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Biomarkers

Cohen Veterans Bioscience was originally launched as Orion Bionetworks in July 2012 with a focus on Multiple Sclerosis. Thanks to generous funding from the Steve A. Cohen Foundation, we changed our name in October 2015 to reflect our commitment to studying Veterans Brain Disorders.

Program Report: Multiple Sclerosis & Neurodegenerative Diseases Biomarkers Workshop

In 4Q14, Orion Bionetworks hosted a two-day workshop on Fluid Based Biomarkers and Diagnostics in Brain Disease co-sponsored by the Foundation for the National Institutes of Health (FNIH) and with funding support from the Alzheimer’s Association, Biogen, Rancho Biosciences and Thomson Reuters. The mission of this workshop was to accelerate the development of fluid-based CNS biomarkers utilizing a case-study approach to refine a roadmap needed to bring diagnostics to market and identify any gaps in this process. Participants included representatives from academia, the National Institutes of Health (NIH), the U.S. Food and Drug Administration (FDA), the Biotechnology Industry Organization (BIO), Accelerated Cure Project for MS, ALS TDI, Alzheimer’s Association, AstraZeneca, Biogen, Genzyme, GNS Healthcare, Human Metabolome Technologies, Janssen Pharmaceutica, MetaCell, MJ Fox Foundation, National MS Society, Rancho Biosciences, Thermo Fisher, Thomson Reuters, and Transcription Diagnostics Incorporated and Vertex.

The Challenge: Lack of Qualified Biomarkers for R&D

For many neurodegenerative diseases (MS, Dementia, ALS, TBI) there are no clear objective markers defining or predicting an individual’s clinical course, disease severity, hallmarks of progression, onset of symptoms/relapse/remission or response to treatment. Although a variety of platforms have been developed to study DNA, gene expression, proteomics and more in a variety of fluids and tissues (saliva, urine, CSF, blood, feces), the use of these different platforms poses several challenges related to the validity, reproducibility, and reliability required for use in diagnostic orpredictive testing. The sources of uncertainty are multiple, from the preparation of tissue specimens, standardization of data and methods, and statistical powering of studies to the computational analysis used to interpret results. Additionally, the regulatory path to qualification of markers, particularly multi-modal panels remains largely untested. This has led to the emergence of many proposed exploratory biomarkers but few validated/qualified ones that can enter clinical practice or be utilized in R&D late-stage studies.

Objectives of the Workshop:

  • Using a case-study approach, examine the full process from discovery to assay development and validation and generate a ROADMAP needed to bring a diagnostic to market and identify any gaps in the current process
  • Review the most advanced biomarker candidates of neuroinflammation/ neurodegeneration based on a review of the literature using manual and computational techniques
  • Generate specific recommendations for technical, scientific and regulatory progress in line with the ROADMAP These discussions led to key insights into the gaps in the biomarker pipeline allowing participants to set actionable goals for the future.

Background

Brain disorders directly affect 1 in 5 people worldwide. Moreover, the number of people suffering from neurological and mental disorders is growing as the global population increases and ages. The associated socioeconomic cost currently exceeds $2T/yr in the US and EU alone, underscoring the need to diagnose and treat these conditions earlier in disease course.

Brain disorders are notoriously difficult to diagnose. The diagnosis of brain disorders largely relies on the use of the DSM V and a subjective physician evaluation of patients. The current process often takes many doctor visits for a diagnosis to be made. Moreover, once diagnosed, finding the right treatment may also require cycling through many drugs before the patient feels relief. Reliable diagnostics will allow for better management of brain disorders by allowing faster diagnoses, earlier treatment, response profiling to treatment, and targeted therapies.

High-throughput technologies now enable the study of cell biology at a systems level — from subcellular systems such as signaling networks, multi-protein complexes and organelles, to cells, tissues/circuits and even entire organisms. Moreover, biochemical, genetic, proteomic markers of neurodegeneration and/or neuroinflammatory processes are emerging as potentially exciting new tools for diagnostics and treatment response monitoring in diseases such as Multiple Sclerosis, AD, Parkinson’s.

A variety of platforms have been developed to study DNA, gene expression, proteomics and more in a variety of fluids (saliva, urine, CSF, blood). The use of these different platforms poses several challenges related to the validity, reproducibility, and reliability required for use in diagnostic or predictive testing. The sources of uncertainty are multiple, from the preparation of tissue specimens to the computational analysis used to quantify ‘omic levels.

Apart from technical issues, brain disorder diagnostics have been difficult to bring to market for a variety of reasons:

1) The translational divide between basic scientific research and clinical application.

2) The lack of infrastructure to confirm the validity of a biomarker and assay.

3) The demanding regulatory environment.

First, basic science research does not currently lend itself to speedy translation into clinical implementation. Many potential biomarkers for brain disorders are described in the scientific literature, but as they are often derived from animal models, must be studied further and correlated to clinical endpoints. Second, the clinical infrastructure for confirmation, that is necessary to confirm biomarker and companion test sensitivity and precision in human populations, is limited and often cost-prohibitive. Specifically, standard procedures for patient information and sample acquisition and appropriate statistical methods for data analysis need to be established. Additionally, validation and confirmation studies need larger sample sizes that include controls individuals who are neurological patients for disorders distinct from the one being tested. Third, the regulatory and reimbursement environment for diagnostics is difficult. The approval process involves more regulatory arms than drug approval process; diagnostics are scrutinized by the CMS in addition to the FDA. Plus reimbursement structure and patent protections are thin. These combined factors have led to a severe lack of brain disorder diagnostics.

Workshop Discussion

The working group identified the major challenges for all stages from biomarker discovery, translation development, assay development, assay performance, biomarker qualification, biomarker validation, analytics and knowledge management, that need to be addressed systematically to advance the field.

Key challenges include:

  • Standardization of specimen collection, extraction and storage practices
  • Access to large patient data repositories with both deep & frequent phenotyping & biosampling
  • Lack of well-powered studies
  • Lack of replication and qualification studies
  • Heterogeneous or unknown bioassay platform performance
  • Bio-statistical analysis of large ‘omic datasets and multi-scale integration

Data-sharing platforms

Participants agreed that progress towards our common goals would be aided by the establishment of a Public-Private Partnership Alliance that would specifically test and pave a standardized and unified process using a focused and selective Case Study Approach.

Biomarkers Resources