDI may provide greater specificity to pathology in Alzheimer's disease.
TL;DR: The evidence is discussed that autoimmune type 1 diabetes has a broad clinical phenotype with diverse therapeutic options, while the term non-autoimmune type 2 diabetes obscures the optimal management strategy because it encompasses substantial heterogeneity.
Abstract: Diabetes is not a single homogeneous disease but composed of many diseases with hyperglycaemia as a common feature. Four factors have, historically, been used to identify this diversity: the age at onset; the severity of the disease, i.e. degree of loss of beta cell function; the degree of insulin resistance and the presence of diabetes-associated autoantibodies. Our broad understanding of the distinction between the two major types, type 1 diabetes mellitus and type 2 diabetes mellitus, are based on these factors, but it has become apparent that they do not precisely capture the different disease forms. Indeed, both major types of diabetes have common features, encapsulated by adult-onset autoimmune diabetes and maturity-onset diabetes of the young. As a result, there has been a repositioning of our understanding of diabetes. In this review, drawing on recent literature, we discuss the evidence that autoimmune type 1 diabetes has a broad clinical phenotype with diverse therapeutic options, while the term non-autoimmune type 2 diabetes obscures the optimal management strategy because it encompasses substantial heterogeneity. Underlying these developments is a general progression towards precision medicine with the need for precise patient characterisation, currently based on clinical phenotypes but in future augmented by laboratory-based tests.