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FDA s Drug-Label Retrofitting Effort Boosts Camptosar Dx, Perhaps Others

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Call it a benefit of second guessing.

The US Food and Drug Administration, trying to open more drugs to personalization, has been relabeling products to promote the availability of molecular diagnostic tests capable of estimating patient responses to therapy. This policy continued with last week's revision of the label for Camptosar (irinotecan), a Pfizer cancer drug, to reflect links between patient response and certain mutations in the UGT1A1 gene.

Diagnostics firms have been taking note of the agency's revamping of indications, and adjusting their development strategies accordingly. "In light of the FDA's discussions from the November 2004 [irinotecan-related] committee meeting, [we thought] there would be a relabel," Stephen Little, CEO of diagnostics firm DxS told Pharmacogenomics Reporter. Anticipating revised indications for irinotecan, 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, he said.

Camptosar's revised label recommends a "reduction in the starting dose" for patients known to be homozygous for the UGT1A1*28 allele, which has been linked to immune disorders in patients taking the drug. The new label does not include specific dosing information, or suggest a specific diagnostic test for the allele, however (See sidebar for further details on the label).

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, the agency has so far revised the labels of four drugs to spell out the utility of new diagnostic tests. 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.

Relabeling will mean clinicians will have more access to molecular information related to drug response, and may be more likely to order tests. What's more, companies with an interest in biomarkers of response can find those markers, validate them, and attempt to open the market by convincing the FDA to rewrite labels. It's not clear if any companies have done so yet.

With the recent relabeling of Camptosar, Third Wave Technologies is also hoping for a piece of the action. As soon as it is cleared by the FDA, the company is planning to release a UGT1A1 diagnostic based on its Invader platform that it has had under development since early 2002 with the Japanese pharmaceutical company Daiichi Pure Chemical. At the time, Lance Fors, then Third Wave CEO, said in a statement that the test "may be the first pharmacogenomic test for adverse drug reactions to reach the market."

"It's not coincidental" that Third Wave is coming out with a UGT1A1 diagnostic soon after the relabeling of Camptosar, said Rod Hise, a Third Wave spokesman.

John Puisis, Third Wave's current CEO, said during last week's Pacific Growth Equities Life Sciences Growth Conference in San Francisco that the company intended to file the diagnostic with the FDA this summer, with possible 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.

Who's Up for a Drug Makeover!?

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. An updated label for this drug "would have to" include information about polymorphisms of both CYP450 2C9 and VKORC1, "because either one alone doesn't make for a persuasive label change," he added [see Pharmacogenomics Reporter 6/9/2005, for recent developments in the genetics of variability in warfarin response].

Beyond warfarin, "we haven't seriously looked at any other drugs," said Lesko. But that doesn't mean the process will come to a stop. "I don't [think] people realize that when you're living through an evolution or a revolution, you don't realize how much is going on," he said. Lesko said he and colleagues are "contemplating" a November Clinical Pharmacology subcommittee meeting concerning warfarin relabeling. "There is a high probability, though not a certainty, that we're going to take this to the advisory subcommittee," he said.

The FDA makes decisions on relabeling by identifying drugs that have "disadvantages in terms of either their benefit or their risk." The agency compiles a list of drugs that might be suited to retrofitting based on the drugs' metabolic characteristics, benefit-risk ratios in the marketplace, MedWatch database information on adverse events of approved drugs, and the prevalence and the penetrance of the genotype of interest, said Lesko.

Companies themselves can also suggest candidates for relabeling consideration, said Lesko. "In this field, new studies occur every day," he added.

Highlights of Camptosar's
New Label

Changes to Camptosar's indications lack specific information about dosing, but that might change in the next cycle of revisions, said Larry Lesko. "We felt the evidence to recommend a specific dose was not strong enough to say conclusively," he said.

In the Dosage and Administration section of Camptosar's indications, the FDA added this:

A reduction in the starting dose by at least one level of CAMPTOSAR should be considered for patients known to be homozygous for the UGT1A1*28 allele (See CLINICAL PHARMACOLOGY and WARNINGS). The appropriate dose reduction in this patient population is not known.

The Clinical Pharmacology section of the label includes this metabolism and excretion information regarding UGT1A1*28:

The metabolic conversion of irinotecan to the active metabolite SN-38 is mediated by carboxylesterase enzymes and primarily occurs in the liver. SN-38 is subsequently conjugated predominantly by the enzyme UDP-glucuronosyl transferase 1A1 (UGT1A1) to form a glucuronide metabolite. UGT1A1 activity is reduced in individuals with genetic polymorphisms that lead to reduced enzyme activity such as the UGT1A1*28 polymorphism. Approximately 10% of the North American population is homozygous for the UGT1A1*28 allele. In a prospective study, in which irinotecan was administered as a single-agent on a once-every-3-week schedule, patients who were homozygous for UGT1A1*28 had a higher exposure to SN-38 than patients with the wild-type UGT1A1 allele (See WARNINGS and DOSAGE AND ADMINISTRATION).

[See the Camptosar label revision here.]

The FDA employs no hard-and-fast rule to decide which drugs get a makeover. "Evidence itself is in the eye of the beholder," said Lesko.

The November committee meeting on Camptosar featured a key prospective trial conducted at the University of Chicago indicating that patients who were homozygous for UGT1A1*28 had a higher prevalence for neutropenia, an immune system disorder, said Atiqur Rahman, a team leader in the Oncology Division of the FDA's Pharmaceutical Evaluation 1 Office of Clinical Pharmacology and Biopharmaceutics. There were also "three or four" studies from the United States and Europe featuring different designs, such as "single-agent plus multiple agents," that all pointed to a link between UGT1A1*28 homozygosity and neutropenia, Rahman said.

The data also implied a weaker link between severe diarrhea and UGT1A1*28 homozygosity, but the evidence was not strong enough to include that information in Camptosar's indication revision, said Lesko and Rahman.

Another effect of the FDA's relabeling policy is that diagnostic and pharma companies, as well as other interested parties, have some incentive to fund new research on drugs that are already on the market. "Because the FDA [is] showing willingness to do this, it gives people encouragement to go off and do the studies to find new diagnostics to improve drug performance," Little said. However, DxS does not do this kind of work, he added.

The Market

Sales of Camptosar may prove to be a useful estimation of the upper limit of the annual market for a UGT1A1 test. 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.

The market for UGT1A1 tests appears to be small, according to several sources interviewed for this article, though there are clearly expectations it will grow. "I think [the market is] very insubstantial at the moment — I think it's very early days for this test, and for the whole idea of UGT testing," said Little. "It's fair to say it's never going to be a huge market," although tests involving UGT1A1will be important for drugs other than irinotecan, he added.

Third Wave's Hise expressed similar feelings. "The market opportunity for a diagnostic like this test, and any other pharmacogenetic test, is very much an emerging one," said Hise. The company is working to position itself "to capture value when the market really does begin to accelerate," he said.

Overcoming oncologists' inertia is part of the key to wider use of the test, suggested Little. New methods will take some time to catch on, and the quicker the test utility with irinotecan grows, the quicker the market will expand, he said. "I think what they've done with the language is, they've very much left it in the hands of the physician what they might do," said Little. "It's going to create a market for the diagnostic," he said.

Whether or not a test is adopted by clinicians depends a great deal on whether it offers a favorable risk-benefit ratio, said Richard Weinshilboum, a professor of Molecular Pharmacology, Experimental Therapeutics, and Internal Medicine at the Mayo Medical School and Mayo Clinic in Rochester, Minn.

The FDA's Lesko agrees. "The question is: 'Does the physician that uses this drug have a dilemma with regard to which patient is going to [experience toxicity] or not, and does testing help the physician make those decisions more confidently?" said Lesko. "My expectation is that there will be an increase in testing, because I believe that physicians do avoid this drug for fear of its toxicity," opting instead for first- and second-line therapies, he said.

Lesko said he expects "wide availability" of the UGT1A1 test and the warfarin-related test.

— Chris Womack ([email protected])

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