Author Archives: researchdx

Finding needles in the tumor haystack: Single cell HER2 testing with DEPArray NxT technology

 

 

Inside the heterogeneous tumor tissue samples sent to clinical pathology laboratories for HER2 gene testing are cancer genomes with their own inherent complexity. The biopsy (or surgical excision) tissue represents a mixture of genomes from the tumor and normal stroma. Further compounding the heterogeneity problem, tumor genomes harboring HER2 gene amplifications may have amplified HER2 in as low as 10% of the tumor genome. Sound complicated? Yes it is! Yet in the era of precision medicine, pathologists are expected to identify all HER2 gene amplified breast and gastroesphageal (GEA) cancers in order to predict whether or not the patient will respond to specific gene-targeted therapies.

Traditionally an IHC score combined with FFPE tissue FISH has been the accepted method for determining the patient’s definitive HER2 status. However, heterogeneous tumors (for which a definitive positive or negative status cannot be assigned) have confused technologists and frustrated physicians for the past decade.

In light of the growing number of equivocal (neither negative nor positive) results, our laboratory has validated an approach that promises to resolve HER2 status in single tumor cell populations rather than as an aggregate of 50 cells randomly selected and representing bias of the technologist evaluating the case.

A total of 80 previously characterized FFPE tissue samples of Breast and GEA metastases origin were used for the study. Prior characterization was either through traditional FISH testing and/or HER2 status by IHC. The samples were dissociated into single cells, immunofluorescently stained and then sorted using DEPArray™ NxT technology to recover pure populations of stromal and tumor cells.

Fluorescence in situ hybridization (FISH) is performed only on the recovered tumor cell population in order to reveal the true status of the biopsy. Every cell on the slide is evaluated individually and an aggregate cut off for single cell amplification is defined on the basis of the counts. The scoring is in line with the CAP/ ASCO guidelines for both percent positive and the number of amplified gene copies per cell.

The method showed > 95% concordance with gold standard IHC and FISH results. Using single cells minimizes truncation or overlapping artifacts observed in traditional tissue FISH and is an effective tool to resolve heterogeneity.

The DEPArray HER2 assay can direct pathologists where to find the HER2 positive needles in a heterogenous tumor haystack and opens the door for a precision medicine approach to HER2 testing!

Smooth Sailing Across a Changing Landscape: Researchdx/ Pacificdx Represents At The AGT 42nd Annual Meeting, St. Louis, MO June 15-17, 2017

 

 

 

The 42nd Association of Genetic Technologists (AGT) Annual Meeting highlighted the underlying theme of change. Change of professional landscape, AGT Board Management and culture. This theme was established starting from the Thursday workshops focused on Management, Molecular genetics techniques and the economics of novel Cytogenetic and Molecular workflows and propagated throughout the remaining conference agenda.

Highlights included a keynote address by Dr. Joshua D. Schiffman (Medical Director, High Risk Pediatric Cancer Clinic, Huntsman Cancer Institute) on comparative oncology titled “Learning from Elephants to help patients with Cancer” on Friday morning and the Gordon W. Dewald lecture by Dr. Rhett P. Ketterling (Co- Medical Director, Mayo Clinic) titled “FISH- The Land of Opportunity in the World of Make Believe” on Saturday morning.

With evolution of lab methods from Cytogenetics to FISH to Sanger Sequencing followed by proliferation of NGS labs in the country Dr. Phil Cotter’s (PhD, FACMGG, FFSc(RCPA), Laboratory Director, ResearchDx) talk titled “The Pathway to FDA Approval for NGS Companion Diagnostics” was exactly what was needed to tie loose ends and provide the much-needed perspective on where diagnostic utility lies and how molecular companion diagnostics pursue the FDA route.

With two scientific posters among thirty eight others ranging on topics from validation, FISH, Cytogenetics, technical notes, Microarray, NIPT, NGS and Whole Genome Sequencing to genetic signatures associated with Breast Cancer patients in the African American and Caucasian populations and novel abnormalities seen in NSCLC; ResearchDX/PacificDx was well represented at the conference with posters titled “Isolation and Low Pass Genome Wide Sequencing For Clinically Relevant Copy Number Analysis in Circulating Tumor Cells”  by Cynthe Sims and “Method Validation for Novel Image and Cell Surface Marker Based Enrichment For Breast and Gastroesophageal FFPE Biopsies with Downstream FISH Application” by Aditi Khurana.

Apart from the posters and talk by Dr. Phil Cotter the icing on the cake was definitely a sweeping victory in the form of “The Best Molecular/Biochemical Platform Presentation” for the entire company. This 15 minute talk was given by Aditi Khurana as a representative of exciting and innovative collaboration with Menarini Silicon Biosystems and the CAP/CLIA validation of their unique Tumor Cell Enrichment Platform called DEPArrayTM.

It will be exciting to see how new technologies presented at this meeting have been integrated into the clinical arena when the 43rd AGT meeting convenes in Tampa Florida in from 1st – 3rd June 2018!

Surveying Genomic Landscapes in the Clinical Laboratory: DNA Views of Tumor Terrain

 

 

A web search for the term ‘genomic landscapes’ brings up a surprising number of publications from esteemed journals such as Cell, Science, and Nature Genetics. At first glance it would seem that the words ‘genomic’ and ‘landscape’ do not belong together. However, review of the many ‘genomic landscape’ publications from the past decade reveals a recurring theme of tumor DNA testing to survey the terrain of human cancer. Within the peaks and valleys of a tumor genome are amplifications and deletions of specific genes that drive tumorigenesis, fuel local recurrence, and promote distant metastases. Amplification (extra copies) of an oncogene such as human epidermal growth factor receptor 2 (HER2) can drive tumor growth by promoting cell division, cell longevity, and formation of new blood vessels. Deletion (loss of one or both copies) of tumor protein 53 (TP53) or other tumor suppressors, makes normal cells vulnerable to DNA replication errors. Cells that cannot repair or eliminate defective DNA are launched on a path towards cancer.

This DNA view of a lung cancer genome from the PacificDx Laboratory reveals the tumor’s unique landscape of peaks (amplified genomic regions in blue) and valleys (deleted genomic regions in red.)

 

 

Within the peaks and valleys of this patient’s tumor genome landscape, are potential therapeutic targets including MET gene amplification (red arrow), a positive biomarker for response to anti-MET therapy.MET amplification was confirmed using a precisely targeted, fluorescently labeled DNA probe (orange) to calculate the average number of MET gene copies in the tumor genome nucleus.

Genome Landscapes (instead of single gene testing) allow multiple genes to be analyzed simultaneously from the same tissue sample! The good news is Genomic Landscape testing is a clinically available and affordable option for any cancer patient when the limited view, single gene testing commonly performed at the time of diagnosis does not identify therapeutic targets.

Identification of gene copy number alterations (CNAs) in an individual patient’s tumor is thus increasingly relevant as a growing number of gene deletions and amplifications are used to identify patients eligible for NCCN designated emerging targeted agents.

 

 

 

 

 

 

 

Genome Landscapes (instead of single gene testing) allow multiple genes to be analyzed simultaneously from the same tissue sample! The good news is Genomic Landscape testing is a clinically available and affordable option for any cancer patient when the limited view, single gene testing commonly performed at the time of diagnosis does not identify therapeutic targets.

 

 

ResearchDx, Inc. and PacificDx Expand Existing Clinical Laboratory and Office Space to Accommodate New Research Partners and Assays

 

 

 

Leading contract diagnostics organization has completed construction of a 12,000 square foot addition to their office in Irvine, CA creating a 30,000 square foot headquarters in Irvine, CA.

Irvine, CA—February 1, 2017—ResearchDx, Inc. announced today that construction is completed on a major addition to their Orange County headquarters. The company’s building at 5 Mason in Irvine, CA is minutes from John Wayne International airport and houses company offices for the Contract Diagnostics Organization and CAP/CLIA certified clinical laboratory, PacificDx. The new space expands the company’s office, conference room, and clinical laboratory capacity while providing additional space for the company’s BioIncubator services.

About ResearchDx
ResearchDx was founded to equip biopharmaceutical companies with the knowledge and expertise to develop and manufacture the next generation of companion diagnostic products. As the preeminent Companion Diagnostics Organization, ResearchDx offers management services for every stage of the diagnostic development process—from initial assay concept and discovery through clinical research and international regulatory approval. Learn how ResearchDx personalizes medicine at http://researchdx.com/about-us/.

About PacificDx
Recognized as a leader in the design and implementation of high-complexity testing, the CAP/CLIA certified PacificDx Laboratory provides outsourcing services to pathology groups and biopharma allowing seamless integration of molecular assays into their existing test menus.

Guidelines to the Galaxy of HER2 Testing in GEA Cancers

 

Say the words “HER2 gene amplification” and what immediately comes to mind is breast cancer. But did you know other cancers, including those of the stomach and esophagus (collectively called gastroesophagel adenocarinoma or GEA) can have too many (> 6) copies of the HER2 gene? That’s right, an estimated 20% of GEA cancers harbor an amplified HER2 gene biomarker, and these tumors are predicted to behave aggressively just like their breast cancer counterparts.  The good news is HER2 gene amplification is now considered a “druggable target” in GEA cancer and the same drug used to combat HER2 positive breast cancer is also FDA approved for HER2 positive gastric cancer.

So how to find the 20% of GEA cancers with amplified HER2 genes? It turns out we can enlist the same clinical laboratory testing methods already in use for identification of HER2 positive breast cancer. Since 2010 when trastuzumab (Herceptin®, made by Genentech, Inc.) was FDA approved for gastric cancer, a percentage of these tumors began to be evaluated by pathologists for HER2 positivity. Yet until recently, many pathologists were still not routinely incorporating HER2 testing into the diagnostic workup of all GEA cancers. This is most likely because the HER2 testing guidelines published in 2007 and updated in 2013 by the College of American Pathologists (CAP) and American Society of Clinical Oncology (ASCO) for breast cancer did not include gastric cancer. So although the clinical tests were the same, how to perform and interpret these tests for gastric versus breast cancer has not been clear.

Guidance for pathologists traversing the galaxy of HER2 testing in gastric cancer arrived on November 16, 2016 with the publication of CAP/ASCO guidelines specifically for GEA tumors.  Prepared by an Expert Panel, the 21-page document contains a list of strong recommendations for accurate determination of HER2 status in GEA tumor issue. All patients with advanced GEA who are eligible for systemic therapy should have their tumor tissue tested for HER2 positivity. The GEA HER2 testing guidelines can be freely accessed and are available through the following link: http://ascopubs.org/doi/pdf/10.1200/JCO.2016.69.4836. According to the guidelines, testing should begin at the protein level with analysis of the HER2 receptor drug target on the surface of the tumor cells. If the protein does not provide an actionable answer, then the HER2 gene copy number on chromosome 17 is tested for amplification. In cases where neither of these tests provide clarification as to how the patient should be treated, novel more accurate methods such as DNA microarray analysis may be considered.

In patients with GEA cancer, tumors harboring HER2 gene amplifications will only be found if pathologists look for them. The CAP/ASCO guidelines bring new hope for the galaxy of GEA tumor testing and move the field closer to a day when HER2 testing is a routine part of the diagnostic workup of every patient’s tumor tissue.

Shelly Gunn MD, PhD| Pathologist| January 24, 2017

A Single Blood Test For All Cancers?

What if a simple blood test could detect any cancer early, when it was still easy to treat?

It sounds like science fiction. But Illumina ILMN +5.20%, the $24 billion (market cap) biotechnology company that has pioneered cheap, efficient sequencing of DNA, says it could be a reality in a few years. It is launching a new startup, GRAIL (because such a test would be a holy grail for cancer doctors), with $100 million in funding. Illumina will hold a majority share. Other backers include Sutter Hill Ventures, ARCH Ventures, Jeff Bezos’ Bezos Expeditions and Bill Gates. The startup could have vast medical, economic and societal implications–if the technology really works.

Jay Flatley Illumina CEO“Everything here is directed at being a pan-cancer test, something that is a universal test,” says Jay Flatley, who has been Illumina’s chief executive for sixteen years and has improved the power of DNA sequencing at a rate that exceeds improvements in microchips over the same period of time.

“It’s our largest investment ever,” says Robert Nelsen, a partner at ARCH, says of GRAIL. Nelsen helped found Illumina, and, more recently, some of the the most well-funded startups ever, including cancer company Juno Therapeutics, which raised $310 million before its IPO, and Denali Therapeutics, focused on brain diseases, which raised $217 million last year.
“It remains to be proven,” Nelsen asserts, “but it’s likely to be the case that you will be able to know deep and large amounts of information about multiple cancers with a single test.”

Flatley says that the idea for GRAIL was hatched eighteen months ago when Illumina researchers were trying the company’s DNA sequencers out on blood. They found that as the company’s sequencers became increasingly powerful, they were able to detect trace amounts of DNA in those samples.

Thank you to Matthew Herper, Forbes, for this excellent article.

21st Century Cures Act Seeks to Expedite Bench to Bedside New Treatments

 

Author: Louis P. Sintasath, MS, MBA
ResearchDx, Director, Business Development

 
Recently this year the U.S. House of Representatives resoundingly passed a bipartisan resolution, H.R. 6, also known as the 21st Century Cures Act. So what is the 21st Century Cures Act and what is it trying to do? In short, the bill would reauthorize the National Institutes of Health (NIH) through FY2018 and provide $8.75 billion in additional funding through FY2020.

Congress logo
For proponents of the 21st Century Cures Act, the mission is to improve the lives of every American by bringing innovation to the health care infrastructure, by reducing the time new therapies gets to the clinic, by paving the way for novel discoveries and cures, and by ultimately saving lives.
Internationally recognized as the “contract diagnostic organization,” ResearchDx specializes in the development of companion diagnostics and in vitro diagnostics for the pharmaceutical,biotechnology, research, and diagnostic industries, and is instrumental in new drug development.
According to Philip Cotter, PhD, FACMG, FFSc (RCPA), co-founder and Principal at ResearchDx, an Irvine, California based life sciences company, “The 21 Century Cures Act has long been needed to introduce the growing discipline of Translational Medicine.” Dr. Cotter further explains, “Translational Medicine is a rapidly growing discipline in biomedical research and aims to expedite the discovery of new diagnostic tools and treatments by using a multi-disciplinary, highly collaborative, “bench-to-bedside” approach. Within public health, translational medicine is focused on ensuring that proven strategies for disease treatment and prevention are quickly implemented within the community.”
Title I of the bill focuses on innovation and discovery. It promotes strategic planning for clinical research at the NIH as well as increase accountability at the NIH, reduce administrative burdens, and standardize data in the clinical trial registry data bank. It encourages collaboration among researchers and aims to remove barriers that discourage it. It supports emerging young scientists and establishes an Innovation Fund. The provision also promotes pediatric research through the establishment of the National Pediatric Research Network (NPRN).
The large bulk of the proposed bill lies in Title II. Title II revamps the regulatory processes for innovative drugs and medical devices. This involves the “development and use of patient experience data to enhance structured risk-benefit assessment framework,” says Dr. Cotter. It would also establish a new drug development tool that includes “(1) a biomarker; (2) a clinical outcome assessment; and (3) any other method, material, or measure that the Secretary determines aids drug development regulatory review.” To help advanced qualified drugs, there would be an accelerated approval development plan that includes agreement on surrogate endpoints. This provision has met with some resistance as some have raised concerns that an expedited process may result in increased risk to safety and efficacy.

Title II also lays out a provision on precision medicine, calling for two guidance documents to be added: “General agency guidance and precision medicine” and “Precision medicine regarding orphan-drug and expedited-approval programs.” Modern clinical trial design and evidence development would be implemented as well as a streamlined data review process.

Lawmakers also recognize the need for new antibiotic drug development, inserting a provision that allow for approval of certain drugs for use in a limited population of patients. For breakthrough medical devices where no approved alternatives exist, there will be a new priority review process for premarket approvals (PMA) as well as 510(k) devices. There will also be a formation of a third-party quality system assessment process. There will also be an easing of regulatory burdens for certain Class I and Class II devices.
Title III targets the disparate landscape of electronic health information technology. Title III calls for interoperability standards of electronic health information technology. In addition, the provision also expands the eligibility of telehealth coverage under the Medicare program and calls for the continuing education for physicians. Issues of price transparency are also addressed, along with patient safety and drug abuse prevention under Medicare.

Title IV proposes changes to Medicare and Medicaid to help offset costs of the program. The provision will establish for the first time an upper limit to the payment for durable medical equipment (DME) under the Medicaid program. There will be an incentive to move away from traditional X-Ray imaging to digital radiography. A provision that benefits drug manufacturers involves the ability to exclude authorized generics from the calculation of average manufacturer price (AMP). Because removing the low price of generics from the AMP, the price would be higher and thus the rebate to manufacturers would be higher on brand name drugs. The majority of funding for the program will come from a key provision to drawdown the Strategic Petroleum Reserve (SPR).
H.R. 6 has recently come under intense scrutiny over potential safety and efficacy concerns as well as loosening of FDA standards in the approval process. As the controversies play out in the media and the floor of the Senate, we will have to wait and see what provisions ultimately makes its way into law.

For the full text of H.R. 6, please visit: https://www.congress.gov/bill/114th-congress/house-bill/6/text

Drawing Battle Lines over Lab Tests

  • For-Profit Developers, Nonprofit Academic Labs Challenge FDA Over LDTs

    A year after the FDA proposed regulating “high-risk” laboratory-developed tests (LDTs) along the lines of Class III medical devices, through draft guidances friendlier to for-profit diagnostic developers than nonprofit academic medical centers, both sides have advanced detailed regulatory counterproposals in hopes of swaying the agency.

    The Association for Molecular Pathology (AMP), whose membership includes academic and community medical centers, has released its own recommended rules for LDTs. AMP contends that the FDA is overreaching in its proposed regulation of LDTs—which it calls “laboratory-developed testing procedures”—because the tests are not medical devices subject to the Food, Drug, and Cosmetic Act (FDCA).

    Instead, the AMP is advocating the most extensive updates to the Clinical Laboratory Improvement Amendments of 1988 (CLIA) since they took effect in phases through 1994, with the goal of accommodating current laboratory practices and technology. Labs may develop and use their own diagnostic tests internally, without FDA oversight, if certified under the waiver program of CLIA, overseen by the Centers for Medicare and Medicaid Services (CMS).

    The AMP’s “Proposal for Modernization of CLIA Regulations for Laboratory Developed Testing Procedures” creates a three-tier, risk-based regulatory system for LDTs. Labs can validate “low risk” tests and put them into service, subject to inspection in the normal course of the inspection process. For “moderate risk” tests, labs would have to submit information to CMS or a CMS-approved nongovernmental “third party” reviewer at least 30 days before being offered to the public, with a 30-day review time limit. That limit extends to 90 days for “high-risk” tests, which also require submissions to CMS or a third party at least 90 days before offering to the public.

    The FDA made its proposals in two draft guidance documents: 1) Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs), and 2) FDA Notification and Medical Device Reporting for Laboratory Developed Tests (LDTs). The FDA has received more than 300 substantive comments on the draft guidance, spokeswoman Jennifer Dooren told Clinical OMICs.

    “We expect to amend the proposed oversight framework for LDTs to incorporate some of the suggestions provided by commenters, and in cases where suggestions were not incorporated, we intend to explain why,” Dooren said. “We cannot comment on the timing of any final guidance on the LDT oversight framework.”

    The FDA would assign LDTs risk classifications of low, moderate, and high, based on existing classes of medical devices. The FDA generally envisions reviewing premarket approval applications for high-risk Class III LDTs, while third parties would review Class II tests. The agency would continue exercising enforcement discretion on premarket reviews for Class I tests.

    Under the AMP’s proposal, the FDA would be limited to reviewing one type of high-risk LDT, multi-analyte assays with algorithmic analysis (MAAAs) with proprietary algorithms—unless the lab behind the MAAA subject its algorithm to third-party review and inspection.

  • “Not a Radical Break”

    “In looking at the regulations themselves, we recognize that they were designed and written at a different time, that technologies and practice standards have changed. What we’re talking about is an attempt to accommodate those changes. It’s not a radical break from CLIA,” Roger D. Klein, M.D., J.D., AMP professional relations chair, told Clinical OMICs. “We would reiterate that neither the FDA nor anybody else has come forward with evidence, with data that suggest a systematic problem with laboratory testing in general or with LDTs in particular.”

    The FDA asserts that as LDTs have become more complex over the past generation, many consist of components that are not legally marketed for clinical use while others are used beyond local populations and manufactured in high volume. The FDA also is concerned that many are used widely to screen for common diseases and for directing critical treatment decisions such as prediction of drug response.

    Dr. Klein, who is also medical director, molecular oncology at the Cleveland Clinic, added that in practice, most laboratories that perform significant molecular pathology testing exceed CLIA requirements—either because of more stringent standards developed by professional groups such as the College of American Pathologists (CAP) or because these labs serve New York state patients. The Empire State became the first state in the nation to establish licensing for laboratories performing clinical testing in 1965: “In a sense, we’re raising the floor of the CLIA regulations.”

    While acknowledging that CLIA modernization would add to the costs of labs, he said the costs of complying with CLIA are much less than with FDA. Costs would be assessed on a sliding scale, as at present, for laboratories based on their volumes of tests.

    “The AMP has a number of industry members, and they have told us that their costs run into the hundreds of thousands, and even millions, of dollars for 510(k)s and PMAs. We’re talking about orders of magnitude lower costs to comply with enhanced CLIA regulations,” Dr. Klein said.

    The AMP is seeking to translate its proposal into a federal law that would preempt FDA regulation. To that end, the association has engaged committee staffers from the U.S. Senate and House of Representatives. “The AMP had a productive discussion with bipartisan committee staff members from the House Energy and Commerce Committee and we look forward to continuing to work with them and also meeting with additional members of the Committee,” Tara Burke, PhD, policy analyst with AMP, told Clinical OMICs.

    By contrast, AdvaMedDx, the diagnostics manufacturers’ division of the Advanced Medical Technology Association (AdvaMed), argues the FDA is better able than CLIA to assure clinical validity for LDTs.

    “We have some labs as members who have gone through the FDA process with their LDTs, so we’re not completely unfamiliar with the issues labs face. We also know that labs can take tests through the FDA, and do so successfully,” Andrew C. Fish, executive director of AdvaMedDx, told Clinical OMICs. “There may in fact be reasons that CLIA should be updated. But there don’t seem to be good reasons for CLIA to be expanded to overlap entirely with the FDA’s expertise and functions.”

    The AMP and groups representing academic labs say the proposed regulations would be burdensome enough to stifle innovation. AdvaMedDx and test manufacturers disagree. Fish noted that the FDA has promised to show greater flexibility in reviewing LDTs for “unmet needs” where no agency-approved test is available. The FDA said it “does not intend to consider” whether the tests use legally marketed components/instruments, or whether the LDT is interpreted by qualified laboratory professionals, without using automated instrumentation or software for interpretation.

  • Bridging the Gap

     

    Click Image To Enlarge +
    A broader category of “in vitro clinical tests” would be regulated by a proposed new center within the FDA focused on in vitro diagnostics. [iStock/Frentusha]

    AMP’s proposal came five months after a coalition of diagnostic manufacturers and clinical labs, the Diagnostic Test Working Group (DTWG), came out with its own regulatory framework intended to bridge the gap between the AMP and the FDA. The working group agreed with AMP that lab tests should not be regulated as devices—but called instead for new FDA regulations governing LDTs, as well as kits, as “in vitro clinical tests.” This broader category would be regulated by a proposed new center within the FDA focused on in vitro diagnostics.  The group also proposed dividing oversight among two federal agencies and state governments: the FDA would oversee in vitro diagnostics development, with CMS responsible for lab operations, and states overseeing medical applications.

    Like the AMP and FDA, the working group also envisions high-, medium-, and low-risk test categories: High-risk tests are not well established, and a wrong result would result in “significant impact on patient outcome or public health.” Such tests would be a “sole determinant for directing or changing clinical treatment for a serious or life-threatening disease or disorder,” the group said.

    The working group would have an advisory panel recommend classification decisions that would stand unless revised by the FDA within six months.

    Harry Glorikian, a life sciences and healthcare industry consultant, told Clinical OMICs the FDA needs to strike a balance between agency scrutiny to ensure that new tests measure results accurately and consistently, while retaining flexibility for labs to develop new tests in response to fast-moving disease, such as last year’s outbreak of Ebola in West Africa.

    “What happens in a hospital setting when we have an outbreak? We need to develop a test very quickly in-house, and we need to test patients. You don’t want to limit the lab by not being able to do an LDT. There are so many LDTs run in the lab that if you tried to stop them, it would stop medicine. You can’t stop medicine from doing that,” Glorikian said. “That would be problematic, because a manufacturer who would need to get regulatory approval could not move fast enough. So you need to have that capability. You need to let research go on.”

    The quest for balance is complicated, he said, by the greater complexity of LDTs compared with drugs or companion diagnostics. Yet new rules are especially needed for tests that drive clinical practice: “If this is narrowing the field of decisions that a physician now makes, you really want to make sure that the answer is right.”

    “The technology is moving so fast that there needs to be some guardrails. I’m not saying that it needs to be draconian. But we need to understand what and how we’re going to be diagnosing patients, and then treating patients appropriately,” Glorikian added. “I don’t want to see that necessarily taken out of the hands of a physician. But there’s going to be some combination of what the working group says, what the AMP is saying, and what the FDA is saying.”

    This article was written by Senior News Editor Alex Philippidis and originally published in the October 2015 issue of Clinical OMICs. For more content like this and details on how to get a free subscription to this digital publication, go to www.clinicalomics.com.

Tissue-Specific Molecular Biomarker Signatures of Type 2 Diabetes An Integrative Analysis of Transcriptomics and Protein–Protein Interaction Data

 

 

 

 

Type 2 diabetes mellitus (T2D) is a major global health burden. A complex metabolic disease, type 2 diabetes affects multiple different tissues, demanding a ‘‘systems medicine’’ approach to biomarker and novel diagnostic discovery, not to mention data integration across omics-es (Günther et al. 2014; Montague et al. 2014; Sahu et al. 2014). The two important key determinants of T2D are the failure of peripheral tissues (such as liver, muscle, and adipose tissue) to respond to insulin doses (so-called insulin resistance), and the failure of suitable insulin secretion by pancreatic betacells in response to increased blood glucose levels (Kaiser and Oetjen, 2014).

Mutual DEGs between only two different tissues/cells

Mutual DEGs between only two different tissues/cells

The duration of hyperglycemia caused by failure of betacells also affects insulin secretory capacity, mass, and apoptosis rate of beta-cells, resulting in additional alterations in several processes such as islet inflammation, amyloid deposition, critical B-cell phenotypic alterations (Prentki and Nolan, 2006). On the other hand, the state of hyperglycemia damages nerves and blood vessels, leading to major healthrelated issues such as cardiovascular diseases, stroke, blindness, dental problems, and diabetes-related amputations. Other complications of T2D include enhanced vulnerability to neurodegenerative diseases, presence of various cancer types, pregnancy problems, loss of mobility with aging, and depression (Musselman et al., 2003; Retnakaran et al., 2006).

Due to the high prevalence of T2D and its fateful complications, identifying the genes or genetic factors associated with the development of T2D and elucidating the mechanisms underlying the disease are crucial in prognosis, and development of personalized medicine and therapeutic strategies.

Since it is a polygenic disorder (i.e., multiple genes located on different chromosomes take active roles in the development of the disease), it is better to reveal that gene expression varies more across tissues than across individuals. Several studies reported findings on T2D gene expression profiles of different tissues individually (Kazier et al., 2007; Cangemi et al., 2011; Misu et al., 2010; van Tienen et al., 2012; Dominguez et al., 2011). Despite individual studies exploring T2D specific genes in various tissues, studies considering the meta-analysis of diverse transcriptomics datasets and integrating gene expression profiles with biological networks are very limited.

Keller and co-workers (2008) studied gene expression profiles in eight experimental groups of lean and obese mice.

This article originally appeared in http://www.genengnews.com.  To read the rest of this article click here.

Top 30 Life Science Startups To Watch In The U.S.

Blog Post 9-14

This list contains 30 life science companies that were launched no earlier than in 2011 and are headquartered in the United States. Once the companies were sorted into that group, they were then weighted by a number of different categories and ranked in a cumulative fashion based on the points awarded each category. Those categories are: Finance, Collaborations, Pipeline, Sales and Editorial.

This article was written by By Mark Terry, at BioSpace.com, Breaking News Staff . The NextGen Bio Class of 2015 is filled with a stellar group of companies that are making enormous impact on the industry now and in the future. Congratulations!

“This recognition is testament to how hard we are working to bring transformative cancer therapies to market. Being named the most promising biopharma startup speaks to the milestones we have achieved in less than a year, including two funding rounds and significant progress in clinical development. It has been an exciting year, but we are even more excited about the progress still to come,” Hans Bishop, chief executive officer of Juno Therapeutics, Inc., told BioSpace.
– See more at: http://www.biospace.com/News/top-30-life-science-startups-to-watch-in-the-u-s/351215#sthash.hp6wzwYe.dpuf


1. Juno Therapeutics

Points: 43
Founded: 2013
Location: Seattle, Wash.
Notable:
• Juno Therapeutics is partnered with Fred Hutchinson Cancer Research Center, the Memorial Sloan-Kettering Cancer Center, and Seattle Children’s Research Institute. In addition to the three cancer centers, additional investors included Arch Venture Partners and Crestline (Alaska Permanent Fund invested through CLAlaska LP, a partnership managed by Crestline Investors).
• Currently has at least three clinical trials ongoing: 4-1BB; CD29; and 4-1BB.
• The initial Series A investment was $120 million.
• A secondary Series A round was completed in April 2014 with $176 million in fully committed funds additional investment came from founding investors as well as investments from Bezos Expeditions, Venrock, and others.
• Two of the company’s founders, Drs. Michel Saelain and Renier J. Brentjens won the New York Intellectual Property Law Association’s “Inventor of the Year” award for their work in the design of chimeric antigen receptors (CARs), a major part of the company’s therapeutic platform.
• In August 2014, the company closed its Series round with $134 million in new investment (between the Series A and B rounds, the company has raised more than $300 million in less than 12 months).

 

2. MyoKardia
Points: 38
Founded: 2012
Location: San Francisco, Calif.
Notable:
• MyoKardia had raised $52 million in three rounds from a single investor. The most recent round was for $10 million in August 2014.
• In May 2014, the company announced the launch of the Sarcomeric Human Cardiomyopathy Registry (ShaRe), a multi-center, international repository of clinical data on individuals with genetic heart disease.
• In September 2014, MyoKardia signed an agreement with Sanofi to collaborate to discover and develop first-of-its-kind targeted therapeutics for heritable heart diseases known as cardiomyopathies. The collaboration provides up to $200 million in equity investments, milestone payments and R&D services through 2018, of which $45 million has already been received in an upfront licensing fee and an initial equity investment.
3. Spark Therapeutics
Points: 33
Founded: 2013
Location: Philadelphia, Penn.
Notable:
• The company was launched in 2013 with a $50 million capital commitment from The Children’s Hospital of Philadelphia (CHOP) to advance and commercialize multiple ongoing gene therapy programs, including its lead candidate for RPE65-related blindness, currently in Phase 3 clinical trials.
• Raised $122.8 million in two rounds from 7 investors.
• Spark has a Phase 1 & 2 program in hemophilia B.
• Spark has a preclinical program to look at neurodegenerative diseases and other inherited retinal dystrophies and hematologic disorders.
• In March 2014, Spark announced a collaboration agreement with Genable Technologies for Genable’s lead therapeutic to treat rhodopsin-linked autosomal dominant retinitis pigmentosa (RHO adRP), GT038.
• In May 2014, Spark completed a Series B financing round worth $72.8 million led by Sofinnova Ventures. It was joined by Brookside Capital, Deerfield Management Company, Rock Springs Capital and others.
4. Apexigen
Points: 27
Founded: 2013
Location: Burlingame, Calif.
Notable:
• Of the company’s seven candidates, four are currently the subject of development partnerships with leading life science companies. The partnerships are with: Simcere Pharmaceutical Group; 3Sbio, Inc.; Jiangsu T-mab Biotechnology, Ltd.; Shanghai Duyiwei Biotechnology Ltd.; Janssen Biotech (a Johnston & Johnston Company); Alcon Research (a division of Novartis); and TORAY Industries.
• In August 2013, Apexigen secured $20 million in Series A1 financing led by Amkey Ventures LLC, WSR Capital, China Development Industrial Bank, Themese Investment Partners, and Sycamore Ventures.
• In 2012, Apexigen signed a manufacturing supply agreement with Boehringer Ingelheim.
5. Audentes Therapeutics
Points: 25
Founded: 2013
Location: San Francisco, Calif.
Notable:
• In July 2013, the company received $30 million in Series A financing from Versant Ventures, 5AM Ventures, and OrbiMed Advisors.
• For its lead programs, Audentes is collaborating with Genethon, Joshua Frase Foundation, myotubular trust, University of Florida, Children’s Hospital Boston and ReGenX Biosciences.
• In July 2013, Audentes entered into an agreement with REGENX Biosciences, LLC for the development and commercialization of their lead products.

 

6. Aerpio Therapeutics
Points: 24
Founded: 2011
Location: Cincinnati, OH
Notable:
• Received $5 million in undisclosed seed financing in 2012.
• Raised $27 million in Series A financing in August 2012 from five investors.
• Raised $9 million in Series A financing in November 2013 from five investors.
• Raised $22 million in venture capital in April 2014.

7. Alector
Points: 23
Founded: 2013
Location: San Francisco, Calif.
Notable:
• In October 2013, Alector closed on Series A financing led by Polaris Venture Partners and OrbiMed Advisors for an undisclosed amount.
• In March 2014, Janssen Pharmaceuticals, the pharmaceutical arm of Johnson & Johnson, agreed to help fund Alector’s efforts to develop new therapies for Alzheimer’s. No financial terms were disclosed.

8. Dimension Therapeutics
Points: 22
Founded: 2013
Location: Cambridge, MA
Notable:
• In conjunction with its launch, Dimension has entered into an exclusive license and collaboration with REGENX Biosciences. REGENX holds exclusive rights to a portfolio of over 100 patents and patent applications pertaining to its NAV vector technology and related applications.
• The company raised $35 million in two rounds from two investors in 2014.
• Dimension entered into a collaboration in June 2014 with Bayer HealthCare for the development and commercialization of a novel gene therapy for the treatment of hemophilia A.

9. Abide Therapeutics
Points: 17
Founded: 2011
Location: San Diego, Calif.
Notable:
• In 2013, Abide entered into a collaboration agreement with Merck to discover, develop and commercialize small-molecule therapies directed against three novel targets to treat metabolic diseases with a focus on type 2 diabetes. Milestone payments for the three products could reach $430 million.
• In February 2014, Abide entered into a strategic collaboration with Celgene Corporation to discover and develop new drugs in inflammation and immunology.
• In 2011, the company received $2.3 million in seed financing.

10. NextCode Health
Points: 17
Founded: 2013
Location: Cambridge, Mass.
Notable:
• The company launched in 2013 as a spinout from deCODE genetics. It also secured $15 million Series A financing from Polaris Partners and ARCH Venture Partners.
• The company has several service agreements with clinical centers, including Queensland University (Australia), Boston Children’s Hospital (U.S.), Newcastle University (U.K.) and Saitama University (Japan).

11. Precision For Medicine
Points: 17
Founded: 2012
Location: Bethesda, MD
Notable:
• In March 2014, the company announced the acquisition of Hobart Group Holdings, LLC, a market access firm.
• Originally financed by $150 million in equity capital from J.H. Whitney and Oak Investment Partners. Some of the money was used to acquire a state-of-the-art biobanking biorespository, which stores and manages human tissues. The samples are tested to provide information about the patient’s history, genetics, and individual needs.

12. Navitor Pharmaceuticals
Points: 16
Founded: 2014
Location: Cambridge, Mass.
Notable:
• Navitor launched with $32.5 million Series A financing with investors including Polaris Partners, Atlas Venture, Johnson & Johnson Development Corporation, SR One, and The Longevity Fund.

13. Arcturus Therapeutics
Points: 15
Founded: 2013
Location: San Diego, Calif.
Notable:
• In June 2013, Arcturus raised $1.3 million from multiple individual investors.
• In August 2013, the company acquired usiRNA Technology and UNA Patent Estate from Marina Biotech.
• In October 2013, Arcturus raised $5 million in a Series A funding round.

14. Jounce Therapeutics
Points: 14
Founded: 2013
Location: Cambridge, Mass.
Notable:
• Launched in 2013 with $47 million in Series A venture capital financing by Third Rock Ventures.
• Company founder Jim Allison won the Breakthrough Prize in Life Sciences in December 2013 for his research on the biology of T cells; in 2014, the National Foundation for Cancer Research (NFCR) awarded him the Szent-Gyorgyi Prize for Progress in Cancer Research that led to the successful development of “immune checkpoint therapy,” and the first FDA-approved drug for the treatment of metastatic melanoma.
• In January 2014, Jounce announced a partnership with Adimab, LLC, a leader in the discovery of monoclonal and biospecific antibodies.

15. Editas Medicine
Points: 13
Founded: 2013
Location: Cambridge, Mass.
Notable:
• The company was founded in 2013 with $43 million in Series A venture capital provided by Flagship Ventures, Polaris Partners, Third Rock Ventures, and the Partners Innovation Fund.
• In April 2014, The Broad Institute and MIT announced the first patent in the U.S. for an engineered CRISPR-Cas9 system that allows scientists to modify genes and better understand the biology of living cells and organisms. One of the co-founders of Editas, Feng Zhang, is a Broad core member and inventor, as well as the senior author of the 2013 “Science” paper that showed that Cas9 can be harnessed to modify DNA in mammalian cells.

16. Middle Peak Medical
Points: 12
Founded: 2011
Location: Palo Alto, Calif.
Notable:
• Middle Peak raised $8.5 million in Series A financing in June 2013, co-led by Wellington Partners and Seventure Partners, along with High-Tech Grunderfonds Management GmbH (HTGF).
• In October 2013, the company raised an additional $3 million in a second closing. Additional investors included bioMedInvest II LP and Edwards LifeSciences.

17. Thesan Pharmaceuticals
Points: 12
Founded: 2011
Location: Carlsbad, Calif.
Notable:
• Thesan Pharmaceuticals raised $65 million in two rounds from seven investors. The most recent was in February 2014, with $49 million in Series B financing.
• Investors include Novo Ventures, Novartis Venture Funds, SV Life Sciences and Lundbeckfond Ventures.

18. Scioderm
Points: 11
Founded: 2012
Location: Durham, NC
Notable:
• In 2013, Scioderm closed a $16 million Series A financing round.
• In 2013, the FDA allowed the IND for SD-101 to proceed.
• In December 2013, the Committee for Orphan Medicinal Products (COMP) gave a positive opinion on the company’s application for orphan status for SD-101.
• In January 2014, SD-101 received Orphan Designation in Europe.
• In September 2014, the company presented positive data on Orblisa (SD-101) from its recently completed Phase 2b study.

19. Sitari Pharmaceuticals
Points: 11
Founded: 2013 (Spinoff from Avalon Ventures and GSK)
Location: San Diego, Calif.
Notable:
• Sitari raised $10 million in Series A financing and R&D support from Avalon and GSK for the development of novel treatments for celiac disease.
• Avalon had also established COI Pharmaceuticals, a venture-pharma entity that will provide operational support and a fully equipped R&D facility, as well as an experienced leadership team to Sitari and future companies the collaboration might develop.

20. Alcresta
Points: 7
Founded: 2011
Location: Newton, Mass.
Notable:
• The company has raised $20 million in two rounds from three investors.
• In April 2014, the company signed an agreement with Cystic Fibrosis Foundation Therapeutics (CFFT) to accelerate the development of the company’s enzyme-based point-of-care products to support the nutritional status of people with CF.

21. SureClinical
Points: 7
Founded: 2012
Location: Rancho Cordova, Calif.
Notable:
• In August 2013, SureClinical successfully completed an FDA 21 CFR Part 11 compliance audit on its SureTrial eTMF clinical trials content management application.
• SSAE-16 Type I and Type II Attestation, PCI Compliance, FDA CFR Part 11 Application Certification, U.S. Commerce Department Safe Harbor Certifications.

22. Syros Pharmaceuticals
Points: 7
Founded: 2013
Location: Watertown, Mass.
Notable:
• The company launched in 2013 with $30 million in Series A financing.
• In December 2013, company founder Nathanael Gray was the sole recipient of the 2013 Meyenburg Cancer Research Award, recognized for his work in developing first-in-class chemical inhibitors for wild-type and mutant forms of protein kinases, which can be used to validate new potential targets to treat cancer and other diseases.

23. Global Blood Therapeutics
Points: 6
Founded: 2012
Location: San Francisco, Calif.
Notable:
• The company was founded in 2012 with a $40.7 million Series A financing round backed by Third Rock Ventures.
• In November 2013, the company announced data on its lead program in sickle cell disease to the 55th American Society of Hematology (ASH) Annual Meeting and Exposition.

24. Semnur Pharmaceuticals
Points: 6
Founded: 2013
Location: Los Altos, Calif.
Notable:
• The company raised $6 million in venture capital in August 16, 2013.

25. Synchroneuron
Points: 5
Founded: 2011
Location: Duxbury, Mass.
Notable:
• In 2012, the company raised $6 million in Series A financing from Morningside Technology Ventures.
• In February 2014, the company started a Phase 2, multi-center clinical trial for SNC-102.
• In July 2014, the company raised $20 million in Series B financing with Morningside Technology Advisory LLC.

26. Thrive Biosciences
Points: 5
Founded: 2014
Location: Beverly, Mass.
Notable:
• The company was founded by entrepreneurs and life sciences veterans Gary Paul Magnant, Thomas Forest Farb, and Dr. Alan P. Blanchard.
• Magnant is co-founder and current advisor to the Life Science Consortium of the North Shore, as well as former CEO of Sage Science.

27. Cerephex
Points: 3
Founded: 2012
Location: Los Gatos, Calif.
Notable:
• In 2012, the company raised $5.9 million in Series A financing from three investors.
• In 2010, the company was granted a patent for its foundational signal modulation technology (also patented in Australia).
• In 2012, the company published data from its clinical trials for its RINCE cortical stimulation technology, which showed significant improvement in key fibromyalgia symptoms.

28. Cibiem
Points: 3
Founded: 2012
Location: Los Altos, Calif.
Notable:
• The company launched in 2010 with a $10 million Series A round led by SV Life Sciences and Third Rock Ventures.
• The company’s technology is being tested in first-in-man clinical trials.

29. Cydan
Points: 3
Founded: 2013
Location: Cambridge, Mass.
Notable:
• Cydan launched in 2013 with $26 million in financing led by New Enterprise Associates (NEA), Pfizer Venture Investments, Lundbeckfond Ventures and Bay City Capital with participation from Alexandria Real Estate Equities, Inc.

30. Arvinas
Points: 2
Founded: 2013
Location: New Haven, Conn.
Notable:
• Arvinas was launched with $15 million in Series A financing. Investors included Elm Street ventures, 5AM Ventures, Connecticut Innovations, and Canaan Partners. It raised $4.25 million in financial support, $1 million which was in the form of equity from the Connecticut Department of Economic and Community Development and Connecticut Innovations. – See more at: http://www.biospace.com/News/top-30-life-science-startups-to-watch-in-the-u-s/351215#sthash.hp6wzwYe.dpuf

This article was written by By Mark Terry, at BioSpace.com, Breaking News Staff