Roche Molecular Diagnostics and Affymetrix have put on hold for at least four weeks the launch of their jointly developed cytochrome P450 multi-analyte diagnostic, according to a Roche official.
Certain “market-preparation” setbacks mean the companies’ AmpliChip product will roll out at the end of June instead of late May, said Tom Metcalfe, senior vice president of genomic and strategic business development at Roche Molecular Diagnostics.
Though Metcalfe declined to say what kinds of issues were responsible for the delay, he said one issue was that Roche and Affymetrix could not agree on what to charge for the chip.
“Certainly by the end of next month it will be commercially available” to CLIA-approved labs, said Metcalfe, who spoke with SNPtech Reporter between sessions at the IBC Molecular Diagnostics meeting in Boston last week. Soon after, Roche and Affy will apply the AmpliChip for FDA review, though Roche has not “yet mapped out“ all of the approval-processing details yet, he said.
Metcalfe stressed that Roche has “a very good design file” that would allow it to submit the chip, whose components comprise software, hardware, and reagents. The reagents are on track, he said. For the software and hardware side, however, “there’s still some ways to go yet. We’re working together with Affymetrix to map that out,” Metcalfe said.
It was unclear whether the delay will also set back the launch of similar diagnostics for human papilloma virus, cystic fibrosis, colorectal cancer, HIV, and leukemia. These products, which are also part of the Roche-Affy collaboration, were scheduled to roll out after the CYP450 chip went live, Roche Dx chief Heino von Prondzynski said in early May.
Metcalfe said Roche also intends to develop a similar diagnostic for solid tumors, a project that would be a “logical offshoot” of an ongoing program with Affymetrix that aims at using the GeneChip platform to develop a “diagnostic panel” for leukemia and lymphomas. He said that a clinical investigator in a European medical center has provided Roche with “clinical content” in the form of gene-expression and phenotype data, and the companies are now composing a development plan.
Jorge Leon, president of Leomics Consulting, a molecular diagnostics-consulting firm in Princeton, NJ, believes the market for these tests when sold to CLIA labs is between $10 million and $20 million. But once the chip is approved and can be marketed to the big reference labs and hospital systems, the potential market balloons to $200 million.
However, there is still some doubt within Roche as to the clinical effectiveness of the product. Klaus Lindpaintner, who heads Roche Genetics, said that while he is confident that the test is accurate, investigators at Roche and Affy “still don’t know what its efficacy will be in day-to-day medicine. How will it play in clinical responses and disease outcomes? We don’t know.” Lindpaintner, who also oversees Roche’s Center for Medical Genomics in Basel, Switzerland, spoke with SNPtech Reporter at the Molecular Diagnostics conference.
In addition, Walter Koch, director of pharmacogenetics at Roche Molecular Diagnostics, doesn’t expect these assays to be adopted quickly. “There is a time lag where new ways of doing medicine need to be validated, its effectiveness proven, and clinicians and patients educated on how this can help them,” he said in February. Microarray technology, he noted, is much more complex. But “we see many scenarios in the future where a clinician likely would want to perform a diagnostic test prior to using a drug.”
Leomics’ Leon, who had been an official at Quest Diagnostics, said flatly that “the market is just not ready” for multi-analyte diagnostics. He cautioned that products like the AmpliChip will catch on only after they are targeted at specific therapeutic areas, “especially antidepressants and antihypertensives, and later for some other drugs.”
The AmpliChip will be the first commercial product to come out of an R&D collaboration Roche and Affy penned in February. The product, which was designed by Roche and manufactured by Affy, is based on cytochrome P450 liver enzymes, which play a role in drug metabolism.
Specifically, the AmpliChip queries the CYP2D6 and CYP2C19 genes. Arrayed at 20 microns, the chip probes for more than 30 polymorphisms in the CYP2D6 locus and two in CYP2C19, and it also detects inherited deletions or duplications.
The 30-member CYP450 family affects the metabolism of a quarter of all drugs. So far, scientists have identified 49 genetic variants that cause deviations in the structure or expression of these enzymes. For CYP2D6, there are at least 70 polymorphisms now known. This gene is involved in the metabolism of over 50 drugs — from cough remedies to antihypertensive agents.
The AmpliChip builds on the research platform that Affymetrix launched as its GeneChip CYP450 assay in November 1997. As described on the Affymetrix web site, the GeneChip CYP450 microarray is a DNA probe-based assay for the simultaneous detection of 18 known genetic variants of two human cytochrome P450 genes. It defines 10 alleles of the 2D6 gene and two alleles of the 2C19 gene, which encode some of the cytochrome p450 enzymes. This assay discriminates homozygous and heterozygous genotypes, while providing sense and antisense strand analysis in a single hybridization experiment, according to Roche.
Affymetrix began designing a CYP450 array in 1993 and at one point developed one for Hewlett-Packard to sell. That deal did not reach fruition and Affy then released its own in 1997 to compete with genotyping methods such as conventional dideoxy sequencing and restriction fragment length polymorphism analysis.
To create a method for distinguishing between deletions and duplications of CYP2D6, both of which generate a unique 3.5-kilobase PCR product and cannot be co-amplified in the same reaction, Roche uses two reactions that separate the primers. The duplication-specific product, when present, is amplified together with 2.8- and 3.1-kilobase amplicons encompassing the entire CYP2D6 coding and promoter regions. The gene deletion-specific amplicon, when present, is amplified together with a 1.4-kilobase product that encompasses exons 4 and 5 of CYP2C19. The two reactions are amplified under identical cycling conditions, and the products are pooled, fragmented, and labeled, then hybridized to the array for detection by a conventional Affymetrix scanner.
“We have several pieces of key technology, and competitive access to these technologies,” Metcalfe said in February. “We have a significant first-mover advantage. There are other arrays, sequencing, and other ways of getting the same information. We will have to compete with those. We are certainly taking some risks, but they are all calculated, driven by a belief in the way that this market will develop.
“We are working like beavers to get products out the door,” he said in an earlier interview.
— KL and MOK