Biomarkers in CNS drug discovery and development – focus on molecular blood markers

In established economies, mental disorders account for a larger burden of disease than all cancers combined. Yet reliable, measurable, markers of such diseases (biomarkers) are not uniformly known and without them, prediction that a new drug candidate makes contact with its target is poor. This is unfortunate because the attrition rate of new chemical entities (NCEs) in clinical development for CNS disorders is high and primarily driven by failure to show efficacy and often without knowing that the drug reached its intended target for action. Today, several companies have reported efforts towards the discovery of molecular biomarkers for CNS disorders. Confirmation, and ultimately validation of molecular (and other) biomarkers will hopefully foster new drug developments for multiple, currently poorly understood and inadequately treated CNS disorders.

Problem statements

According to the National Institute of Mental Health (NIMH), mental disorders affect an estimated 26.2 percent of Americans aged 18 and older in a given year (www.nimh.nih.gov/health/publications/the-numbers-count-mental-disorders-in-america). Unlike many other chronic and disabling disorders, mental illnesses strike early in life and cause significant disability in people aged 15-44 years1. This underscores the considerable burden of disease accounted for by mental illness in established market economies, which is more than the disease burden caused by all cancers. These data also indicate that current treatments leave ample room for improvement1.

This is particularly striking for major depressive disorder, which by far exceeds the disease burden of all other disease2. Yet, major depression remains a condition that is treated using a trial-and-error approach, with no objective markers to predict and monitor treatment outcome in a given patient.

While this situation could represent a potentially highly profitable challenge for the pharmaceutical industry, very few truly new drug development approaches for depression are on the horizon. To make matters worse, several companies are reported to have retracted their efforts towards antidepressant drug development. This unsatisfactory situation, particularly from a patient and health care provider perspective, is likely to reflect the paucity of translatable animal models with construct validity for the human disorder3. This in turn contributes to the high attrition rate due to failure to show efficacy for NCEs targeting CNS disorders in general3,4.

While this alarming situation could have enticed major research efforts into the biological underpinnings of mental illness, the biomarker discovery and development for CNS disorders is still immature, particularly compared to biomarkers in the cancer field. This conundrum has been attributed to often ill-defined disorders that result in the inclusion of heterogeneous patient populations in clinical trials if based exclusively on currently used clinical diagnostic criteria. One consequence of patient heterogeneity and the genetic complexity of these diseases has been the lack of validated biological markers for characterising and distinguishing the different disorders. This seems particularly true for genetic markers in many (but not all) CNS disorders: most markers published so far eventually fail to replicate or have a very small contribution towards a disease or the susceptibility for a disease, and hence provide limited insights into the disease biology.

Key initiatives towards a solution

The Psychiatric Associations

The American Psychiatric Association (APA) has set itself an ambitious research agenda for their new version of the Diagnostic (and Statistical) Manual, the DSM-V, aiming to develop ‘an etiologically based, scientifically sound (diagnostic) classification system’5. Biomedical research that focuses on the disease rather than on treatment may improve our understanding of core biological alterations associated with psychiatric disorders. A better understanding of the disease biology, and the biological differences among patients, should advance the diagnostic classification through use of objective markers (biomarkers).

In fact, a range of biological read-outs are mentioned in the DSM-V research agenda, including neuroendocrine, protein, transcription and genetic markers, neuroimaging and neurophysiological approaches. All of these are, at some level, pursued with the goal to improve understanding of disease biology. The efforts by the APA towards DSM-V are not exclusively focused on the North American populations, but recognise the need to include contributions from European and Asian experts.

Public-private partnerships

In view of few truly new drug developments for major psychiatric disorders in the last decades, and the remaining high disease burden for our societies, several major initiatives in Europe and the USA have been launched to address the much needed progress in this field. One commonality of these efforts is the creation of substantial public private partnerships, and the inclusion of regulatory authorities as well as healthcare companies into these new collaborations.

In Europe, the Innovation Medicines Initiative (IMI) has set itself the goal to stimulate faster discovery and development of better medicines, with greater efficacy and improved safety and tolerability. IMI’s strategic research agenda states that the initiative will foster collaborations between large and small biopharmaceutical companies and academia to address bottlenecks in the current R&D process, such as prediction of safety, efficacy and knowledge management. While this research agenda is not necessarily focused on biomarkers per se, the planned collaborations will include biomarker research to achieve the goal to discover and develop drugs with better efficacy and safety.

In the US, the US Biomarkers Consortium is a major public-private biomedical research partnership with broad participation from stakeholders across the health enterprise, including government, industry, academia, patient advocacy and other non-profit private sector organisations. It is managed by the Foundation for NIH, and includes as additional founding members the NIMH, FDA and PhRMA.

One of the most difficult tasks facing biomarker assessment and evaluation is harmonising the approaches of various stakeholders. The consortium founding members and other partners recognised the critical need for a coordinated cross-sector partnership effort by bringing together expertise and resources to identify, develop, and qualify potential high-impact biomarkers. The consortium, formally launched in late 2006, has created five disease-specific steering committees in the areas of cancer, inflammation and immunology, metabolic disorders, other therapeutic areas, and neuroscience, with the latter focusing on psychiatric disorders and neurodegenerative diseases.

Large consortia face the challenge to find the right balance between striving for consensus between sometimes diverging stakeholders’ objectives and the ultimate goal to shape the field in a proactive and timely manner. On the other hand, the opportunity to work with key stakeholders towards a common path forward, to discover and consolidate broadly accepted biomarkers is key in a field that has been dominated by small (and often not reproducible) efforts from individual groups.

Another exciting potential of the US Biomarkers consortium, which has not yet been realised to its full extent, is the cross fertilisation between therapeutic areas. Thus, neuroscientists could learn from the more advanced biomarker efforts in the cancer field, particularly with regard to pathway identification related to cellular proliferation and differentiation that may ultimately reveal relevant treatment targets for neurodegenerative indications.

In addition, several pharmaceutical companies have embarked on longer-term sizeable partnerships with a specific academic institution to tackle CNS disorders. Thus, Johnson & Johnson recently announced a collaboration with Vanderbilt University (R&D Magazine, March 2009) which ‘underscores the synergies between academia and industry that can help create solutions for addressing unmet medical needs’ [in schizophrenia]. Similarly, many other big pharmaceutical players in the CNS field, including AstraZeneca, GlaxoSmithKline, Lundbeck, and Merck, have crafted public-private partnership to address specific unmet needs in CNS drug discovery and development6.

The business perspective

In a market research report from August 2008 specifically on CNS biomarkers (http://researchandmarkets.com/reports/ 651258/), the authors estimate that in 2015 the global CNS biomarker market will account for sales worth over US$ 3.4 billion. It is expected that the maturation of the markets will be driven by growth in biomarkers for neurodegenerative and neuropsychiatric diseases, specifically depression and schizophrenia. The biomarkers are expected to provide clinical trial guidance as well as commercialisation of molecular tests to predict conversion from mild cognitive impairment (MCI) to probable Alzheimer’s disease (AD) and to differentiate patients suffering from Multiple Sclerosis (MS). The majority of this CNS biomarker market (57%) is envisioned to be taken by the biomarker discovery sector, including target identification efforts based on understanding of disease biology and target validation efforts that use preclinical models with improved construct validity, at least for a segment of patients.

This optimistic prediction is based on the increasing number of publications demonstrating success at predicting conversion to AD from MCI7, conversion from clinically isolated syndrome, the earliest clinical manifestation of MS, to clinically definite MS8, and the development of posttraumatic stress disorder (PTSD) after trauma exposure9.

One unifying feature of these predictive molecular profiles is that they are based not on a single marker, but a biomarker panel selected from a broader range of markers. Another commonality is, however, that these are single publications with relatively small sample sizes. Therefore, an independent replication that confirms a prospectively defined biomarker hypothesis is pertinent.

In addition, while the validation of a biomarker panel and the approval of a molecular diagnostic test, even after a positive replication study, is still some time away, biomarker profiles that could predict the course of a CNS disorder would at least facilitate internal decision making for drug developers. Thus, a clinical trial could select patients with a more progressive disease course and hence a greater chance to show a benefit over placebo of a new drug. Such use of objective markers for inclusion of patients and monitoring of progression should help the industry to lower the attrition rate, currently estimated at 92%. This means there is only an 8% chance for a (CNS) drug that enters clinical trials to eventually reach the market (http://researchandmarkets.com/reports/651258/).

Methodological aspects

Traditionally and understandably, biological markers for CNS disorders were focused on the brain, where the pathophysiology of mental disorders occurs. Although the brain certainly is a critical site to study the biology of mental disorders, there is increasing evidence for peripheral changes that are associated with mental disorders per se as well as changes in response to treatment.

Obviously, markers identified in post-mortem brain tissue can neither address the diagnostic nor the treatment prediction problem. In addition, several variables can affect results of gene expression studies in post-mortem brain tissue and need to be carefully controlled for, as recently discussed in a publication by the members of the NIMH Conte Center and the Pritzker Neuropsychiatric Disorders Research Consortium10.

Though quality control remains a very critical issue for all biomarker investigations, including blood-based markers, simple procedures are available to ensure standardised blood collection with good preservation of RNA and reproducible transcription data in multi-center clinical trials. For protein and metabolite biomarkers on the other hand, there are no standardised, easy-to-use and agreed upon procedures for sampling of plasma or serum. Therefore, the detection and subsequent validation of protein biomarkers for psychiatric disorders will have to await agreed upon standards and guidelines, e.g. from initiatives such as the ‘Proteomics Data Collection’ (ProDaC) workshops.

Meanwhile, data on gene transcription profiles from blood samples show interesting changes in patients suffering from an acute psychiatric disorder, suggesting that this approach is an encouraging route for the discovery of disease biomarkers in CNS disorders11,12. As some of the very targeted transcription data also show normalisation with treatment, peripheral leukocyte transcription profiles can provide both disease as well as treatment-related biomarkers13.

It is not expected that all gene transcript changes in blood will reflect CNS changes. However, transcripts related to cellular signaling and metabolism show a high correlation between blood and brain in humans7,14. Thus, transcription analysis from blood that includes signaling pathways rather than focusing only on downstream products, could discover profiles that distinguish between patients and controls as well as between subgroups of patients and reflect changes that are also occurring in the CNS. Such pathway-based analysis rather than a focus on end-products is also more likely to achieve the needed high accuracy, in the range of 95% and higher, for a biological signature to become a clinically relevant tool. These data reinforce the notion that transcription-based markers from blood will be useful to guide hypotheses on the pathophysiology in CNS disorders and will provide critical information for the discovery of novel (and improved) treatment targets.

Competitive landscape

A number of companies are currently developing blood transcription diagnostic tests for CNS disorders, all employing microarray-based approaches: Diagenic (Norway), that launched a diagnostic test for breast cancer, claims to also be developing a similar biomarker test for AD (http://www.diagenic.com/site.php?id=pr&year=2007&id1=16978320196325). Press reports from May 2007 indicate that Curidium (UK), recently acquired by the Avacta Group, has developed a test that can classify patients with schizophrenia/bipolar disorder into four subgroups, albeit with an accuracy of only 78% (http://www.curidium.com/ pressreleases.asp). Further news on the validity of this test has not emerged, but it was announced that Curidium entered into a strategic partnership with Takeda to also include major depressive disorder. AbaStar MDx (California) is a second company in the process of developing an assay aimed at diagnosing and differentiating patients with schizophrenia and bipolar disorder, but proof of the validity of their approach remains to be demonstrated (http://www.abastarmdx.com/ products.asp).

Thus, at present there appears to be a keen interest from companies and some progress in developing blood transcript biomarker tests for psychiatric disorders. However, so far no validated biomarker assay for a psychiatric disorder has been reported.

Technological aspects

In the past decade vast strides have been made in improving the methodology for assessing transcripts, including real time quantitative PCR (qPCR) and DNA microarrays. However, studies measuring expression across microarray platforms agree that such data should be confirmed by a quantitative method such as qPCR. Therefore, a conclusion with regard to the validity and clinical usefulness of currently published array-based blood transcription markers has to await further data.

Of note, as the throughput of quantitative transcript measurements, such as qPCR, is continuously improving, such technologies may become the approach of choice in the future, addressing in the same assay both a wider range of transcripts and their quantitative assessment.

Summary and outlook

A better understanding of the biological underpinnings of many CNS disorders, though ambitious, is a critical step towards development of much needed new drugs with improved efficacy and safety profiles.

In this regard, discovery and validation of biomarkers, related to the disease biology, will be useful to: 1) make the correct (biologically-based) diagnosis, 2) guide treatment selection and 3) monitor treatment impact. Furthermore, human biomarker profiles could help develop animal and cellular models with better construct validity15.

Blood markers in general and blood transcription profiles in particular are receiving increasing attention from academic and industry scientists working in the field of CNS disorders. An obvious reason is the accessibility of blood (in humans and animals), allowing for large sample sizes and repeated sampling in the same individual. Proteomics and metabolomics approaches are certainly measuring functionally relevant biological products. However, the lack of agreed upon standards with regard to sample collection, storage and bioanalysis, and the considerable costs for the latter, makes these approaches currently less tractable for large clinical studies. These approaches could and should be explored in smaller proof-of-principle trials, which could also help generate data needed to establish standards for collection and evaluation.

On the other hand, for transcription profiling from blood samples both easy and standardised methods exist for blood collection as well as data generation. As diagnostic companies have started to use blood transcription profiles towards biomarker discovery for CNS disorders, the hope is that these efforts will yield relevant insights and stimulate further biomarker developments, including proteins, metabolites, lipids and other measurable molecules in accessible body fluids.

Finally, it is important to point out that blood markers may not provide a complete picture of an altered (CNS) biology. Therefore, exploratory and proof-of-concept clinical trials should explore a wider range of biomarkers, including functional neuroimaging and electrophysiological measures. Ideally, these studies would examine correlations between functionally complex markers and simpler molecular markers from blood or CSF (cerebrospinal fluid) and then use the simpler biomarkers in multi-center confirmatory studies.

References

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