AutoGenomics' Warfarin Panel

GenomicWeb News (sub required) reported on Harvard-Partners Center for Genetics and Genomics' completion of an evaluation of AutoGenomics' Infiniti 2C9-VKORC1 assay; a genetic test to determine correct dosing for warfarin. This announcement has come on the heels of the FDA's approval of new labeling for warfarin suggesting that an individual's response to the drug is dependent upon their genetic makeup.

HPCGG is participating in a clinical trial entitled: Creating an Optimal Warfarin Nomogram Trial (CROWN) to incorporate both clinical and genetic information in determining the correct warfarin dosing.

FDA Steps into Personalized Medicine

Last week the FDA approved new labeling on the blood thinner Coumadin and its generic form, warfarin. The new labeling suggests that an individual's response to the drug is dependent upon their genetic makeup. Not only is the FDA opening the door to personalized medicine, but they are actually taking a leadership role in doing so, a role not characteristic of the agency.

Warfarin has been in use for some 50 years during which time it was evident that individual response to the drug was widely varied. Dosing requires careful monitoring of patients who could suffer life-threatening bleeding if dosages were too high and life-threatening clotting if the dosage were too low. A number of factors such as patient size, age and other medications were attributed to the variability in results but it was obvious that these factors did not explain the entire story.

A story in the WSJ (sub required) last week pointed out that studies over the past decade have identified two genes that were tied to the variance in results: CYP2C9 and VKORC1. Variants in either or both genes lead to different drug responses in individuals. Combining size, age and an individual's genotype can increase the confidence with which a doctor can prescribe a patient's dosage.

The FDA's leadership in making this move is a direct result of its Critical Path Initiative, a broad initiative undertaken by the agency to modernize biomedical sciences with the goal of improving the nation's healthcare. A cornerstone the CRI is the improvement of evaluation tools, specifically biomarkers and disease models. By taking this step the FDA is actively encouraging the use of pharmacogenomics; the use of genetic markers to predict an individual's response to a drug.

Already a number of labs have begun offering genetic tests for CYP2C9 and VKORC1 such as the Mayo Clinic and Labcorp. Osmetech announced last Friday that they are developing a warfarin assay that they plan to have available by the first half of 2008.

This is all being done without a critical clinical trial; the trial that compares a group of patients that are treated without genetic testing against a group that are treated with genetic testing. Given the fact that the health risk to patients without genetic testing is reduced by the extensive monitoring they undergo during their initial dosing, it is questionable whether the genetically tested patients will actually have a lower health risk. However, by taking some of the guess work out of the dosage process, doctors can more quickly converge on the correct dosage, reducing the time the patient must spend in an over- or underdosed state and certainly cutting down on visits to the doctor for monitoring.

Risk Mitigation

As a serial entrepreneur you may think Dr. Michael Bristow has a high tolerance for risk, but in a talk yesterday morning at the downtown Denver offices of Holland & Hart, Dr. Bristow stressed the importance of mitigating risk in the drug development process. Dr. Bristow was a founder and the Chief Science and Medical Officer of Myogen, a biopharmaceutical company focused on the discovery, development and commercialization of small molecule therapeutics for the treatment of cardiovascular disorders. In November 2006, Myogen was sold to Gilead Sciences for $2.5 billion.

Although a whopping success by most counts, Myogen did not achieve this lofty value without a few pitfalls. Development of enoximone, their first drug to be brought to clinical trials, was halted in Phase III after burning through $100 million on development due to its failure to demonstrate significant benefit. Ironically, Myogen's stock began to climb after this, the result of investor confidence in the other drugs in Myogen's pipeline.

When asked what could have been done to have better predicted the outcome of the enoximone trial, Dr. Bristow indicated that it was known that a certain patient sub-group characterized by a phenotype responded better to the drug than the population as a whole. He felt that by selecting for patients with this phenotype for inclusion in the clinical trial would have greatly improved the efficacy of the drug to the point where it would have received approval. But either because recruiting a sufficiently large patient sub-group with this phenotype would have taken too long or the FDA had not yet accepted a personalized approach to drug therapy, that approach was scrapped and the more risky strategy of recruiting patient's from the broader population was adopted.

Dr. Bristow has once again taken a risk on risk mitigation by starting up a new company; ARCA Discovery that is developing genetically-targeted therapies for cardiovascular disease. The FDA and the pharmaceutical industry is warming to the idea of personalized medicine as a way of improving patient health and reducing the costs of drug development.

ARCA Discovery and LabCorp

Early stage PGx company ARCA Discovery and mega-lab LabCorp have announced a deal to develop and commercialize a genetic test to aid in prescribing bucindolol, a drug now under development at ARCA. As a pharmacogenomic drug, bucindolol will be prescribed only to a select patient sub-group who have shown a benefit from using the drug. Although bucindolol has yet to receive FDA approval, such an approval will be contingent upon both the efficacy of the drug in the selected patient sub-group and the ability of the diagnostic test to select those patients. Bucindolol has already undergone extensive phase III trails where was shown to be ineffective over an unfiltered patient population. However, in a subsequent substudy it was shown that patients with certain genetic variations showed significant improvement on the drug.

It's interesting to see the progression of this idea from the universities where it was first discovered, to a start-up company where its commercial potential was analyzed and promoted and now to a large diagnostic company where its commercial potential will (hopefully) be realized. It is a classic example of technology transfer and how it can be done.