Katie Streicher

Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: a randomised, double-blind, placebo-controlled, phase 2b trial

BACKGROUND Interleukin 13 is a central mediator of asthma. Tralokinumab is a human interleukin-13 neutralising monoclonal antibody. We aimed to assess the efficacy and safety of two dosing regimens of tralokinumab in patients with severe uncontrolled asthma. METHODS We did a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 2b study at 98 sites in North America, South America, Europe, and Asia. Patients aged 18-75 years with severe asthma and two to six exacerbations in the previous year were randomly assigned (1:1), via an interactive voice-response or web-response system, to one of two dosing regimen groups (every 2 weeks, or every 2 weeks for 12 weeks then every 4 weeks) and further randomised (2:1), via computer-generated permuted-block randomisation (block size of six), to receive tralokinumab 300 mg or placebo for 1 year. All participants received high-dose fluticasone and salmeterol and continued other pre-study controller drugs. Treatment was administered by an unmasked study investigator not involved in the management of patients; all other study site personnel, patients, the study funder, and data analysts were masked to treatment allocation. The primary endpoint was the annual asthma exacerbation rate at week 52 in the intention-to-treat population. Key secondary endpoints included prebronchodilator forced expiratory volume in 1 s (FEV1), Asthma Control Questionnaire-6 (ACQ-6), and Asthma Quality of Life Questionnaire-Standardised Version (AQLQ[S]). This trial is registered with ClinicalTrials.gov, number NCT01402986. FINDINGS Between Oct 4, 2011, and Feb 22, 2014, we randomly assigned 452 patients to receive placebo (n=151) or tralokinumab every 2 weeks (n=150) or every 4 weeks (n=151), of whom 383 (85%) completed the treatment period up to week 52. The annual asthma exacerbation rate at week 52 was similar between patients receiving tralokinumab every 2 weeks (0.91 per patient per year [95% CI 0.76-1.08]) and every 4 weeks (0.97 [0.81-1.14]), and those receiving placebo (0.90 [0.75-1.08]). At week 52, percentage changes in annual asthma exacerbation rate were not significant with tralokinumab every 2 weeks or every 4 weeks versus placebo (6% [95% CI -31 to 33; p=0.709] and -2% [-46 to 29; p=0.904], respectively), with positive changes showing a decrease in exacerbation rate and negative changes showing an increase. Prebronchodilator FEV1 was significantly increased compared with placebo for tralokinumab every 2 weeks (change from baseline 7.3% [95% CI 2.6-12.0]; p=0.003), but not every 4 weeks (1.8% [-2.9 to 6.6]; p=0.448); however, we did not identify significant changes in the other key secondary endpoints. In a post-hoc subgroup analysis of patients not on long-term oral corticosteroids and with baseline FEV1 reversibility of 12% or greater, we noted a non-significant improvement in asthma exacerbation rate (44% [95% CI -22 to 74]; p=0.147) and significant improvements in key secondary endpoints (FEV1 12.2% [1.7-22.7]; p=0.022; ACQ-6 -0.55 [-1.07 to -0.04]; p=0.036; and AQLQ[S] 0.70 [0.12-1.28]; p=0.019) in patients given tralokinumab every 2 weeks (n=33) compared with placebo (n=48). In patients in this subgroup who also had baseline serum dipeptidyl peptidase-4 (DPP-4) higher than the population baseline median, we noted additional improvements in prebronchodilator FEV1, ACQ-6, and AQLQ(S), and, in those with periostin concentrations higher than the median, we noted improvements in asthma exacerbation rate, prebronchodilator FEV1, and ACQ-6. The incidence of treatment-emergent adverse events was similar between the tralokinumab and placebo groups. Treatment-emergent serious adverse events regarded as related to the study drug were pneumonia (one [1%] patient in the placebo group), pneumococcal pneumonia (one [1%] in the tralokinumab every 2 weeks group), angioedema (one [1%] in the placebo group), and worsening asthma (one [1%] in the tralokinumab every 2 weeks group and two [1%] in the tralokinumab every 4 weeks group). INTERPRETATION In this phase 2b study, both tralokinumab regimens had an acceptable safety and tolerability profile but did not significantly reduce asthma exacerbation rates in patients with severe uncontrolled asthma. Improvement in FEV1 with tralokinumab given every 2 weeks and results of post-hoc subgroup analyses suggested a possible treatment effect in a defined population of patients with severe uncontrolled asthma. This effect is being further investigated in ongoing phase 3 trials, along with the potential utility of DPP-4 and periostin as biomarkers of interleukin-13 pathway activation. FUNDING MedImmune.

A novel oncogenic role for the miRNA-506-514 cluster in initiating melanocyte transformation and promoting melanoma growth.

Malignant melanoma is the most aggressive form of skin cancer and its incidence has doubled in the last two decades. It represents only 4% of skin cancer cases per year, but causes as many as 74% of skin cancer deaths. Early detection of malignant melanoma is associated with survival rates of up to 90%, but later detection (stage III to stage IV) is associated with survival rates of only 10%. Dysregulation of microRNA (miRNA) expression has been linked to tumor development and progression by functioning either as a tumor suppressor, an oncogene or a metastasis regulator in multiple cancer types. To understand the role of miRNA in the pathogenesis of malignant melanoma and identify biomarkers of metastasis, miRNA expression profiles in skin punches from 33 metastatic melanoma patients and 14 normal healthy donors were compared. We identified a cluster of 14 miRNAs on the X chromosome, termed the miR-506-514 cluster, which was consistently overexpressed in nearly all melanomas tested (30–60 fold, P<0.001), regardless of mutations in N-ras or B-raf. Inhibition of the expression of this cluster as a whole, or one of its sub-clusters (Sub-cluster A) consisting of six mature miRNAs, led to significant inhibition of cell growth, induction of apoptosis, decreased invasiveness and decreased colony formation in soft agar across multiple melanoma cell lines. Sub-cluster A of the miR-506-514 cluster was critical for maintaining the cancer phenotype, but the overexpression of the full cluster was necessary for melanocyte transformation. Our results provide new insights into the functional role of this miRNA cluster in melanoma, and suggest new approaches to treat or diagnose this disease.

Inhibition of Myogenic MicroRNAs 1, 133, and 206 by Inflammatory Cytokines Links Inflammation and Muscle Degeneration in Adult Inflammatory Myopathies

The molecular basis of inflammatory myopathies such as dermatomyositis (DM), polymyositis, and inclusion body myositis, which share the characteristics of chronic muscle inflammation and skeletal muscle wasting, are poorly understood. As such, effective targeted treatments for these diseases are lacking, resulting in critical unmet medical needs for these devastating diseases. The purpose of this study was to identify possible new targets for drug development by exploring the mechanism by which inflammation may play a role in the pathology of the inflammatory myopathies.

A whole genome transcriptional analysis of the early immune response induced by live attenuated and inactivated influenza vaccines in young children.

The protective mechanisms of influenza vaccines in young children are not completely understood. A phase 2 clinical study was conducted in 85 children 12-35 months of age to describe and compare the immune responses to live attenuated influenza vaccine (LAIV) with trivalent inactivated influenza vaccine (TIV). To better understand the biology of vaccine effects, oligonucleotide microarrays were employed to measure the genome-wide changes in transcript profiles in whole blood at approximately 7 days after 1 dose of LAIV or TIV. Of the total 265 differentially expressed genes identified in this study, 6 clusters of genes were identified to be tightly coexpressed, many of which are likely modulated by cytokines including type 1 interferons (IFNs) and granulocyte-macrophage colony-stimulating factor. Additional functional analyses revealed that the type 1 IFN pathway and cell cycle regulation-related genes are enriched in the 6 coexpressed gene sets. Promoter characterization of these coexpressed genes also supported this conclusion. Moreover, it is suggested that the IFN-stimulated response element is likely to be a potential bidirectional promoter, and the CCAAT/enhancer-binding protein might cooperate with the E2F transcription factor family in the regulation of the cell cycle in the early immune response induced by the influenza vaccine. Overall, our study clearly indicates that the expression profile changes induced by LAIV are significantly different from those induced by TIV. These results suggest that the pattern of overexpression of type 1 IFN-stimulated genes can potentially be used as a biomarker to identify the early vaccination response of LAIV and may also explain, to a certain extent, previous clinical study observations of LAIV-induced protection against influenza-like illness in the first 2 weeks after administration.

MicroRNA‐206 induces G1 arrest in melanoma by inhibition of CDK4 and Cyclin D

Expression profiling of microRNAs in melanoma lesional skin biopsies compared with normal donor skin biopsies, as well as melanoma cell lines compared with normal melanocytes, revealed that hsa‐miR‐206 was down‐regulated in melanoma (−75.4‐fold, P = 1.7 × 10−4). MiR‐206 has been implicated in a large number of cancers, including breast, lung, colorectal, ovarian, and prostate cancers; however, its role in tumor development remains largely unknown, its biologic function is poorly characterized, and its targets affecting cancer cells are largely unknown. MiR‐206 reduced growth and migration/invasion of multiple melanoma cell lines. Bioinformatics identified cell cycle genes CDK2, CDK4, Cyclin C, and Cyclin D1 as strong candidate targets. Western blots and 3′UTR reporter gene assays revealed that miR‐206 inhibited translation of CDK4, Cyclin D1, and Cyclin C. Additionally, hsa‐miR‐206 transfection induced G1 arrest in multiple melanoma cell lines. These observations support hsa‐miR‐206 as a tumor suppressor in melanoma and identify Cyclin C, Cyclin D1, and CDK4 as miR‐206 targets.

Pharmacogenomics and Translational Simulations to Bridge Indications for an Anti-Interferon-α Receptor Antibody

A type I interferon (IFN) gene signature shared by systemic lupus erythematous (SLE) and systemic sclerosis (SSc) was used to evaluate an anti‐type I IFN‐α receptor (IFN‐αR) monoclonal antibody, MEDI‐546, in a phase I trial in SSc. MEDI‐546 suppressed IFN signature in blood and skin of SSc patients in a dose‐dependent manner. To bridge clinical indications to SLE, we developed a model incorporating (i) pharmacokinetics (PK) and pharmacodynamics (PD) in SSc patients, (ii) internalization kinetics of MEDI‐546/IFN‐αR complex, and (iii) the different IFN signatures between SSc and SLE. Simulations predicted that i.v. administration of MEDI‐546 at 300‐ or 1,000‐mg monthly doses could suppress IFN signature in blood to levels of healthy subjects in 53 and 68% of SLE patients, respectively. An innovative approach utilizing a novel biomarker characterized the PD of MEDI‐546 by modeling and simulation and allowed rapid progression of MEDI‐546 from a phase I study in SSc to a randomized, multiple‐dose phase II trial.

Altered expression of insulin receptor isoforms in breast cancer.

Purpose Insulin-like growth factor (IGF) signaling through human insulin receptor isoform A (IR-A) contributes to tumorigenesis and intrinsic resistance to anti-IGF1R therapy. In the present study, we (a) developed quantitative TaqMan real time-PCR-based assays (qRT-PCR) to measure human insulin receptor isoforms with high specificity, (b) evaluated isoform expression levels in molecularly-defined breast cancer subtypes, and (c) identified the IR-A:IR-B mRNA ratio as a potential biomarker guiding patient stratification for anti-IGF therapies. Experimental Design mRNA expression levels of IR-A and IR-B were measured in 42 primary breast cancers and 19 matched adjacent normal tissues with TaqMan qRT-PCR assays. The results were further confirmed in 165 breast cancers. The tumor samples were profiled using whole genome microarrays and subsequently subtyped using the PAM50 breast cancer gene signature. The relationship between the IR-A:IR-B ratio and cancer subtype, as well as markers of proliferation were characterized. Results The mRNA expression levels of IR-A in the breast tumors were similar to those observed in the adjacent normal tissues, while the mRNA levels of IR-B were significantly decreased in tumors. The IR-A:IR-B ratio was significantly higher in luminal B breast cancer than in luminal A. Strong concordance between the IR-A:IR-B ratio and the composite Oncotype DX proliferation score was observed for stratifying the latter two breast cancer subtypes. Conclusions The reduction in IR-B expression is the key to the altered IR-A:IR-B ratio observed in breast cancer. The IR-A:IR-B ratio may have biomarker utility in guiding a patient stratification strategy for an anti-IGF therapeutic.

The Plasma Cell Signature in Autoimmune Disease

Production of pathogenic autoantibodies by self‐reactive plasma cells (PCs) is a hallmark of autoimmune diseases. We undertook this study to investigate the prevalence of PCs and their relationship to known pathogenic pathways to increase our understanding of the role of PCs in disease progression and treatment response.

Genomic Landscape Survey Identifies SRSF1 as a Key Oncodriver in Small Cell Lung Cancer.

Small cell lung cancer (SCLC) is an aggressive disease with poor survival. A few sequencing studies performed on limited number of samples have revealed potential disease-driving genes in SCLC, however, much still remains unknown, particularly in the Asian patient population. Here we conducted whole exome sequencing (WES) and transcriptomic sequencing of primary tumors from 99 Chinese SCLC patients. Dysregulation of tumor suppressor genes TP53 and RB1 was observed in 82% and 62% of SCLC patients, respectively, and more than half of the SCLC patients (62%) harbored TP53 and RB1 mutation and/or copy number loss. Additionally, Serine/Arginine Splicing Factor 1 (SRSF1) DNA copy number gain and mRNA over-expression was strongly associated with poor survival using both discovery and validation patient cohorts. Functional studies in vitro and in vivo demonstrate that SRSF1 is important for tumorigenicity of SCLC and may play a key role in DNA repair and chemo-sensitivity. These results strongly support SRSF1 as a prognostic biomarker in SCLC and provide a rationale for personalized therapy in SCLC.

Increased IR-A/IR-B ratio in non-small cell lung cancers associates with lower epithelial-mesenchymal transition signature and longer survival in squamous cell lung carcinoma

BackgroundTo evaluate the insulin receptor isoform mRNA expression status in non-small cell lung cancer (NSCLC) patients.MethodsRNA-seq data from 614 NSCLC [355 adenocarcinomas (LUAD) and 259 squamous cell carcinomas (LUSC)] and 92 normal lung specimens were obtained from The Cancer Genome Atlas (TCGA) to evaluate the mRNA expression of insulin receptor isoform A (IR-A) and insulin receptor isoform B (IR-B). The differential expression status of the insulin receptor isoforms in NSCLC patients was confirmed using qRT-PCR assays with lung cancer cDNA arrays and primary tumor samples.ResultsThe mRNA expression levels of IR-B were significantly lower in some NSCLC samples compared to normal lung specimens, including both LUAD and LUSC. Notably, no IR-B transcripts were detected - only the IR-A isoform was expressed in 11% of NSCLC patients. This decrease in IR-B expression contributed to an elevated IR-A/IR-B ratio, which was also associated with lower epithelial-mesenchymal transition gene signatures in NSCLC and longer patient survival under standard of care in LUSC. In addition to NSCLC, RNA-seq data from TCGA revealed a similar increase in IR-A/IR-B ratio in many other cancer types, with high prevalence in acute myeloid leukemia, glioblastoma multiforme, and brain lower grade glioma.ConclusionsOur results indicate a common reduction of the mRNA expression level of IR-B and an increased IR-A/IR-B mRNA ratio in NSCLC and other tumor types. The relationship of altered IR-A/IR-B ratios with cancer progression and patient survival should be prospectively explored in future studies.