Chip-based diagnostic test technology wins FDA approval

The US Food and Drug Administration (FDA) has cleared Swiss pharmaceutical and diagnostic company Roche's AmpliChip CYP450 microarray-based test for diagnostic use in the USA.

This is the first microarray-based pharmacogenomic test for diagnostic use and combines two industry gold standards ­ Roche PCR and Affymetrix microarray technology ­ in a test for genetic variations that can influence drug efficacy and adverse drug reactions.

It does this by offering comprehensive analysis of the CYP2D6 and CYP2C19 genes, including identification of specific gene duplication alleles. Variations in these genes are important because they can result in altered enzyme activity (Fig.1).

This test works by analysing a patient's Cytochrome P450 2D6 and 2C19 genotypes from genomic DNA extracted from a blood sample. Test results will allow physicians to consider unique genetic information from patients in selecting medications and doses of medications for a wide variety of common conditions such as cardiac diseases, pain and cancer.

In humans, enzymes encoded by the CYP450 genes are found primarily in the liver, where they metabolise drugs, toxins and other foreign substances that enter the body. Through a process called oxidative metabolism the P450 enzymes enhance the water solubility of foreign compounds to aid in their excretion. For drugs, this process affects the blood levels of the therapeutic compound by enhancing clearance and in some cases is a required step to convert and inactive drug into its active metabolite.

There is extensive scientific research showing that inherited genetic variations in the CYP2D6 and CYP2C19 genes can play an important role in how patients metabolise, and therefore respond to, many widely prescribed drugs. Knowledge of these variations can be used to help individualise drug treatment through selection of the more appropriate drugs and adjustment of dosages. These measures should improve patient outcome by reducing adverse drug reactions and improving drug efficacy. Additional applications include patient stratification for clinical trials for more effective and safer dosing, and establishing a genetic role of CYP450 in new drug development programmes.

Drugs metabolised by CYP2D6 & CYP2C19

The enzyme encoded by the CYP2D6 gene plays a primary role in the metabolism of drugs used to treat severe depression, schizophrenia, bi-polar disorder, cardiovascular disease treated with beta-blockers, attention deficit, hyperactivity disorder and others. The enzyme encoded by the CYP2C19 gene metabolises many anti-convulsants, proton pump inhibitors, benzodiazepines and anti-malarials. Both are involved in the metabolism of certain tricyclic antidepressant drugs used to treat depression.

Patients treated with drugs that are extensively metabolised by the two enzymes are at increased risk of experiencing toxicity with standard dosing, while ultra-rapid metabolisers may not achieve therapeutic levels of the same drug in their blood with standard dosing. In the case of pro-drugs (drugs that require metabolic enzyme activity before they become the therapeutic compound in the body) the opposite phenomenon occurs and poor metabolisers will obtain no benefit from these drugs.

Genetic and ethnic distribution

The new test also has implications ethnic distribution of people taking such drugs. This is because genetic variations ­ polymorphisms ­of the two genes are unequally distributed among people of different geographical origins and their descendents, with some polymorphisms and alleles found virtually in only one racial population.

Approximately seven per cent of Caucasians are CYP2D6 poor metabolisers, whereas only 1­2percent of Asian and 2­4percent of African-American populations are in the same category.

However, high prevalence of several reduced activity alleles such as the CYP2D6 10 allele in Asians (50percent frequency) or the CYP2D6 17 and CYP2D6 29 alleles (approximately 30percent each) in certain African populations, lead to a higher percentage of intermediate metabolisers with low enzyme activity.

Although the extreme activities of the poor and ultra rapid metaboliser phenotypes have the greatest potential effect in individual drug response, intermediate metabolisers have also been show to respond differently to certain drugs.

In contrast, approximately 29percent of Ethiopians, 10percent of southern Europeans and 1-2percent of northern Europeans, having inherited CYP2D6 gene duplications, carry CYP2D6 gene duplications, many of which lead to the ultra rapid metaboliser type.

The vast majority of poor CYP2C19 matabolisers are accounted for by the two common CYP2C10 2 and CYP2C10 3 alleles. Each of these null alleles is caused by a single nucleotide polymorphism that either causes a splice site defect or a stop codon. These two alleles are quite common among Asian populations where approximately 13­23percent exhibit the poor metaboliser phenotype. The CYP2C19 poor metaboliser phenotype is present in about 3­5percent of Caucasian and African-American populations.

To allow highly accurate prediction of patient phenotype, the AmpliChip CYP450 test offers the ability to detect not just the presence of CYP2D6 gene duplications, but also to discern which variation of the gene (allele) has been duplicated. This specificity is important in correctly predicting the ultra-metaboliser phenotype and avoiding potential miss-classification of the patients tested.

“We are extremely pleased that the AmpliChip CYP450 Test has gained FDA clearance for use in this important market,“ said Heino von Prondzynski, ceo division Roche Diagnostics and member of the Roche executive committee. “This new test allows physicians access to information that could help to prevent harmful drug interactions and to assure drugs are used optimally. Adverse drug reactions cause a huge number of hospitalisations in the US. Our new test also will, in some cases, enable patients to avoid suboptimal or even harmful treatment choices. For patients it is extremely important to know whether pain killers or anesthetics might work differently or not at all for them. Poor or slow metabolisers may experience much longer lasting effects of the treatment. The knowledge of the reasons behind this will empower people to ask for different and better-to-tolerate medicines. The use of this test is an important step forward in making personalised medicine a reality and has the potential to help physicians improve patient outcomes.“

Some experts believe that the market for such diagnostic tests could reach US$12b in the next few years, while von Prondzynski told the Financial Times that sales of AmpliChip CYP450 could reach US$100m a year. While this is small compared with some sales in the pharmaceutical industry, it is high for the diagnostic sector where a top-seller might generate annual sales of around US$15m.

Eventually Roche hopes that people will be able to take a one-off test to identify their metabolic characteristics. This could then be used by doctors to help determine the most appropriate drug treatment strategies.

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