Hertz D.L.,University of North Carolina at Chapel Hill |
Roy S.,North Carolina State University |
Motsinger-Reif A.A.,University of North Carolina at Chapel Hill |
Motsinger-Reif A.A.,North Carolina State University |
And 8 more authors.
Annals of Oncology | Year: 2013
Background: Paclitaxel-induced neuropathy is an adverse event that often leads to therapeutic disruption and patient discomfort. We attempted to replicate a previously reported association between increased neuropathy risk and CYP2C8*3 genotype.Patients and methods: Demographic, treatment, and toxicity data were collected for paclitaxel-treated breast cancer patients who were genotyped for the CYP2C8*3 K399R (rs10509681) variant. A log-rank test was used in the primary analysis of European-American patients. An additional independent replication was then attempted in a cohortof African-American patients, followed by modeling of the entire patient cohort with relevant covariates.Results: In the primary analysis of 209 European patients, there was an increased risk of paclitaxel-induced neuropathy related to CYP2C8*3 status [HR (per allele) = 1.93 (95% CI: 1.05-3.55), overall log-rank P = 0.006]. The association was replicated in direction and magnitude of effect in 107 African-American patients (P = 0.043). In the Cox model using the entire mixed-race cohort (n = 411), each CYP2C8*3 allele approximately doubled the patient's risk of grade 2+ neuropathy (P = 0.004), and non-Europeans were at higher neuropathy risk than Europeans of similar genotype (P = 0.030).Conclusions: The increased risk of paclitaxel-induced neuropathy in patients who carry the CYP2C8*3 variant was replicated in two racially distinct patient cohorts. © The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology.All rights reserved.
Shen X.,U.S. Center for Disease Control and Prevention |
Yuan Z.,U.S. Center for Disease Control and Prevention |
Mei J.,U.S. Center for Disease Control and Prevention |
Zhang Z.,U.S. Center for Disease Control and Prevention |
And 18 more authors.
Drug Safety | Year: 2014
Introduction: The most reliable liver safety signal in a clinical trial is considered to be 'Hy's Law cases' defined as subjects experiencing hepatocellular injury and serum bilirubin elevations with no more likely cause than study drug. However, there is little published data to support the current biochemical criteria for Hy's Law cases or their use to estimate postmarketing risk of severe liver injury. Objectives: The primary objective of this study was to identify and characterize Hy's Law cases in patients treated for tuberculosis (TB). A secondary objective was to identify patient risk factors for drug-induced liver injuries. © Springer International Publishing Switzerland 2013.
News Article | February 15, 2017
Akonni Biosystems, a molecular diagnostics (MDx) company that develops, manufactures, and intends to market integrated MDx systems, announced today the appointments of key members to its leadership team. Michael Murphy, M.Sc. joined as Vice President, Regulatory Affairs; Sandra Foster, Ph.D. as Director of Quality Assurance and Michael Reinemann, MPH as Director of Business Development. The new additions to Akonni’s leadership team fill critical gaps needed to ensure Akonni’s successful commercialization of its robust product lines. These experienced individuals further strengthen Akonni’s leadership team as the company prepares for its first FDA submission for a pharmacogenomic test on the Akonni TruDiagnosis® system. Michael Murphy is an industry pioneer and thought-leader in the field of Pharmacogenomics, with more than 33 years of scientific and business experience. He is a serial entrepreneur in the personalized medicine space and in 1997 was founder of Intek Labs, the first international Pharmacogenomics company. Following the acquisition of Intek Labs by PPD, Inc., Mr. Murphy was the co-founder, President and CEO of Gentris Corporation. Gentris was acquired by Cancer Genetics Inc. in 2015 while Mr. Murphy served on the Board of Directors at Gentris. In 2007, Gentris spun off its diagnostic group and Mr. Murphy served as the President and CEO of ParagonDx, one of the first companies to win FDA clearance of a Rapid Genotyping Kit for patients taking the anticoagulant, Warfarin. He has also held Executive Vice President management positions with PPGx and Clingenix. Prior to joining Akonni, Mr. Murphy served for 7 years as President of Conatus Consulting, a regulatory consulting practice based in Raleigh, NC. Mr. Murphy is a frequent lecturer and author on Pharmacogenomic topics, and currently sits on the editorial review board of the journal, Pharmacogenomics. He has been responsible for over 15 successful 510(k) submissions, FDA audits and inspections. He brings the expertise in FDA regulations and Quality Management Systems for medical devices that Akonni needs to advance its commercialization and registration efforts. Sandra Foster brings a unique blend of scientific knowledge and quality experience. She began her scientific career as a Medical Technologist (MT, ASCP), working in hospital laboratories. From the clinical lab she transitioned to research before going to graduate school. She earned a Ph.D. in Immunology from the University of Texas Southwestern Medical Center, followed by a post-doctoral fellowship at Duke University. Dr. Foster spent 12 years in clinical-phase biotechnology companies in roles of increasing responsibility from pre-clinical research and product design and development, to directing the manufacture of clinical trial materials and leading Quality Assurance and Regulatory Compliance. She designed ISO 14644-compliant clean room facilities for the manufacture of cellular therapy products for clinical trials, and implemented quality systems to support those activities. She designed, wrote and implemented process validations, operator qualifications, aseptic process simulations, comparability protocols, and authored multiple CMC sections for INDs. Immediately prior to joining Akonni, Dr. Foster owned her own consulting company, Triangle GxP Solutions, LLC as well as worked collaboratively with Mr. Murphy at Conatus. Client projects included translating R&D protocols into cGMP compliant SOPs, implementing quality systems, conducting client staff training, BLA, and pre-approval inspection (PAI) readiness. In her role as Director of Quality Assurance for Akonni, she leads design control efforts for product development, manages Device History Files, and prepares Akonni’s first audit for ISO 13485 Certification and FDA submission. Michael Reinemann has an exceptional track record of developing and implementing strategic, data-driven marketing and sales initiatives for diagnostic products resulting in strong double-digit growth and increased market share. Mr. Reinemann brings a diverse background, with experience in both technical and business roles. While earning his Master’s in Public Health at Columbia University in New York and working at the Mailman School of Public Health’s Center for Infection and Immunity, Mr. Reinemann worked on pioneering research projects in immunotherapy and pathogen discovery, and implemented cutting-edge technologies for highly multiplexed analysis and next-generation sequencing. Prior to joining Akonni in June of 2016, Mr. Reinemann served in various Commercial Operations roles at Qiagen. During his time at Qiagen, Mr. Reinemann led marketing and sales efforts that accelerated the growth of what has become the company’s single biggest revenue-contributing product. As Regional Marketing Manager of North America, Mr. Reinemann’s achievements included year-over-year growth of 55%, and the introduction of innovative co-marketing initiatives with strategic accounts, resulting in customer-specific growth of 75%. As Senior Global Product Manager, Mr. Reinemann managed a $150M product line with an annual growth rate of 25%, leading cross-functional project teams on commercial efforts as well as product development and product launches. His international business experience positions Akonni for success as the company navigates late-stage product development, registration, and commercialization of its technologies. “We are very excited to announce these essential additions to Akonni’s leadership team,” said Charles Daitch, Ph.D., President and CEO of Akonni Biosystems. “Each of these talented individuals bring valuable experience, demonstrated core competencies and dynamic industry insights from successful careers in clinical diagnostics. Our ability to hire people of this caliber speaks to the competitiveness of our product lines and their readiness to move expeditiously through the regulatory process. We are confident that we have the expertise needed to achieve our first FDA clearance and successful commercial launch of our TruDiagnosis platform.” Akonni is aggressively pursuing regulatory clearance of two product platforms – the TruDx®2000 platform and the TruTip® Automated Workstation. TruDx2000 is Akonni’s modular version of the TruDiagnosis® system, consisting of TruArray® three-dimensional (3D) gel-drop microarray diagnostic test devices and the TruDx Imager, complete with custom software for data analysis and reporting; the TruDx2000 can be bundled with or without the TruTip sample prep workstation depending on the needs of each clinical lab. The TruArray microfluidic device incorporates new, proprietary on-chip PCR technology, resulting in a much more user-friendly workflow, multiplexed detection, and a closed-amplicon system that virtually eliminates the risk of PCR contamination. The proprietary 3D gel-drop microarray nano-test-tubes can be tailored to detect genetic, protein or metabolite markers, providing the potential for access to a much broader range of diagnostic information from a single platform. The TruTip Automated Workstation is a small, affordable, fully-automated benchtop instrument. TruTip is a revolutionary technology that simplifies sample preparation by combining the complex protocols of DNA or RNA purification into just a few easy steps. The TruTip Automated Workstation is Akonni’s new nucleic acid purification instrument, which, in addition to blood and saliva, can homogenize and purify difficult samples such as sputum, stool and tissue. For more information visit: http://www.akonni.com About Akonni Biosystems Akonni Biosystems was founded in 2003 and has been issued 17 US and 24 International patents primarily covering sample preparation, microfluidic devices, bioinstrumentation, and integrated systems. Product development has been supported by a series of government grants and contracts from NIH, CDC, DOE, DOD, NIJ, and NSF. The company significantly advanced the original technology by improving the system’s capabilities from sample preparation to test result. Commercial products in Akonni’s near-term pipeline include rapid sample preparation technologies for nucleic acid extraction and multiplex panel assays for detecting clinically relevant genotypes for pharmacogenomics, human chronic diseases, and genotypes for infectious diseases such as multidrug-resistant tuberculosis (MDR-TB), extensively drug-resistant tuberculosis (XDR-TB), upper respiratory infections, viral encephalitis, and hospital-acquired infections (MRSA).
Zhang L.,Fudan University |
Simpson D.A.,University of North Carolina at Chapel Hill |
Innes C.L.,U.S. National Cancer Institute |
Chou J.,Wake forest University |
And 5 more authors.
Physiological Genomics | Year: 2013
Ataxia telangiectasia (AT) is a rare autosomal recessive disease caused by mutations in the ataxia telangiectasia-mutated gene (ATM). AT carriers with one mutant ATM allele are usually not severely affected although they carry an increased risk of developing cancer. There has not been an easy and reliable diagnostic method to identify AT carriers. Cell cycle checkpoint functions upon ionizing radiation (IR)-induced DNA damage and gene expression signatures were analyzed in the current study to test for differential responses in human lymphoblastoid cell lines with different ATM genotypes. While both dose- and time-dependent G1 and G2 checkpoint functions were highly attenuated in ATM-/- cell lines, these functions were preserved in ATM+/- cell lines equivalent to ATM+/+ cell lines. However, gene expression signatures at both baseline (consisting of 203 probes) and post-IR treatment (consisting of 126 probes) were able to distinguish ATM+/- cell lines from ATM+/+ and ATM-/- cell lines. Gene ontology (GO) and pathway analysis of the genes in the baseline signature indicate that ATM function-related categories, DNA metabolism, cell cycle, cell death control, and the p53 signaling pathway, were overrepresented. The same analyses of the genes in the IR-responsive signature revealed that biological categories including response to DNA damage stimulus, p53 signaling, and cell cycle pathways were overrepresented, which again confirmed involvement of ATM functions. The results indicate that AT carriers who have unaffected G1 and G2 checkpoint functions can be distinguished from normal individuals and AT patients by expression signatures of genes related to ATM functions. © 2013 the American Physiological Society.
Rudek M.A.,Johns Hopkins University |
Connolly R.M.,Johns Hopkins University |
Hoskins J.M.,University of North Carolina at Chapel Hill |
Hoskins J.M.,Gentris Corporation |
And 11 more authors.
Breast Cancer Research and Treatment | Year: 2013
The pro-drug capecitabine is approved for treatment of anthracycline- and paclitaxel-resistant metastatic breast cancer. However, toxicity and large interpatient pharmacokinetic variability occur despite body surface area (BSA)-dosing. We hypothesized that a fixed-dose schedule would simplify dosing and provide an effective and safe alternative to BSA-based dosing. We conducted an open label, single-arm, two-stage study of oral capecitabine with fixed starting dose (3,000 mg total daily dose in two divided doses × 14 days q21 days) in patients with metastatic breast cancer. We correlated pharmacodynamic endpoints [e.g., efficacy (response) per RECIST and toxicity], adherence and pharmacokinetics/pharmacogenetics. Sample size of 45 patients was required to detect a 25 % response rate from null response rate of 10 % using a Simon two-stage design. Twenty-six patients were enrolled in the first-stage and 21 were evaluable after a median of four cycles of capecitabine. Two thirds of patients received either the same dose or a dose 500 mg lower than what would have been administered with a commonly used 2,000 mg/m2 BSA-dosing schedule. Eight patients had stable disease but progressed after a median of seven cycles. Despite a clinical benefit rate of 19 %, no RECIST responses were observed following the first stage and the study was closed. Dose-reductions were required for grade 2 hand-foot syndrome (28 %) and vomiting (5 %). Adherence was similar when using both patient-reported and Medication Event Monitoring System methods. High interpatient variability was observed for capecitabine and metabolite pharmacokinetics, but was not attributed to observed pharmacogenetic or BSA differences. Single agent activity of capecitabine was modest in our patients with estrogen receptor-positive or -negative metastatic breast cancer and comparable to recent studies. BSA was not the main source of pharmacokinetic variability. Fixed-dose capecitabine is feasible, and simplifies dosing. © 2013 Springer Science+Business Media New York.
Hertz D.L.,University of Michigan |
Roy S.,North Carolina State University |
Jack J.,North Carolina State University |
Motsinger-Reif A.A.,North Carolina State University |
And 7 more authors.
Breast Cancer Research and Treatment | Year: 2014
The development of paclitaxel-induced peripheral neuropathy (PIPN) is influenced by drug exposure and patient genetics. The purpose of this analysis was to expand on a previous reported association of CYP2C83 and PIPN risk by investigating additional polymorphisms in CYP2C8 and in hundreds of other genes potentially relevant to paclitaxel pharmacokinetics. Clinical data was collected prospectively in an observational registry of newly diagnosed breast cancer patients. Patients treated with paclitaxel-containing regimens were genotyped using the Affymetrix DMET™ Plus chip. Patients who carried the CYP2C82,3, or4 variant were collapsed into a low-metabolizer CYP2C8 phenotype for association with PIPN. Separately, all SNPs that surpassed quality control were assessed individually and as a composite of genetic ancestry for associations with PIPN. 412 paclitaxel-treated patients and 564 genetic markers were included in the analysis. The risk of PIPN was significantly greater in the CYP2C8 low-metabolizer group (HR = 1.722, p = 0.018); however, the influences of the2 and4 SNPs were not independently significant (2: p = 0.847,4: p = 0.408). One intronic SNP in ABCG1 (rs492338) surpassed the exploratory significance threshold for an association with PIPN in the Caucasian cohort (p = 0.0008) but not in the non-Caucasian replication group (p = 0.54). Substantial genetic variability was observed within self-reported racial groups but this genetic variability was not associated with risk of grade 2+ PIPN. The pharmacogenetic heterogeneity within a cohort of breast cancer patients is dramatic, though we did not find evidence that this heterogeneity directly influences the risk of PIPN beyond the contribution of CYP2C83. © 2014 Springer Science+Business Media New York.
Rotroff D.,North Carolina State University |
Jack J.,North Carolina State University |
Campbell N.,Gentris LLC |
Clark S.,Gentris LLC |
Motsinger-Reif A.A.,North Carolina State University
BioData Mining | Year: 2014
Background: PGxClean is a new web application that performs quality control analyses for data produced by the Affymetrix DMET chip or other candidate gene technologies. Importantly, the software does not assume that variants are biallelic single-nucleotide polymorphisms, but can be used on the variety of variant characteristics included on the DMET chip. Once quality control analyses has been completed, the associated PGxClean-Viz web application performs principal component analyses and provides tools for characterizing and visualizing population structure. Findings: The PGxClean web application accepts genotype data from the Affymetrix DMET chip or the PLINK PED format with genotypes annotated as (A,C,G,T or 1,2,3,4). Options for removing missing data and calculating genotype and allele frequencies are offered. Data can be subdivided by cohort characteristics, such as family ID, sex, phenotype, or case-control status. Once the data has been processed through the PGxClean web application, the output files can be entered into the PGxClean-Viz web application for performing principal component analysis to visualize population substructure. Conclusions: The PGxClean software provides rapid quality-control processing, data analysis, and data visualization for the Affymetrix DMET chip or other candidate gene technologies while improving on common analysis platforms by not assuming that variants are biallelic. The web application is available at http://www.pgxclean.com. © 2014 Rotroff et al.; licensee BioMed Central Ltd.
Evers R.,Merck And Co. |
Blanchard R.L.,Merck And Co. |
Warner A.W.,Merck And Co. |
Warner A.W.,Gentris Corporation |
And 3 more authors.
Clinical Pharmacology and Therapeutics | Year: 2014
Understanding genetic variations that influence pharmacokinetics (PK) in humans is important for optimal clinical use of drugs. Guidances for making decisions on when to conduct pharmacogenetic research during drug development have been proposed by regulatory agencies, but their uniform adoption presents problems due to an inherent lack of flexibility. A questions-based approach (QBA) was developed to enable drug development teams at Merck to iteratively and flexibly evaluate the potential impact of pharmacogenetics (PGx) on clinical pharmacokinetic variability.
Patel M.,University of North Carolina at Chapel Hill |
Patel M.,Gentris Corporation |
Gomez N.C.,University of North Carolina at Chapel Hill |
McFadden A.W.,University of North Carolina at Chapel Hill |
And 8 more authors.
Molecular Cancer Research | Year: 2014
Recent evidence implicates the insulin-like growth factor (IGF) pathway in development of Ewing sarcoma, a highly malignant bone and soft-tissue tumor that primarily affects children and young adults. Despite promising results from preclinical studies of therapies that target this pathway, early-phase clinical trials have shown that a significant fraction of patients do not benefit, suggesting that cellular factors determine tumor sensitivity. Using FAIRE-seq, a chromosomal deletion of the PTEN locus in a Ewing sarcoma cell line was identified. In primary tumors, PTEN deficiency was observed in a large subset of cases, although not mediated by large chromosomal deletions. PTEN loss resulted in hyperactivation of the AKT signaling pathway. PTEN rescue led to decreased proliferation, inhibition of colony formation, and increased apoptosis. Strikingly, PTEN loss decreased sensitivity to IGF1R inhibitors but increased responsiveness to temsirolimus, a potent mTOR inhibitor, as marked by induction of autophagy. These results suggest that PTEN is lost in a significant fraction of primary tumors, and this deficiency may have therapeutic consequences by concurrently attenuating responsiveness to IGF1R inhibition while increasing activity of mTOR inhibitors. The identification of PTEN status in the tumors of patients with recurrent disease could help guide the selection of therapies. © 2014 American Association for Cancer Research.
PubMed | Gentris Corporation, Central South University and University of North Carolina at Chapel Hill
Type: Journal Article | Journal: Pharmacogenomics | Year: 2015
To evaluate the potential usefulness of selected SNPs to predict specific HLA alleles that are associated with drug-induced hypersensitivity reactions (HSR) in different ethnic groups.Five specific HLA alleles known to predict HSR were tagged by seven SNPs (rs1061235-HLA-A*31:01; rs2395029-HLA-B*57:01; rs3909184-HLA-B*15:02; rs9469003-HLA-B*58:01; rs3117583-HLA-B*58:01; rs9270986-HLA-DQA1*01:02 and rs3129900-HLA-DQA1*01:02). DNA from 24 African-Americans, 56 Asian, 44 Caucasians and 36 Hispanics of known high resolution HLA-A, B and DQA1 status were genotyped for tagSNPs using TaqMan. Sensitivity and specificity were considered the primary end points and were 100% across the four populations for rs2395029-HLA-B*57:01. SNP prediction of HLA-A*31:01 had 100% sensitivity and 84% specificity.This study demonstrates the utility of SNP tagging as a real time approach to predict or exclude the presence of specific HLA alleles of known importance to HSR across diverse ethnic groups. Original submitted 24 April 2014; Revision submitted 2 April 2015.