The Continual Search for Biomarkers - Cancer, Cardiovascular, Immunology, Infectious Diseases and Neurological Diseases

Biomarkers are a highly dynamic space within life science characterized by individual progression through discovery; validation; initial standardized applications in preclinical studies and clinical trials; and incorporation into clinically approved in vitro diagnostic (IVD) assays. In addition to vertical movement, individual biomarkers can be viewed in a horizontal manner across the spectrum of applicable diseases. This spectrum of biomarker usage is encompassed in Kalorama Information’s The Global Market for Biomarkers. The report provides industry analysis of biomarker-enabled IVD products and biomarkers in development along the lines of cancer, cardiovascular disease, immunological diseases, infectious diseases, neurological diseases, and other specialty testing areas.

Cancer Biomarkers

Cancer biomarkers are heavily utilized in clinical diagnostics, but many are demonstrated to be less than ideal for accurately identifying candidates for confirmatory biopsies or intervention. The role of protein biomarkers for cancer diagnosis is at best incomplete as screening tools, and has been overshadowed by a wealth of cancer diagnostics based on more specific and sensitive nucleic acid biomarkers. The roles of nucleic acid biomarkers extend to surrogate biomarkers for tumor size and metastasis. More accessible cancers biomarkers are also being sought through liquid biopsies or blood samples that contain circulating tumor cells (CTCs) or cell-free DNA (cfDNA).

Another growing trend in cancer biomarkers has been the development and introduction of panels that assess a person’s risk for developing several different cancers. For example, Myriad Genetics offers the myRisk Hereditary Cancer, which is a 25-gene panel to help determine a patient’s risk by evaluating a number of hereditary cancer syndromes. Certain genes also represent drug activity biomarkers and are determinative of tumor resistance or susceptibility to targeted therapies. Detected EGFR and BRAF gene mutations, for instance, work as companion diagnostics to determine patient eligibility for targeted therapies.

CVD Biomarkers

Cardiovascular disease biomarkers are most common for the diagnosis of myocardial infarction (MI; heart attack) and heart failure. Additional biomarkers such as cholesterols and lipids are prognostic tools that are used to assess the risk of CVD progression. Testing for genetic biomarkers of thrombophilia or clotting disorders is also common in order to inform anticoagulant therapy.

Immunology and Infectious Disease Biomarkers - Autoimmune, Sepsis

Immunological diseases and conditions include autoimmune disorders; inflammation or inflammatory disease; and allergies. Numerous immunoassays can be performed, primarily lab-based, to detect and characterize associated diseases of rheumatoid arthritis, lupus, Crohn’s disease, Celiac disease, and multiple sclerosis. Genetic tests are in development to determine the risk of immunological disorders such as Amarantus’s MSPrecise next-generation sequencing (NGS) test for the identification of relapsing-remitting multiple sclerosis (RRMS). Axela has also developed the research use only (RUO) Inflammation Xpress Chip for the detection of molecular profiles associated with inflammatory response.

Another immune response, sepsis, is caused by acute bloodstream infections. Formerly known as blood poisoning, sepsis is a syndrome characterized by an overwhelming systemic patient response to infection, which can rapidly lead to organ failure and ultimately death. The myriad of pathogens that cause sepsis necessitate the use of non-specific analytes or biomarkers that indicate patient response to severe or bloodstream infection. Immunoassays and molecular assays detecting pathogen analytes are not suitable for the general detection of sepsis or assessing the severity of the syndrome. Rather, immunoassays targeting patient-produced biomarkers (immune system proteins) have been developed for such applications. Additionally, surface proteins expressed by immune system cells in response to sepsis can be assayed using flow cytometry. However, blood cultures are the traditional procedure and remain the primary test for sepsis. The development of assays for sepsis-specific biomarkers has been in response to the lengthy timeline for blood cultures, which may not provide a definitive result of sepsis for at least 24 hours.

One company, Immunexpress, is developing its SeptiCyte product or a panel of different combinations of hundreds of validated nucleic acid and protein biomarkers in patient blood. The individual biomarker results are associated and analyzed by advanced algorithms. Biomarker combinations under consideration for development as algorithm-assisted assays include biomarkers related to a patient’s own immune response to bloodstream infections or sepsis.

Neurological Disease Biomarkers - Alzheimer’s, Parkinson’s, Autism

The debilitating neurodegenerative diseases Alzheimer’s and Parkinson’s have vexed healthcare in terms of both therapy and definitive antemortem diagnosis. The localized nature of the diseases in the central nervous system (CNS) complicates the discovery of more accessible biomarkers from alternative samples. The incentive to develop marketable clinical assays for neurodegenerative diseases such as Alzheimer’s is diminished to an extent by a lack of curative therapies. Clinicians are less apt to request or use a lab test to direct decision making for a disease without curative therapies.

Still, clinical value exists for diagnostics able to detect pre-symptomatic onset of Alzheimer’s and Parkinson’s and inform earlier implementation of palliative care and neuroprotective therapy. Outside of clinical applications, lab diagnostics for the neurological diseases are in demand for life sciences research and clinical trials. Research use assays can assist in the characterization of neurodegeneration-associated biomarkers to improve understanding of cellular disease pathways and explore potential drug targets.

Researchers have heavily targeted Alzheimer’s Disease (AD) diagnostics development using CSF samples and even skin samples. One study in Mexico took skin biopsies from patients with Alzheimer’s, Parkinson’s and non-Alzheimer’s dementia as well as similarly aged healthy patients and used immunohistochemistry (IHC) tests to assay levels of tau protein. The biomarker was found to be significantly elevated in the skin samples of Alzheimer’s and Parkinson’s patients; alpha-synuclein protein was also found to be elevated in the samples of Parkinson’s patients. Skin samples are theorized to be feasible proxies for brain tissue because of the samples’ common origin in embryonic development.

Another study identified protein kinase C epsilon (PKCe) as a biomarker for AD with reduced levels observed in AD patient skin samples. Development-stage therapeutics company Neurotrope is interested in a PKCe modulator as a potential treatment for AD patients. While CSF biomarker tests for AD are further along in development, skin biopsy tests would be much more widely implementable in healthcare.

Autism spectrum disorders (ASDs) include syndromes that can range in severity from the social awkwardness and narrow interests to severe communication and intellectual disabilities. Autism, which is marked by deficits in social interaction and language development, as well as by repetitive behaviors and restricted interests, is known to have a strong genetic component. But until a few years ago, genomic research had failed to decisively associate individual genes with the disorder. Current diagnosis of ASD requires development screening and comprehensive diagnostic evaluation. The need for an IVD component to ASD diagnosis has been argued on the basis of rising rates of diagnosis, especially among higher functioning children.

Chromosomal microarray analysis (CMA) has been proposed for detection of genetic imbalances in infants or children with characteristics of developmental delay/intellectual disability (DD/ID), autism spectrum disorder (ASD), and/or congenital anomalies. CMA is a technique that identifies chromosomal abnormalities, including submicroscopic abnormalities that are too small to be detected by conventional karyotyping. It is considered to be a first-tier test in the genetic evaluation of infants and children with unexplained intellectual disability, congenital anomalies, or autism spectrum disorder. Within this population, chromosomal microarray analysis has been useful in detecting causative genomic imbalances or genetic mutations in as many as 15% of children with a normal conventional karyotype.

Next-generation sequencing (NGS) has been proposed to detect single gene causes of autism and possibly identify a syndrome that involves autism in patients with normal array-based testing. Ambry Genetics offers multiple tests for autism and ASD including testing for PTEN-related disorders by sequencing analysis and deletion/duplication analysis, fragile X, CDKL5 mutations, and SNP+CGH array and 180K oligo array testing. SynapDx is developing a test service based on multiple biomarkers and proprietary algorithms for the diagnosis of autism spectrum disorders. In March 2013, SynapDx announced an agreement with Illumina that joins SynapDx’s proprietary autism technologies with Illumina’s sequencing platform to develop early detection tools for ASDs. The press release also reported that the companies would also leverage their joint expertise to broadly evaluate other opportunities in neurodevelopment. Also, in March 2014, SynapDx announced a collaboration with the Broad Institute on NGS analytics for diagnostic applications.