While Ortho and Amgen wrangle over cross-licensing agreements, market share, and the correct cost and dosage comparators for their products, other debates remain:
* whether and how indications for use of erythropoietin agents might be expanded in cancer patients.
* whether current clinical practice is appropriately evidence-based.
* how to improve upon the current response rates in cancer patients.
Some clinicians believe, as does CMS, that a head-to-head randomized trial comparing epoetin alfa and darbepoetin alfa will be the only way to definitively establish whether one is superior to the other, what the optimum dosing schedules are, and who will benefit most from therapy.
John R. Glaspy, MD, MPH, Proessor of Medicine at UCLA School of Medicine and a lead researcher of many Aranesp studies, believes the evidence already exists for choosing a dose of that agent that produces results equivalent to those observed with current Procrit use in the United States.
One thing is certain: the stakes are high, since the US cancer anemia market currently stands at approximately $2 billion, according to industry analysts.
Using a variety of dosages, both Procrit and Aranesp have demonstrated comparable activity in patients with chemotherapy-related anemia: an average rise of 2 g/dL from baseline hemoglobin levels over a period of 12 weeks, thus avoiding transfusion in approximately 60% of patients treated.
Epoetin alfa, developed and still manufactured by Amgen, was the first human recombinant erythropoietic agent to gain FDA approval. Its first approved indication in 1989, as Epogen (also known as EPO), was to treat anemia in renal dialysis patients. In 1985, Johnson & Johnson had acquired the licensing rights from Amgen to market epoetin alfa in the non-dialysis market. Under the name Procrit, Johnson & Johnson expanded the indications for the agent.
In the late 1990s, meanwhile, Amgen developed a new compound, darbepoetin alfa, adding two new glycosylation sites to epoetin's protein structure. This erythropoietic stimulation agent has a 25% higher molecular weight than Epogen/Procrit and a three-fold longer half-life, effectively increasing in vivo potency and extending the interval between treatments.
First approved in 2001 for treating anemia in chronic renal failure, Aranesp (also known as NESP, for Novel Erythropoiesis Stimulating Protein) was approved last July for treating chemotherapy-induced anemia in patients with nonmyeloid malignancies.
Amgen has moved quickly to emphasize Aranesp's less-frequent dosing as a greater convenience to patients. In fact, less-frequent dosing has been the trend for epoetin alfa as well. Procrit was first administered thrice-weekly (10,000 units at each dose) and now is given in once-weekly doses of 40,000 units.
According to a 20-patient pilot study presented at last year's ASCO Annual Meeting as a poster presentation by Jeffrey Patton, MD, et al (Abstract #1469), an initial dosage of Procrit was switched from 60,000 units a week to 120,000 units every three weeks after a hemoglobin improvement of at least 2 g/dL, and the hemoglobin response was maintained.
Not Just Molecular Structure
The differences between the two drugs are not limited to molecular structure: While Procrit is measured in units per kilogram of the patient's weight, Aranesp is measured in micrograms per kg. There is currently no formula for direct comparison of dosages measured in units to those measured by weight.
Both drugs are costly: January 2003 prices posted by Medicare put reimbursement rates at $12.69 per 1000 units of Procrit (translating to about $534.32 for the Average Wholesale Price [AWP] for a once-a-week dose of 40,000 units) and $23.69 per 5 micrograms of Aranesp (about $994.98 for the AWP for a 3 mcg/kg dose every other week).
At those dosages, monthly costs for both drugs would be roughly $2,000. (Medicare reimbursement rates for the office setting are based on 95% of the AWP, information furnished by pharmaceutical manufacturers and published in the Red Book and First DataBank reference sources.)
Dr. Glaspy points out that any cost scenarios entail “making some big assumptions about what people actually pay for a drug. Obviously, everyone pays a different price, so when you talk about the cost of a drug at a given dose, you're always talking at least a little bit inaccurately, because most of your audience will be paying a slightly different price.”
Given the current choices (and now different Medicare-reimbursement standards) for erythropoietic stimulation, how do physicians make their treatment decisions?
When asked about Procrit vs. Aranesp, Michael S. Gordon, MD, Associate Dean for Research at the University College of Medicine, Phoenix Campus, and Associate Director of the Arizona Cancer Center—Greater Phoenix Area, responded, “What physicians always want is (1) a drug that works, or is better than, the standard that they have available; and (2) a drug that has fewer side effects or impacts their patients' quality of life less than the standard. To that end, an agent that can be administered less frequently and maintain its efficacy would, for many physicians, be viewed as being strongly beneficial.”
So, he continued, both the dosing regimen and the perceived activity of the drug play significant roles in physician decision-making.
“We know that many physicians will employ, on a regular basis, relatively new therapies, based upon non-randomized trials. If the studies are done well and are very compelling, that is very reasonable. But these studies aren't necessarily the sine qua non.”
Dr. Gordon cites the years spent developing lung cancer chemotherapy combination therapies, which, independently, in large Phase II trials, seemed very active. However, when compared in a large cooperative group study, there was no difference between therapies.
What to Compare?
According to Charles Loprinzi, MD, Chairman of Medical Oncology and Professor of Oncology at Mayo Clinic Rochester and Principal Investigator of the Community Clinical Oncology Program research base of the North Central Cancer Treatment Group (NCCTG), discussions held at NCI in December revealed a variety of opinions about how best to conduct such a trial.
For instance, would investigators use a defined patient group, with a single disease and a single chemotherapy regimen or, alternatively, a more diverse population that might better mirror what will be done in clinical practice?
The question about comparator doses is especially controversial. Would investigators use the FDA-approved doses for the two agents, the marketed doses, or the doses now used in most clinical practices?
Scott McKenzie, MD, Director of Clinical Affairs for Ortho Biotech, said he believes “the ultimate question is what dose of the two drugs provides the timely, significant hemoglobin improvement that we've seen over the last 10 years with Procrit.
“Of the published data that's available for Aranesp so far, we have not really seen what dose of that drug gives the same hemoglobin improvement of Procrit,” Dr. McKenzie continued. “There have been some dose-finding studies published, but they have been small, and the exact dose giving the same response is unclear.”
Asked whether Dr. Glaspy's December ASH poster study helped to clarify the issue of cost-effectiveness, Dr. McKenzie cited several concerns: (1) the study was a model design, not an actual clinical study; (2) the dose of darbepoetin selected was 200 mcg weekly, a dose for which there are no clinical data; and (3) the dose escalation used in the Procrit arm was set at six weeks, when in actual practice the decision to escalate Procrit is usually made at four weeks.
Michael Beckerich, an Amgen spokesperson, asserts that Dr. Glaspy's study compared the most commonly used dosages of Procrit (40,000 units weekly) with the most commonly used dosages of Aranesp (200 mcg given every other week).
“When you make that comparison, Aranesp is the more cost-effective regimen,” Mr. Beckerich said. “We are disappointed that that was not done [by CMS].” Amgen, he said, “would not have stuck its neck out and been so adamant about how wrong we think the decision was if we didn't believe that we have strong evidence [supporting Aranesp's cost-effectiveness].”
Beyond Current Paradigms
According to Sean R. Tunis, MD, MSc, Acting Chief Medical Officer for CMS, the agency is “aggressively pursuing” several strategies for obtaining better cost and dosing data: looking at their own claims data; asking both companies to supply additional data not available in November; and pursuing the clinical trials approach.
Dr. Loprinzi reported that currently, it appears that the Eastern Cooperative Oncology Group is most likely to be the cooperative group to lead in the trial effort. Spokespersons from NCI were not available for comment at press time.
Dr. Glaspy said he has hopes that in the meantime, a large randomized study building on a loading-dose paradigm study presented last year at the ASCO Annual Meeting will be quickly completed.
“If we do that,” he stated, “we may have rewritten the standard before these guys have finished arguing about what the appropriate comparator dose is. I'm comfortable that the data we've published are dead-on accurate, and that a larger study will confirm our findings: that 3 micrograms/kg every other week, or 2.25 micrograms/kg a week of NESP or 40,000 to 60,000 units of Procrit a week produce similar responses.”
The real challenge, Dr. Glaspy believes, lies in pushing responses beyond the current levels.
“My personal opinion is that we use both drugs wrongly. The doses we are giving all produce slow, sluggish responses, and that's not good enough. We need to manage cancer patients differently than dialysis patients,” he declared.
With no clear consensus about one drug being superior ot the other, CMS, researchers, & drug companies all weigh in on the comparison debate
With dialysis patients, one has to “start slowly,” with dosing, because if their hemoglobin levels rise quickly, that is a problem. But with cancer patients, “you have 20 weeks to make a difference. Going up quickly is good for them, not bad.
“I think we need to invert the pyramid—give larger doses and then reduce those quickly. You don't want to produce equivalent results to 40,000 units of Procrit—you want better [results] than that.”
Dr. McKenzie of Ortho Biotech agrees on this point: “Patients treated for chemotherapy-induced anemia are only on erythropoietic agents for a short time course, as opposed to those with kidney diseases. So moving toward a timely, rapid response would be a good thing.”
Dr. Glaspy had some final thoughts about the costs of the drugs: “The naysayers think these drugs are expensive, but no one has systematically looked at what anemia itself costs. If people stay home from work, if people end up in the hospital, these are also costs and we need to measure them.”
History of Friction
The relationship between Amgen and Johnson & Johnson/OrthoBiotech regarding Procrit has been contentious for more than a decade. In 1995, Amgen filed suit against Johnson & Johnson, charging that the latter had breached its license rights by improperly marketing and selling epoetin alfa in Amgen's exclusive dialysis market.
In October 2002, an arbitrator found that J&J had made sales of Procrit into markets where Amgen had retained exclusive rights, and awarded $150 million in damages to Amgen. However, the arbitrator, former federal judge Frank McGarr, stopped short of terminating the licensing agreement.© 2003 Lippincott Williams & Wilkins, Inc.
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