Pharmaceutical drugmaker Genzyme (GENZ), based in Cambridge, Massachusetts, specializes in creating drugs for rare diseases. It's a small market, but it's highly lucrative: the Orphan Drug Act gives the company tax credits and enhanced patent protection, virtually guaranteeing that its drugs become blockbusters.
Consider Genzyme's drug Cerezyme, which treats a rare, chronic genetic disease called Gaucher, and which has an astonishing price tag that netted the company $1.24 billion last year -- more than a quarter of its total revenue. But when a recent manufacturing problem threatened a potential Cerezyme shortage, Genzyme's response seemed to confirm some critics' long-held suspicions that the company may be encouraging inflated dosage -- and therefore higher sales -- of its drug, which costs patients hundreds of thousands of dollars a year.
After announcing weeks ago that it would shut down a Boston-area plant through July, Genzyme said it would ask some consumers to conserve their stocks of the drug by temporarily skipping or reducing doses. The missed doses will not cause significant health problems, Genzyme's chief executive, Henri Termeer, said in a recent conference call: "It is not a life-and-death, immediate acute situation we're dealing with here."
What's troubling is that Genzyme has a monopoly on treatment for Gaucher, among other rare diseases. Without significant competition for drug treatment, the medical community is left to provide its own checks and balances on an intricate, delicate symbiosis that benefits patients and doctors as much as it benefits Genzyme's bottom line.
Gaucher affects fewer than 10,000 people worldwide, many of them Ashkenazi Jews and northern Swedes. Sufferers lack enough glucocerebrosidase, the enzyme that breaks down lipids which would otherwise amass in the liver, spleen, bones and bone marrow, preventing cells and organs from working properly. Symptoms include enlarged spleen and liver, anemia, low blood platelets, painful skeletal disorders and bone lesions, osteoporosis, and neurological complications.
Genzyme has monopolized Gaucher treatment: some 5,000 patients take Cerezyme -- roughly half of the people with the disease. (Rival drugmaker Actelion Pharmaceuticals markets a medicine called Zavesca for patients who can't take Cerezyme; many patients take no drug at all.)
The drug's astronomical cost is related to the common dosage of 60 units per kilogram every two weeks. Median prices are $1,225 for a 200-unit supply and $2,781 for a 400-unit supply, according to the Canadian Patented Medicine Prices Review Board. The average cost for treatment is $200,000 a year. Approximately 10 percent of Cerezyme users receive the drug free from Genzyme.
"Recent analyses of data from the Gaucher Registry established that treatment with Cerezyme leads to a dose-dependent improvement in key bone, hematologic, and visceral parameters in patients with Gaucher disease type 1," says John Yee, M.D., Genzyme's vice president of Global Medical Affairs. But not everyone agrees such high dosage is necessary. Ari Zimran, M.D., is director of the Gaucher Clinic at Shaare Zedek Medical Center in Jerusalem, which treats nearly 200 Gaucher patients and monitors more than 700. Zimran administers roughly a quarter of the average dosage given in the U.S., arguing that no clinical evidence suggests that a higher dosage is more effective in treating the symptoms or preventing bone disease.
Zimran says the higher dosage isn't necessarily harmful, but he argues that a patient should take what he believes is the minimal efficient dosage. Zimran says dosage should depend on the severity of symptoms, the patient's age -- and the cost. "Gaucher is a benign disease," he says. "Unlike cancer or bacterial infection, which must be eradicated -- often at the expense of making the patient sick in other ways, such as chemotherapy, which kills healthy cells too -- there is no need to go that length with Gaucher."
Genzyme's Yee says, "Studies show that higher doses generally lead to better clinical response and greater achievement of published therapeutic goals." But he acknowledges: "Evidence regarding dose in the peer-reviewed, published medical literature is not consistent," and adds that some studies show little difference in outcomes for Gaucher patients treated with lower Cerezyme doses.
Zimran was a part of a clinical trial in the early 1990s to examine the impact of the frequency of the the low-dose regimen. The results for the patients were the same, he says, for high and low frequency, and similar to the high-dose study in the U.S. While the trial results, published in leading medical journal The Lancet, are not often cited, Zimran says, other studies support its conclusion on a clinical basis.
The International Collaborative Gaucher Group Gaucher Registry (supported by Genzyme) reveals the symbiotic relationship among the company, health-care professionals, and Gaucher patients. The largest cooperative, observational registry on Gaucher was established in 1991 as a longitudinal database tracking outcomes of routine clinical practice. Genzyme's access to the registry's patient and treatment data gives the company highly unusual clout in following up with -- and potentially influencing -- doctors treating Gaucher patients. At times, Genzyme funded full-time data-entry personnel for Gaucher centers.
Genzyme says its registry is meant only to benefit the patients, an important study tool that benefits patients and medicine with longterm tracking and with treatment options that help optimize patient care. But it's also a brilliant marketing tool for the for-profit drugmaker -- and a controversial one. The medical community would probably not accept such a registry for treating other diseases; doctors and patients typically calibrate a dosage without the intervention of a pharmaceutical company. Indeed, the registry has been criticized for monopolizing treatment of the disease and for breaching ethical boundaries on patient information.
Of course, Genzyme has a duty to maximize shareholder value, and it does so with great science, a high-quality product, and superb marketing, as Zimran says. But Genzyme's ability to question a doctor's dosage, and its access to patients' consumption of Cerezyme, makes the registry a minefield of potential conflict.
"Data from the Gaucher Registry have contributed to more than 20 peer-reviewed publications on Gaucher disease," Yee says. Nevertheless, Zimran counters that this data isn't often used to the fullest.
Some also question the practice of treating Gaucher patients with minimal or no symptoms, Zimran says. Gaucher patients may have some natural immunity, due to elevated levels of glycollipid, a fat molecule, in their plasma, he says. "While Cerezyme itself does not cause diabetes, heart disease or cancer," he says, "mild patients who take it may lose a natural selective advantage -- thus making them more susceptible to common diseases they had better natural immunity against."
Genzyme strives to appear uninvolved in the treatment process. Officially, at least, the company recommends individualized dosing for all patients. "Numerous studies have supported the need to determine dose on an individual basis," Yee says.
Physicians, as a profession, generally claim they're immune to pharmaceutical company marketing. But evidence suggests that drug-company marketing, including promotional materials and free samples, influences doctors' attitudes and increases drug sales. (Such marketing is feeling pressure from Congress, under this year's bipartisan Physician Payment Sunshine Act.) The mission statement of NoFreeLunch, a non-profit watchdog organization founded by health-care providers, states: "We discourage the acceptance of all gifts from industry by health care providers, trainees, and students. Our goal is improved patient care." A World Health Organization database also documents the impact on health professionals of biased marketing information and gifts and other inappropriate promotions.
Zimran, it should be noted, admires Genzyme for the medical advances it's made. He gets research grants from the company, and he has contributed to Britain-based Shire and Israel-based Protalix Biotherapeutics developing enzyme therapies similar to Cerezyme. He predicts that both new enzymes will get approval from the U.S. Food and Drug Administration, which is moving to speed up access to these drugs to help offset likely Cerezyme shortages. However, he doesn't anticipate the company's severing ties with its network of physicians.
With the expected Cerezyme shortage, Genzyme's critics will watch to see whether patients' taking a "vacation" from the higher dosage notice any health effects. And if many patients don't feel any worse on a lower, cheaper dosage, then many Cerezyme consumers could decide to make it a permanent vacation.
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