May 1, 2014 (Vol. 34, No. 9)

States Sue BMS and Sanofi Over Drug’s Effects on Subpopulations

Drug developers have long trumpeted the potential of personalized medicine to revolutionize disease treatment by targeting new drugs to patients most likely to benefit. Now, the tangle of lawsuits nationwide over Plavix (clopidrogel) threatens to turn personalized medicine into a weapon against the biopharma industry.

In addition to plaintiffs from 24 states and the District of Columbia filing dozens of lawsuits linking Plavix to injuries or wrongful deaths, attorneys general in five U.S. states—California, Hawaii, Louisiana, Mississippi, and West Virginia—have sued Plavix co-developers Bristol-Myers Squibb (BMS) and Sanofi, accusing the companies of lying to authorities about the blockbuster blood thinner’s ability to treat specific subpopulations.

While many state lawsuits cite elderly users as being at-risk, Hawaii and its Attorney General David M. Louie accuse BMS and Sanofi of promoting the drugs despite research showing diminished effect on two key segments of the Aloha State’s population—East Asians (38.6% of Hawaii’s population in the 2010 U.S. Census) and Pacific Islanders (10%); another 23.6% are of mixed race.

BMS and Sanofi refuse comment on the Hawaii suit while touting Plavix’ track record: “Plavix is one of the most studied medicines with over a decade of real-world experience in patients with acute coronary syndrome, recent stroke, recent heart attack, and peripheral arterial disease.”

Plavix generated 2013 sales of $2.811 billion, most of it overseas. In the United States, where patent protection ended in 2012, sales plummeted from $2.5 billion in 2012 to $258 million last year.

Additional billions are at stake, if the percentage of Hawaii’s population that was prescribed Plavix equals the 16% of all Americans. Hawaii seeks civil penalties of up to $31,000 per patient, including $10,000 per elderly patient for “repeated and willful violation” of UDAP. Multiply that by 16% of Hawaii’s population of 1,360,301, and you get $6.8 billion—not counting punitive damages and disgorgement of profits.

The Plavix lawsuits are unlikely to slow down personalized medicine by making biopharma companies reconsider developing new drugs for subsets of the general population. “It may even have a positive impact because the pharmaceutical companies will understand that it is in their collective interests to share noncompetitive data,” Edward Abrahams, Ph.D., president of the Personalized Medicine Coalition, told GEN.

“How pharmaceutical companies share data with each other and the public on nonresponders, that is an ongoing issue. It’s an extremely competitive industry. They’re not conditioned to easily just share information,” Dr. Abrahams noted, adding that “they are moving in that direction” through research consortia and clinical collaborations.

Raju Kucherlapati, Ph.D., Paul C. Cabot professor in the Harvard Medical School Department of Genetics, notes that industry has long ago changed its drug development paradigm toward addressing targeted populations.

“Many drugs are now approved for subsets of patients who are most likely to respond to such a drug. Examples of this include herceptin in breast cancer, tarceva in lung cancer, zalkori in lung cancer, vemurafinib in melanoma and so on,” said Dr. Kucherlapati, also a professor in the Department of Medicine at Brigham and Women’s Hospital, and a member of the Presidential Commission for the Study of Bioethical Issues. “It is my understanding that most of the new cancer drugs that are in development are associated with the use of one or more biomarkers. This trend will continue.”

Alleles and Ethnicity

Hawaii argued that BMS and Sanofi “have known or should have known of additional information regarding Plavix’ diminished or complete lack of effectiveness in many patients since at least March 1998,” when the companies began marketing the drug.

Several studies have linked diminished response to Plavix in some patients with alleles of the Cytochrome P450 2C19 (CYP2C19) liver enzyme. A team led by David A. Flockhart, M.D., Ph.D., of Indiana University School of Medicine published a 2002 study in Clinical Pharmacokinetics finding that CYP2C19*2 was the most frequent CYP2C19 allele (95%), with LOF alleles seen in 40% of blacks and more than 55% of East Asians, compared with about 30% of whites.

Those percentages differ somewhat from earlier studies showing 33% of African Americans and 51% of Asians populations with at least one copy of CYP2C19*2—and are well below figures printed on Plavix’ product label, stating that “published frequencies for poor CYP2C19 metabolizer genotypes are approximately 2% for whites, 4% for blacks, and 14% for Chinese,” unaccompanied by a footnote—though the Chinese figure matches that of a 2000 study by Hong-Guang Xie, M.D., Ph.D., in the journal Life Sciences.

Should the Plavix cases advance beyond procedural arguments, BMS and Sanofi can be expected to play up differences in the percentages, to suggest lack of consensus or shortcomings in the research. Plaintiffs will likely argue the variation reflects study differences. Or they could take the tack of a 2012 meta-analysis of 16 studies including 7,035 patients carrying more than one CYP2C19 loss-of-function allele, and 13,750 patients with the wild-type genotype.

Kyoung-Im Cho, M.D., Ph.D., led a team that found higher odds of adverse clinical events in Asians with LOF variants of CYP2C19, while acknowledging differences in clinical significance according to patient ethnicity. But those differences didn’t diminish the study’s key finding that associated carrier status for LOF CYP2C19 with an increased risk of adverse clinical events in Plavix users with coronary artery disease.

A team led by Jessica L. Mega, M.D., and Marc S. Sabatine, M.D., concluded that *2 and other common polymorphisms in the CYP2C19 gene “significantly diminish both the pharmacokinetic and pharmacodynamic responses to clopidogrel by approximately one quarter to one third.” Those findings were published January 2009 in the New England Journal of Medicine.

Seven months later in Journal of the American Medical Association, a study linked CYP2C19*2 to diminished platelet response to Plavix and poorer cardiovascular outcomes: “The strength of effect of CYP2C19*2 genotype on clopidogrel response may depend on other factors such as genetic background or environmental exposures, which may differ among ethnic groups,” Alan R. Shuldiner, M.D., and colleagues concluded.

By 2009, the FDA added to Plavix’ label a caution that the drug’s effectiveness was diminished in poor metabolizers. That caution was strengthened in 2010 to a black box warning that advises doctors to “consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers.”

Hawaii and other states have cited the black box warning and CYP2C19 studies as part of their complaints, which allege that BMS and Sanofi mismarketed Plavix and covered up unfavorable safety and efficacy data, a charge the companies have denied.

Effect on Elderly

Several of the lawsuits have linked elderly patients to increased risk of problems associated from Plavix. A “master” complaint filed by dozens of New York plaintiffs faulted the companies for burying within the product label statistics on the population percentage experiencing major bleeding events after taking a Plavix-aspirin combination—2.5% in patients under age 65; 4.1% in patients ages 65–74; and 5.9% from age 75 onward. The percentages for placebo-aspirin patients were 2.1% for

Yet as the product label notes, the rate of major bleeding events “was dose-dependent on aspirin,” rising from 2.6% for patients taking less than 100 mg, to 4.9% for patients taking more than 200 mg.

Those findings come from the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial. CURE results published in the New England Journal of Medicine in 2001 indicated that larger percentages of patients older than age 65 also had increased risks of a first primary outcome, specifically death from cardiovascular causes, nonfatal myocardial infarction, or stroke—though that was true of both Plavix and placebo users. For the 6,208 patients older than 65, 15.3% of placebo users and 13.3% of Plavix users had an event, compared with 7.6% of placebo users and 5.4% of Plavix users among the 6,354 patients 65 or younger.

Courts hearing the Plavix cases will decide whether the CURE results reflect specific harm to elderly patients. Interestingly, the study published from the single Phase III trial that underpinned FDA’s 1997 approval of Plavix—Clopidogrel vs. Aspirin in Patients at Risk of Ischemic Events (CAPRIE)—did not detail how many patients were over age 65; patients were grouped by stroke, recent heart attack, or peripheral arterial disease.

How courts decide harm to subpopulations attributable to Plavix could affect how much further study of subpopulations drug developers will need for new treatments, potentially raising costs and timeframes for new medicines, two measures that personalized medicine is designed to reduce.

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