Biomarkers making a mark..!!

Biomarkers have proved to be a boon with their ability to reduce cost and time of drug discovery. 

Many Indian CROs, biopharma companies as well as physicians have now started using biomarkers for the research, treatment and developmental work in therapeutic areas. "The global biomarkers market is expected to grow at a compound annual growth rate (CAGR) of 28.5 percent from $0.63 billion in 2004 to $2.90 billion in 2008," says Dr Vinod Mattoo, Chief Scientific Officer, Eli Lilly and Company (India). No wonder, despite the early stages of market development, leading drug companies are already responding by investing in biomarker discovery programme.

Biomarkers are favoured because they have proved to be a very promising research tool. The use of biomarkers have not just helped the development of pharmaceuticals but also improved the process of diagnosis and hence treatment of individual health conditions. The added advantage is its cost effectiveness. A research analyst explains, "The clinical trials phase currently accounts for over 60 percent of drug discovery and development cost, and it may take up to $1.7 billion to get a drug to market." Webster suggests that use of biomarkers to indicate drug efficacy and toxicity or to stratify patient populations has the potential to significantly reduce clinical trial costs and duration.

Making research faster

Failure of potential drugs to clear clinical trials is another factor driving research in biomarkers. Approximately 90 percent of compounds fail during clinical development. Over 60 percent of those failures are due to absorption, distribution, metabolism, excretion (ADME) problems, as well as toxicology. Researchers believe that they can be influential in every phase of drug development. Biomarkers are often instrumental in eliciting disease targets and pathways.

Biomarkers can also act as pharmacodynamic indicators of drug activity, response, and toxicity for use in clinical development. They help researchers in validating mechanisms of drug action by predicting the progression of a particular disease or disorder. It also indicates in advance a specific patient's response to a compound and hence is helpful in clinical studies.

Biomarkers for treatment

Physicians too have started using biomarkers to monitor and treat several diseases. Reason being, new and established biomarkers are helpful in detecting the disease at its earliest stage and enables to seek vital information as every disease progresses with the progression or expression of the unique biomarker. The early diagnosis also makes the conditions more manageable and hence the treatment becomes easier with favourable results.

Biomarkers serve as indices for health and physiology related assessments such as disease risk, psychiatric disorders, environmental exposure and its effects, disease diagnosis, metabolic processes, substance abuse, pregnancy, cell line development and epidemiological studies. Any and every disease can be diagnosed through biomarkers. "However, primary work is on cardiovascular diseases, psychiatric diseases, Alzeimer’s, cancer and sepsis," adds Mattoo. Many of diagnostic biomarkers discovered in a number of diseases are actually low-molecular weight processed products," explains Wagle. According to Wagle, low-molecular weight proteins such as defensins (recently shown to be important for inhibition of viral replication) are a novel biological function in addition to their known anti-microbial function.

However, cancer is one area where biomarkers are extensively used. The evaluation of biomarkers help diagnose as well as monitor the response to the treatment of cancer. "Biomarker test gives information regarding activities of disease, particularly in cancer. They are also used to judge the response to the treatment. These biomarker tests are carried out in serum," informs Dr Suresh H Advani, Consultant, Oncologist. According to Advani, biomarkers are also very helpful in the development of new drugs for cancer treatment. "Specific biomarkers are done to see the response to the new drug for cancer. These are very helpful to judge the response very early in clinical trials," he adds. Due to its early diagnostic quality, biomarkers are used in many of the rapid diagnostic kits. Many genetic disorders, cardiac related problems are diagnosed through biomarkers. "Carcinoma of ovary, testicular tumour, colon cancer, carcinoma of pancreases can be diagnosed with the use of biomarkers like Beta SCG, CA-125, CEA, CA19.9 and alfa feto protein," suggests Advani.

Cost cutting

Apart from being helpful in clinical research, drug discovery and treatment of diseases, biomarkers also have significance in terms of cost. The early identification and treatment of disease not just leads to best outcome but also less long term expense. Biomarkers are often instrumental in making efficacious and cost saving decisions. With the early prediction of disease and the effects of drug, it is easier to terminate drug entities more quickly during clinical trials. Biomarkers help in identifying certain patient populations that are more likely to respond to the drug therapy or to avoid specific adverse events. This serves immensely in terms of time and money. With biomarkers targeting at the detection of individual states of diseases, there is a shift towards personalised medicine where a particular patient receives a treatment based on his genetic and medical profile. This shift has proved to be a boon for pharmacos and CROs who are desperate to expedite the drug discovery process while decreasing the expense.

Stumbling blocks

While biomarkers are increasingly used by researchers, pharmacos and biotechnology companies all over the world, reliability of biomarkers is still in question. Reliability of the biomarkers is the major challenge in drug development. Currently, there is a pre-conception that biomarker tests are unreliable, with biomarker validation being regarded as expensive and adding a further level of complexity to the clinical development phase. Molecular technology is an answer to improve the reliability of biomarkers. The advent of biomarker pattern profiling in the post-genomic era rather than reliance on a single target promises to improve results. Dynamic range of genome and proteome means low abundant protein and multi-analyte profiling are the challenges faced during use of biomarkers in drug discovery. "The problem of dynamic range of genome and proteome can be overcome by using SELDI Time of Flight technology which is combination of chromatography and mass spectrometry analysis. Whereas, multi-analyte profiling can be addressed by label tagged detection which uses colour beads based profiling (Bio-Plex-Protein array system) and label free detection for active analate determination based on surface plasmon resonance technique (SPR ProteOn XPR technology)," suggests Wagle.Beside the reliability factor the sizeable initial investment required in terms of time and money is a major stumbling block to the increased uptake of biomarkers. An appropriate strategy is needed to maximise benefit and ultimately reduce the financial cost involved in clinical development. "Since the cost of failure is high, and this increases at later stages of the clinical trial phase, biomarkers can be used to identify potential drug failures at an early stage and save costs in the long term," suggests Webster. Webster also argues that although biomarkers initially increase the cost of clinical development, as a larger biomarker portfolio is developed and other drug discovery technologies are integrated, the cost and duration of clinical development are expected to drop to acceptable limits.

However, regulatory agencies are currently unwilling to compromise drug safety and efficacy and are, therefore, being cautious about implementing new regulations regarding biomarkers. There are regulatory barriers but once adequate biomarker data has been assembled, regulatory authorities are likely to be more forthcoming in acknowledging the biomarkers' capabilities and promote their registration as validated surrogate endpoints.

The way ahead

Future prospects are great. While organisations are gearing up to get global trials and infrastructure in place to conduct trials to indentify and use biomarkers for diagnosis and management of diseases, researchers are now examining ways to put powerful laboratory technologies to work for clinical applications by developing more precise and accurate measures of disease. These tools, which were developed to assess cellular and molecular processes or to study animal models of disease, are now being refined for use in human patients and may play a key role in speeding assessment of new therapies. Novel applications of these discovery tools are enabling researchers to identify biological markers, that describe and predict the status of disease or conditions. Blood pressure, cholesterol, certain tumour markers such as prostate-specific antigen, and brain plaques that occur in multiple sclerosis include some of the classical biomarkers that serve this purpose.

With increased prevalence of terminal diseases among the ageing baby boomer generation, the US Food and Drug Administration (FDA) has recognised the need for an accelerated drug pipeline and is proving to be more supportive of biomarkers and their capabilities in making drug approval quicker and cheaper. For sustained growth in the biomarkers market, researchers need to integrate biomarker identification with the drug development and pre-clinical testing process.