Alzheimer’s Disease Assays Target Clinical Trial Markets First

Alzheimer’s Disease Assays Target Clinical Trial Markets First

Outside of the $50+ billion clinical in vitro diagnostics (IVD) market, analytical instruments and lab diagnostics find major applications in the discovery of clinically significant biomarkers, therapeutics development, and other life sciences research activities. Entire classes of assays are originally developed to validate biomarkers as surrogate endpoints for disease, or as mechanism targets for drug development. The potential of pre-clinical assay markets is not lost to Amarantus BioScience, developer of neurological therapeutics and diagnostics. The company is targeting drug development and clinical trial applications with an investigational use only (IUO) Alzheimer’s Disease (AD) assay. Selling to pharmaceutical clients could help position the assay as a companion diagnostics to future therapies while also penetrating an immediately significant market. The validation and reproducible quantitative assay of blood-based biomarkers for AD risk and mild symptomatic disease onset are a notable market opportunity for various life sciences companies.

The challenge for Alzheimer’s Disease diagnostics has been specificity. Alzheimer’s Disease is just one subset of several neurodegenerative diseases manifest as dementia. Autopsy examination is effective at diagnosing AD post-mortem but has no clinical efficacy or potential use in clinical trials. Positron emission tomography (PET) imaging is an expensive and not widely accessible procedure for AD diagnosis, and its associated labeling techniques using Amyvid and Tau tangle tracers have shown inacceptable specificity (with false diagnosis of AD for unrelated dementias). Similarly, amyloid and tau biomarkers collected from cerebrospinal fluid (CSF) have demonstrated only 60-70% specificity. Sample collection for CSF biomarker studies are also very invasive - limiting future clinical potential. These currently available and established tests also suffer from diminished sensitivity to AD during the early disease period of minor cognitive impairment (MCI).

The lack of specificity in available AD tests has become a major burden on AD therapeutics development programs, which hold a relatively high 99.6% failure rate. Part of the problem is the 20% to 50% of clinical trial participants who are not suffering from AD, but another form of dementia, that dilute and complicate trial data across sites. The development of treatments effective in the early onset of AD also requires patients to be effectively screened for AD risk and MCI. Responding to outstanding pharmaceutical industry demand for effective AD screening, Amarantus BioScience adjusted its development plan for its AD assay to focus on investigational use only (IUO) applications initially rather than CLIA clearance. The company plans to target a $150 million opportunity in supplying tests and biomarker services to pharmaceutical clients involved in AD therapeutics development.

The Amarantus Bioscience Lymphocyte Proliferation (LymPro) assay is able to differentiate AD individuals from other forms of dementia and healthy individuals. The test measures the expression of CD69 protein during stimulated lymphocyte mitosis or cell division. In AD individuals, CD69 expression is down regulated compared to healthy individuals and those with other forms of dementia. The lymphocyte cell surface CD69 markers are measured using flow cytometry. In the test, peripheral blood lymphocytes are used as surrogates for neurons that theoretically exhibit the same cell cycle dysfunction.  The data is used to create a stimulation index (SI) value that is significantly lower in AD individuals. The significance of cell mitosis to AD onset is related to the accumulation of tau and amyloid beta proteins in the brain, which is believed to be the result of neurons in an arrested cell cycle. The neurons are stimulated for mitosis, but such cells are largely unable to complete cell division.

Biopharmaceutical clinical trials are increasingly turning to the proteomic tool kit for highly sensitive, specific and flexible assays. One biomarker services company, Proteome Sciences, offers a multiplex panel assay for the absolute quantitation of 9 AD biomarkers. The method uses clinical plasma samples, high-performance liquid chromatography (HPLC), and triple quadrupole mass spectrometry (MS) in selected reaction monitoring (SRM) mode. The targeted mass spec analysis is able to determine absolute quantities of AD protein biomarkers in plasma samples through the relative abundance of associated peptide fragments and the use of tandem mass tags (TMT) reagents or isotope-labeled peptide internal standards. Proteome Sciences’ test targets a different application within the clinical trial market than Amarantus’ assay; the TMT-SRM assay is intended to stratify patients rather than provide initial AD diagnosis.

Assays of tau proteins and beta amyloid in CSF are still widely used in AD therapeutics clinical trials. While products such as Amarantus’ LymPro seek to deliver improved assay specificity to AD, other research has sought to improve assay selectivity of biomarkers. Researchers at Merck have seized upon MS to meet evolving protein analysis demands, selecting immunoaffinity microflow LC-triple quad MS to identify different isoforms of tau biomarkers arising from post-translational modification. Immunoassays do not provide the specificity necessary to identify tau modifications that potentially influence disease progression.

Thermo Fisher has applied its own immunoenrichment triple quad MS approach for low-abundance blood proteins to the discovery and monitoring of AD biomarkers. Researchers have used Thermo’s multiplexed mass spectrometric immunoassay (MSIA)-SRM assays for the quantitation of aberrant ceruloplasmin (affects homeostasis of free copper and results in AD-associated protein degradation and aggregation) and apolipoprotein E (promotes AD-associated beta amyloid fibril formation).

The current state of AD biomarker research and significant remaining needs for AD assay development in drug development will stall the emergence of a larger clinical market for AD diagnostics. Companies such as Amarantus and proteomics suppliers are best served targeting the IUO or research assay market currently valued at $150 million. The potential multi-billion market in clinical AD diagnostics is tied to companion diagnostics (CDx) developments, or the advancement of AD therapeutics. Oncology represents the overwhelming majority of the current global CDx market, with neurological diseases not expected to represent any more than 2% of the CDx market through 2018.