CEO SUMMARY: Each year, over 100 million new prescriptions are written for two classes of drugs with metabolic pathways affected by genetic variations in cytochrome P450. There are strong clinical arguments in favor of testing individuals for these genetic mutations to determine whether they are no, slow, or ultra-fast metabolizers of these drugs, before writing the prescription.
IT’S SIMPLE TO UNDERSTAND the clinical reasons for adopting testing based on cytochrome P450 (CYP450). In the United States, adverse drug reactions (ADRs) are a major source of deaths and tens of billions of dollars in related healthcare expenses.
That’s because drug efficacy and toxicity vary substantially across individuals. In today’s healthcare system, drugs and doses are typically adjusted by trial and error. That means physicians use a “hit or miss” approach to identify the right drug and the right dose.
Factors Causing ADRs
Many factors may influence the effect of a drug on an individual. These factors include age, liver function, concomitant diseases, nutrition, smoking, and drug-drug interactions. Other factors that may also have major effects on the efficacy or toxicity of a drug are inherited DNA sequence variation (polymorphisms) in genes for drug-metabolizing enzymes, drug receptors, drug transporters, and molecules involved in signal transduction pathways.
New and emerging pharmacogenomic tests have the capability to predict therapeutic failures in individual patients or severe adverse drug reactions. These tests evaluate genotypes for important polymorphisms that affect key drug-metabolizing enzymes, receptors, and transporters.
Such pharmacogenomic tests have the potential to help clinicians optimize the choice of drug and proper dose much earlier in the treatment cycle. These pharmacogenomic tests would position laboratory testing as a major contributor to better therapeutic outcomes, the avoidance of serious side effects, and reduced medical costs.
These are the reasons why the laboratory industry is poised to hit a major clinical home run with CYP450 and other pharmacogenomic testing. This testing has the potential to dramatically reduce many problems related to prescription drugs. Adverse drug reactions (ADRs) are a major source of poor clinical outcomes and the healthcare system is eager to find effective solutions to manage this problem.
Recently, Michael Caldwell, M.D., Ph.D., Director of Medical Research at Marshfield Clinic in Marshfield, Wisconsin, made a presentation to the Food and Drug Administration (FDA titled “Predicting the Stable Dose of Warfarin.” Dr. Caldwell quoted studies that estimate the number of adverse drug reactions for hospitalized patients to be 2.25 million per year, causing more than 106,000 deaths annually.
If these studies are accurate, ADRs are the fourth leading cause of death in the United States, ahead of pulmonary disease, diabetes, AIDS, pneumonia, accidents, and automobile deaths. Dr. Caldwell observed that there is no reliable methodology for estimating ADRs and related deaths in ambulatory settings, but that 350,000 ADRs occur in nursing homes each year.
Tens Of Billions Of Dollars
Caldwell also referenced a study that estimates the annual cost of ADRs to the United States is $136 billion! This exceeds the cost of cardiovascular or diabetic care in this country. Further, one out of five injuries or deaths to hospitalized patients may be the result of ADRs and a “two-fold greater mean length of stay, cost, and mortality has been reported for a hospitalized patient experiencing an ADR compared to a control group of patients without an adverse drug reaction.”
These are huge numbers and explain why there is support and interest in CYP450 and similar tests. Clinicians need a way to more accurately predict how individual patients will respond to a specific drug and whether that patient may experience adverse drug reactions.
Roche Sees A Market For CYP450 Testing
IN PUBLIC STATEMENTS, Roche Diagnostics has predicted sales of CYP450 testing to reach $100 million by 2008. But that is only the first phase in the market development of CYP450 testing.
Roche executives are optimistic about the long-term growth potential for such testing. In public statements, Heino von Prondzynski, CEO of Roche Diagnostics, predicted that the gene chip market worldwide may reach $8 billion to $10 billion by 2015.
Von Prondzynski believes that clinical benefits will not be the only motive to expand CYP450 testing. In general, he believes the demand for pharmacogenomic tests will be driven, in part, by litigation fears. “If a patient suffering from an adverse drug reaction learns he could have avoided it if his physician had done such a test because he is a poor metabolizer, this is something that will drive the use of the test,” stated Von Prondzynski to a reporter from Reuters.
Because Roche is big in both pharmaceuticals and diagnostics, its confidence in the future of CYP450 testing and pharmacogenomics in general represents an important shift from the existing mindset with in the pharmaceutical industry. Until now, most big pharmaceutical companies have approached pharmacogenomics with caution. The drug industry has traditionally relied on a small number of multi-billion-dollar “blockbuster drugs” to drive sales and profits. Pharmacogenomics threatens to explode that model if, in the future, drugs are tailored to small groups of patients.
That is not the belief at Roche, a company with a considerable presence in both therapeutic drugs and in vitro diagnostics. Von Prondzynski has stated that, by the year 2020, it is possible that, for every $2 spent on prescription drugs, pharmacogenomic testing could generate $1.
As noted in the preceding story, CYP450 tests are capable of identifying genetic variants that impact metabolism for at least 25% of all prescription drugs now in the formulary. That gives CYP450 testing the potential to be a blockbuster for the laboratory industry, both clinically and financially.
A look at key numbers reveals why. In 2000, there were 2.8 billion prescriptions written in the United States, which is an average of almost 10 prescriptions per person. Estimates are that about 64% of patient visits to physicians result in prescriptions and the incidence of ADRs increases exponentially once a patient is on four or more prescriptions.
Other remarkable statistics suggest why CYP450 testing would be of high value to patients and physicians. Within certain population subsets, there are significant polymorphisms which contribute to potentially fatal outcomes connected to specific drugs.
For example, CYP29C has a polymorphic distribution in the population. It is missing in about 1% of Caucasians. It is a primary enzyme responsible for metabolism of many non-steroidal anti-inflammatory drugs, including second generation COX-2 inhibitors. CYP450 2C9 plays a key role in metabolizing warfarin (Coumadin). Caldwell notes that “almost all interpatient variability in warfarin levels and anticoagulant effects can be explained on the basis of CYP2C9 activity (not the differences in protein binding as thought).”
Cytochrome P450 2C19 is genetically absent in between 20% and 30% of Asians. Caldwell says “this enzyme metabolizes many anticonvulsants, diazepam (Valium), omeprazole (Prilosec), and several of the tricyclic antidepressants…Asians have a reduced clearance of diazepam compared to Caucasians.”
In terms of rapid metabolization, upwards of 30% of Ethiopians in a study were determined to have multiple copies of the 2D6 gene (as many as 13 copies). In affected individuals, this causes lower blood levels of a standard dose of any drug metabolized by this enzyme. In particular, 2D6 affects standard doses of beta blockers, narcotic analgesics, and antidepressants. These individuals may need higher dosages to achieve clinical results.
Psychiatry is one of the first medical specialties to use CYP450 testing to help guide clinicians in prescribing the most effective drug for individual patients. In her presentation on molecular diagnostics and pharmacogenomics at the Executive War College in New Orleans last May, Gwen McMillan, Ph.D., described how psychiatrists were using CYP450 tests to eliminate “trial and error” prescribing practices and more quickly match an effective drug to the patient, while minimizing negative side affects. McMillan is the Medical Director of Clinical Toxicology and Trace Elements Laboratories at ARUP Laboratories in Salt Lake City, Utah and has seen a pick-up in pharmacogenomic testing by psychiatrists referring tests to her laboratory.
Financial Home Run
One fact and one statistic dramatically demonstrate the potential of CYP450 testing to be a financial home run for the laboratory industry. The fact is that CYP450 testing predicts how patients will metabolize individual drugs comprising 25% of the current formulary. The statistic is that 2.8 billion prescriptions are written each year in the United States.
By implication, this means that the laboratory industry is likely to be doing high volumes of CYP450 testing in coming years. Because of the value of this testing to the healthcare system (in outcomes improvement and cost reduction), there are reasons to be optimistic that reimbursement for these tests will be adequate.