Third Wave claimed to have developed "the first pharmacogenetic test to be approved by the [US Food and Drug Administration] for use as a companion diagnostic to a specific drug therapy," with its Invader UGT1A1 molecular assay, in a statement issued this week.
"We believe that this is the first molecular diagnostic test that detects specific genetic variations that impact a patient's response to a particular drug," said Rod Hise, a Third Wave spokesperson. Whether that claim is valid — Herceptin and its associated antibody and FISH tests come to mind — is a semantic question. The UGT1A1 test aims to identify patients at risk for adverse responses to Pfizer's Camptosar, known by the non-commercial name irinotecan.
The real story is that the FDA is encouraging companies to create such diagnostics, partly by changing Camptosar's label to link patient genotype with drug dose. "What's interesting about this particular assay is that the drug label's been changed to reflect the diagnostic, and not the other way around," said Stephen Little, CEO of United Kingdom-based molecular diagnostics firm DxS. "So it's a good example of the diagnostic industry to actually influence the way that a drug is sold."
Now that the test has been cleared, clinicians can order it to determine whether a patient carries the UGT1A1*28 variation before prescribing. That genetic variation conferred a five-fold greater risk of Camptosar-triggered adverse events in some of the 66 patients involved in the agency's trial of the diagnostic, according to an FDA statement. Adverse events can include neutropenia, an immune-system disorder, according to the drug's label. Other events include severe diarrhea.
The FDA became aware of research Third Wave was conducting in mutations in the gene, and "contacted us about making a product in the United States," said Hise. "We said we'd be happy to work with them, and did," he said.
The timing of Third Wave's FDA submission and the FDA's June relabeling of Camptosar could not have been more striking — Third Wave had been working with Japan-based Daiichi Pure Chemical since early 2002 without releasing a product.
"It's not coincidental" that Third Wave is coming out with a UGT1A1 diagnostic soon after the relabeling of Camptosar, Hise told Pharmacogenomics Reporter in June.
The Camptosar relabeling itself was part of an FDA effort to encourage companies to develop and submit their own UGT1A1 assays. The newer label recommends a lower starting dose of the drug in patients homozygous for the UGT1A1*28 allele.
At least one other diagnostics firm took note. "In light of the FDA's discussions from the November 2004 [Camptosar-related] committee meeting, [we thought] there would be a relabel," DxS' Little told Pharmacogenomics Reporter in June. Anticipating revised indications for Camptosar, the UK-based company developed its UGT1A1*28 diagnostic service "about six months ago," and announced its availability in April. The company is "in the process" of establishing CE Mark self-certification for the PCR-based molecular diagnostic, and is working its way through "IP issues" for marketing the product in the United States, he said.
The FDA has so far revised the labels of four drugs to spell out the utility of new diagnostic tests, in a practice dubbed "retrofitting" by Larry Lesko, director of the FDA Office of Clinical Pharmacology and Biopharmaceuticals at the FDA's Center for Drug Evaluation and Research. Before Camptosar, the agency relabeled 6-thioguanine (Thioguanine, GlaxoSmithKline), 6-mercaptopurine (Purinethol, Teva), and azathioprine (Imuran, Prometheus Labs) between July and November of last year to reflect these drugs' activities in patients having certain alleles of the gene TPMT.
Warfarin is a likely next candidate for labeling revision. "The next one we're looking at, as the evidence mounts very rapidly, is the anticoagulant Coumadin (Bristol-Myers Squibb) or warfarin," Lesko told Pharmacogenomics Reporter in June.
The Invader UGT1A1 diagnostic's clearance vindicates a prediction made by John Puisis, Third Wave's current CEO, during the June Pacific Growth Equities Life Sciences Growth Conference in San Francisco. At the time, he said the test could be awarded clearance before the end of the year.
Besides diagnostics from DxS and Third Wave, as well as a test available at the University of Chicago Medical School, no sources interviewed for this article could name other providers of a UGT1A1 test.
As with many pharmacogenomics products, the market for UGT1A1 tests is difficult to estimate. "I don't think it's that big," said Little this week. "It's certainly less than $10 million a year." The people using the test will be a subset of those with the disease, and those who are tested need only be tested once, said Little. "Often with pharmacogenetics, the markets themselves may not be huge, but obviously the impact could be significant."
Camptosar brought Pfizer first-quarter 2004 revenue of $212 million, up 132 percent compared to the same period in 2004, according to a company statement. Sales in the United States account for about half of the drug's worldwide sales, the company said in a statement.
— Chris Womack ([email protected])