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At the 2010 BIO Conference in Chicago with about 15,000 attendees there were ten Breakout Sessions on Biomarkers (BM) encompassing Intellectual Property, commercialization, reimbursement, drug development and diagnostics. This explosive new technology niche, is a nascent paradigm for exploiting breakthroughs in the molecular basis of disease and more targeted medicine, and assumes a need for co-development of diagnostics and drugs. Genomics transformed biology and now we will see the impact on drug development.
Here is a good definition from www.biomarkers.org, a site hosted by the Massachusetts General Hospital/HST Centers for Biomarkers in Imaging:
What are biomarkers?
Biomarkers are anatomic, physiologic, biochemical, or molecular parameters associated with the presence and severity of specific disease states. Biomarkers are detectable and measureable by a variety of methods including physical examination, laboratory assays and medical imaging.
go Biomarkers in Cancer-On a Fast Track
Two disease areas that can be most advanced by biomarkers (BM) were covered at the BIO sessions were Cancer and Alzheimer Disease (AD). Cancer is a priority because targeted drugs like Herceptin (trastuzumab), Gleevec (imatinab)and Iressa (gefitinib) are already on the market and can benefit from a more targeted therapy utilizing biomarkers.
In a session chaired by Bernward Garthoff Ph.D., Chair of Cluster Biotechnology of the Federal State of North Rhine -Wesphalia D., the potential for use of Biomarkers in Diagnosis/ Therapy in Breast Cancer and Other Tumors was explored. Breast cancer was a prime example where chemotherapy may be reduced after surgery to prevent metastases as it is claimed that only 5% of women would need this algetic therapy. As a case in point in the treatment of node negative breast cancer(NN-BC) after molecular profiling only 30% would benefit from chemotherapy treatment.
Three diagnostic (potential biomarker) tests for breast cancer that are currently available to predict tumor recurrence were presented with pros and cons: 1.) uPA (urokinase plasminogen activator ) and PAI-1, a test for two proteins from American Diagnostica (Japan).It costs $250 and performed on fresh frozen tissue and can indicate a low risk of recurrence. 2.) Mammaprint from Agendia (Netherlands) is a “gene signature” test from 70 related genes in a breast tumor, FDA approved oligonucleotide array also performed on fresh frozen tissue.It costs $3000 and can define low risk from high risk patients requiring chemotherapy. 3.) Oncotype DX breast cancer from Genomic Health (GHDX) predicts chemotherapy response from ER+ tumors from FFPE tissue and recommending a treatment regimen from this data although the clinical utility needs to be proven in more studies. The test profile costs about $3200.
The most studied biomarker the ErbB2 receptor for Her2 show that in 25% of breast cancers that receptor is amplified so that chemotherapy can possibly be reduced by 33% as all patients do not respond to trastuzumab. Another promising biomarker is P13k as it controls important cellular pathways and several drugs are currently in development. A potential model would be testing ErbB2+++ patients in combination with the P13k biomarker as this mutation would also elucidate therapy with trastuzumab. The KRAS mutation predicts response to EGFR receptor drugs such as cetuximab and is a good predictive biomarker.
The commercial perspective was presented by Dr. Stephen Little, VP of Personalized Healthcare at Qiagen (QGEN). Dr. Little believes that the timing is right for biomarkers because of breakthroughs in the molecular basis of disease and that more accurate diagnostics can result in improved therapy. Although the trend for companion diagnostics (CDx) is widely recognized and compelling, progress may be slow as it will require extensive collaboration between diagnostic and drug companies. Some of the issues presented were as follows:
1.) Political-can large drug companies expend the time and dollars to develop biomarkers in parallel with drug development?
2.) Scientific/Platform-there is a strong basis for the science as patients can be selected through “omics” expression profiling and more likely to succeed. However a robust,reliable assay must be developed.
3.) Regulatory-many of the proposed markers are run in CLIA labs and not approved diagnostic kits. Regulatory pathway may be onerous.
The major challenge for biomarker discovery and evolution to a diagnostic kit is proving clinical utility and the major investment in clinical trials. Dr. Little estimates that a Phase 3 drug
trial for a drug can cost $100M and a companion diagnostic (CDx for the same indication could cost as much as $20M. The available market for an FDA approved companion diagnostic could be $20-50M a year.
In summary biomarkers are transformative but the business model has not yet been proven other than a new approach to drug and diagnostic R&D. Dr. Little outlines three possible business models: 1.) a biomarker such as PI3 kinase inhibitor gets accepted as part of the drug/development process.2.) A Payor driven model evolves as it shows that a sub-population can be targeted for improved drug efficacy and cost effectiveness. 3.) A patient driven model such as Genomic Health’s OncoType DX tests where an individual seeks test data for their own treatment.
Biomarkers in Alzheimer Disease-Critical Need
Alzheimer Disease is a huge problem that can overwhelm the healthcare system particularly with 5.3M current cases exploding to a potential cost of $20B by 2020.No tests nor cures are on the horizon so AD can benefit immensely from a biomarker which could predict the course of the disease or track drugs in clinical trials. In the session chaired by Jeffrey Cummings MD of UCLA, Development of Translational Biomarkers to Accelerate Clinical Treatment for Alzheimer Disease,the latest ideas and key hurdles from industry and academia were presented. Although amyloid plaques are associated with AD their presence does not predict course of the disease. The most likely R&D focus in the near term is studying the amyloid protein precursors (APP) such as A4. The enzymes alpha and gamma- secretase can cleave amyloid precursor proteins and are potential drug targets as they disrupt the the pathway and prevent accumulation of beta amyloid peptides in the brain. Lilly has a gamma secretase inhibitor(semagacesat in advanced clinical trials. Dr. Randall Bateman of Washington U. presented a neural network approach using fcMRI to track whole brain connectivity that may be correlated with clinical outcomes. A biomarker for AD would most likely come out of studies involving genetic markers such as APOEe4, the AB precursors and imaging with PET and MRI. PIB-PET is a new imaging biomarker that recently confirmed that a humanized anti-AB antibody,bapineuzamab can shrink plaques. The most likely progress from these efforts will be in targeting AD sub-populations for further study. See previous GEN article,
Population Biobanks-A Suitable and Fast Route to Biomarker Discovery and Validation
Kristian Hveem Ph.D. of Hunt Biosciences chaired a session showing the potential of population Biobanks for tracking samples collected over time with a project involving populations of up to 210,000 individuals in Norway with disease outcomes. Urine and serum samples were tested for DNA and RNA markers. A “biobank” is an investment in infrastructure and dat and can be quite valuable over the long term for drug and biomarker development. A significant issue with biobanks is informed consent and IP.From the business side,another member of the panel Linda Pullan Ph.D. an independent consultant asked why there were no significant biomarket deals announced such as a Pharma/Diagnostic partnership. It could be that that the value proposition is unknown and the predictive power of the biomarker (or CDx) is unknown.Dr. Hans Bostrom of Merck R&D reiterated that big pharma is not interested in more targets but validation of existing targets through translational medicine. Michael Hehenberger Ph.D. of IBM reiterated the need for biobanks for long term global studies to track genomic data with “epigenetic “changes. IBM has been involved in information based medicine since 2003 and this should be a growing trend. deCode Genetics now a private Company. was the first megaproject/Company focused in the field and we need to learn more from this as we pursue biobanks.
Effective Use of Biomarkers in Early to Late Stage Drug Development
The session was chaired by Lewis Bender CEO of Interleukin Genetics,Inc.(ILI) and focused on the need for biomarker and genetic profiling tools at an earlier stage of drug development. All inflammatory diseases can most benefit from biomarkers and examples were given such as TNF, Interleukins, and fLQT a cardiac marker. Obstacles to development were given by John Schultz a VP of Clinical Data Corp (CLDA). Discovery and validation of biomarkers can be expensive and who owns the IP?Which assay platform should be used as that affects pricing and marketing. How will the diagnostic be marketed as a kit or certified CLIA lab as is currently done. Chris Roberts Director of Molecular Profiles and Research Informatics at Merck says that major drug companies ” need to understand the genetics of response and stay ahead of the curve as the field is mind boggling and moving fast”. The cost of sequencing is dropping to the $1000 per sample range so the science will evolve rapidly with the explosion of sequence data. One direction of the business model and opportunity for smaller companies is specialized capability by disease and biomarkers to partner with drug companies. Another critical issue for evolution of the field is awareness by the physician and patient. If the physician orders the test then it will get the Payors attention.
“Pure Play” Companies focused in Companion Diagnostics
In addition to the companies mentioned above here are several other companies developing “biomarkers”: Celera (CRA), Genoptix (GXDX), Illumina(ILMN) Rosetta (ROSG), Response Genetics (RGDX) and Sequenom (SQNM).All of these companies will be reviewed in the future.
Illumina and Sequenom are in the Rayno Life Science Model Portfolio.
There is a wealth of material on biomarkers from the 2010 BIO Conference. Watch for R&D alliances to track value. Expect initial breakthroughs in Cancer followed by Inflammatory diseases. The market for products will develop slowly but this is clearly a long term trend that will transform drug and diagnostic R&D and make personalized medicine a reality within 15-20 years.
(This article appeared on www.genengnews.com WEB site on 5/6/10)