Want to talk about the latest industry issues? Join the discussion forum. August 2012 NPT | The Community of Big Thinkers

From the Bench to the Bedside

BIOMARKERS 101

by Suzanne Elvidge

While a cure is not yet possible for people suffering with Alzheimer’s disease, early treatment can slow progression and limit mental decline. However, as of now, diagnosis

is only done through an assessment of symptoms, which are often vague and require the disease to have already progressed significantly. Recent studies have shown the vast potential for early diagnosis with “biological markers”, or biomarkers.

Biomarkers are objective and measurable markers of health or disease, most commonly, but not exclusively, biological molecules. Biological biomarkers include proteins such as troponins in heart failure; hormones, such as insulin, in diabetes; and lipids, including HDL and LDL, in heart disease. Biomarkers can also come from the diet, such as glucose, used to monitor diabetes; and vitamin D levels which are used as markers for a number of disorders. Other biological biomarkers in early stages of research include microRNAs (short stretches of non-coding genetic material) in the blood that have been linked to heart disease; proteins in the CSF (cerebrospinal fluid) marking Alzheimer’s disease; or enzymes in the urine that could point to cancer. Biomarkers can also be physical indicators like an eye tremor found in very early Parkinson’s disease cases or inflammation spotted during PET imaging in depression.

Biomarkers have a long history – they have effectively been used in one form or another since the beginnings of medicine. Ian Pike, COO at Proteome Sciences, explains:

“In early medicine, physicians were effectively using whole-organism biomarkers, such as fever or lameness, as objective indicators of poor health. In the last century, we have moved to more specific markers at the organ and cell level; and now, in the last ten or twenty years, we have moved to molecular markers at a subcellular level.”

“In the last century, we have moved to more specific

markers at the organ and cell level; and now, in the last

ten or twenty years, we have moved to molecular markers

at a subcellular level.”

BIOSIMILAR

Biomarkers can be divided into a number of different types:

Diagnostic biomarkers: Biomarkers that can be used to diagnose the presence of a disease, sometimes at a very early stage, before the presence of symptoms

Prognostic biomarkers: Biomarkers that predict the course of the disease in an individual, if untreated.

Predictive biomarkers: Biomarkers that predict the response to treatment for the disease. This could be used to select those patients who are most likely to benefit from treatment

The Challenges of BiomarkersBiomarkers are often inconsistent throughout the course of a disease. They can change as the disease develops. For example, Pike explained to New Pharma Magazine that a hippocampal biomarker present in the very early, pre-symptomatic stages of Alzheimer’s disease might disappear in the later stages as the disease destroys the hippocampus.

Since the sequencing of the human genome, a huge quantity of genomic data has become available. Many saw the sequencing of the human genome as the key breakthrough, but the sequence data alone has limited applications. Other than in diseases that arise from a single genetic mutation, such as Huntington’s disease or cystic fibrosis, mutated genes generally imply only a likelihood of developing a disease. This likelihood is dependent on the influence of other genes and environmental factors, and is unlikely to be useful as a predictive or prognostic biomarker on its own. For example, one of the challenges for genetic cancer biomarkers is that tumours are not homogenous, and the genetic profile can vary between different parts of the tumour. Pike speaks about genomics, saying:

“Genomics is a starting point, but biomarker development also needs to be based on transcriptomics – how the genes translate to proteins – and then, perhaps of greater significance, how these proteins are modified with a process known as epiproteomics. Combining these with other ‘omics’, such as metabolomics and lipidomics, will provide a much more holistic approach and unlock the power of the genomics data.”

The Role of Biomarkers: Now and in the FutureThe role of biomarkers, now and in the future, is likely to be two-pronged – the early diagnosis of disease and the support of drug development. Catching disease early and treating them, and perhaps even preventing progression, is the best possible outcome for everyone. Reducing distress and disability is good for the patients, cutting lost days to work and school is good for society, and lowering healthcare costs is good for payors.

Drug development is very costly, with some reports suggesting that it could cost up to $1.4 billion, and takes many years from start to finish. By stratifying the patients using biomarker-based tests, clinical trials could be based on fewer patients and shorter trials with the same confidence in the results. These tests could then enter the market as companion diagnostics, saving those patients who are less likely to respond or who may suffer from more severe side effects from the cost and distress of unnecessary treatment.

Biomarkers are unlikely to be used singly, thus creating a panel of biomarkers, perhaps combining markers from genomic, proteomic and metabolomic sources, that will increase the specificity and sensitivity of the test. Diagnostics based on blood and urine biomarkers are the least invasive. Biomarkers that rely on sampling from the CSF, for example, are not practical for everyday use. These considerations are vital in both diagnosis and personalised medicine.

Pike predicts that in the next ten years we will see the advent of biomarker panel-based diagnostics on biochips for a range of solid and haematological tumours and CNS disorders. These could be read in simple mass spectroscopy-based machines in a clinic or in a hospital ward, bringing biomarker diagnostics from the bench to the bedside.

Pike adds that “the ideal of the holy grail, if you like, of biomarker development is the biomarker, or panel of biomarkers, that are non-invasive and can accurately detect disease before the symptoms show, allowing doctors to treat the disease and prevent progression. This could transform healthcare.”

Case study

Alzheimer’s disease and plasma biomarkersIn March 2012, Proteome Sciences completed a 1000-sample Alzheimer’s disease biomarker validation study, identifying three panels of 11 to 16 plasma proteins that could form the basis of blood tests for the diagnosis, prognosis and management of the neurological disorder.

In the study, the panels were able to discriminate between mild cognitive impairment (which can precede Alzheimer’s disease), Alzheimer’s disease, and healthy controls.

These panels are now undergoing further validation and assessment in clinical trials and could be a step towards objective and early diagnosis, especially if they can reliably pick out those people with mild cognitive impairment who are likely to progress to full-blown Alzheimer’s disease.

Suzanne Elvidge is a UK-based freelance writer with many years experience writing on the biopharma industry. She is the editor of the weekly newsletter FierceBiomarkers

FROM THE BENCH TO THE BEDSIDE: BIOMARKERS 101 - BIOSIMILAR