Washington Editor

While Amgen and Ortho Biotech tried to put a positive spin on Tuesday's votes by a federal advisory panel about anemia drugs, the outcome of the meeting is not as benign as it appeared for the future of the drugs, predicted Lazard Capital Markets analyst Joel Sendek.

The FDA had asked its panel of outside experts whether product labeling for erythropoiesis-stimulating agents (ESAs) should specify a target hemoglobin of approximately 11 g/dL, a level shown to be associated with better survival and fewer cardiovascular events.

Amgen, which markets darbepoetin alfa as Aranesp and epoetin alfa as Epogen, and Ortho Biotech, which markets epoetin alfa as Procrit under an agreement with Amgen, want labeling to specify a hemoglobin target range of 10 to 12 g/dL.

In a move appearing favorable for Thousand Oaks, Calif.-based Amgen and Ortho Biotech, a Bridgewater, N.J.-based subsidiary of Johnson & Johnson, the committee voted 14-5 to reject the single 11 g/dL target.

Several of the expert panelists supported the 10 to 12 g/dL range proposed by Amgen and Ortho Biotech.

However, after eight hours of clinical presentations, discussions and debate, the 19 panelists could not agree on what the hemoglobin target should be.

"We were hoping to walk away with a clear consensus," Dwaine Rieves, acting director of FDA's Division of Medical Imaging and Hematology Products, told reporters after the meeting. "Clearly, that didn't happen."

But the stock market reacted well to the vote. Shares of Amgen (NASDAQ:AMGN) closed Wednesday at $55.64, up $1.76.

In a research report, USB analyst Maged Shenouda said the panel's 14-5 vote resulted in a "major cloud of uncertainty" being lifted for the future of ESAs and Amgen.

He interpreted the committee's vote as letting dosing guidelines stand, "with an implied hemoglobin target of 10-12 g/dL."

Baird & Co. analyst Christopher Raymond said he expected the FDA to leave ESA labeling "as is, in spirit, if not in letter," with maybe minor language tweaks.

However, Sendek noted that nine of the 19 panelists supported a maximum target of 11 or 11.5 g/dL. One panelist even said that, because the FDA had stated "approximately" 11 g/dL in its question - which led to several minutes of discussion about what regulators meant by "approximately" - that he thought 11.3 g/dL would be an appropriate target hemoglobin.

The panel's overall discussion, Sendek told BioWorld Today, was more important to what the FDA ultimately will decide about labeling changes than the committee's vote.

He said he did not view the 14-5 vote as a "major victory" for Amgen. He predicted that FDA will choose to set a target hemoglobin at 11 or 11.5 g/dL.

Current labeling for ESAs advises prescribers to use the lowest dosage of ESAs that will gradually increase the hemoglobin concentration to the lowest level sufficient to avoid the need for red-blood-cell transfusion.

Two randomized controlled clinical trials, known as the Normal Hematocrit Cardiac Trial and Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR), showed increased cardiovascular risks for patients randomized to hemoglobin targets exceeding 13 g/dL compared with patients at lower targets.

Results from those studies prompted the FDA in March to call for a black-box warning on ESA labeling alerting that the products increased the risk of serious cardiovascular events and death when targeting a hemoglobin of greater than 12 g/dL.

While neither the Normal Hematocrit nor the CHOIR study was designed to confirm the safety and efficacy of 11 g/dL as the optimal hemoglobin target, FDA officials said that approximately 11 g/dL is a reasonable clinical management target based on the results of the two studies.

Malazia Y. Scott, the patient representative on the FDA panel and a kidney dialysis patient herself, argued that "11 is not a magic number," noting that she functions better at a target hemoglobin of 12 g/dL.

The National Kidney Foundation has suggested a hemoglobin target range of 11 to 12 g/dL.

Panelist Lawrence G. Hunsicker of the University of Iowa Hospitals expressed frustration that there are no available data showing at what hemoglobin level patients cease to need a blood transfusion. He also expressed anger that FDA would ask the panel to vote on a specific target without that data.

Speaking on behalf of Amgen, Marc Pfeffer, professor of medicine at Harvard Medical School, noted that a large ongoing randomized, placebo-controlled, double-blind trial of 4,000 participants will help better determine the clinical outcomes of ESA use.

The study, known as the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT), is assessing whether treatment of anemia with darbepoetin alfa compared with no treatment decreases mortality and cardiovascular morbidity in anemic kidney patients not on dialysis with Type II diabetes.

"If the emperor has no clothes, we will know that," Pfeffer said.

But the FDA's Rieves noted that it may be at least two years before data from TREAT is available.

The committee also struggled with the FDA's request to define how to identify patients with insufficient responses to ESAs, or so-called hypo-responders.

Amgen and Ortho Biotech proposed defining hypo-responders as those patients "unable to achieve desired hemoglobin target within range of 10-12 g/dL despite use of appropriate dose titrations per label over a 12-week period."

But most panelists agreed that better data from randomized, controlled clinical trials were needed before a valid definition of hypo-responders could be characterized.

Because hypo-responders generally are given larger dosages of ESAs to achieve an appropriate hemoglobin level to avoid transfusions, they are at an increased risk for cardiovascular events.

Sendek said he thinks FDA will "carve out" warnings specific to hypo-responder in ESA labeling, which ultimately could affect increases in use of the products.

If the FDA continues to focus on hypo-responders, Raymond said, the issue could create another "overhang" for the ESA market.

In a report last week, Raymond noted that one industry contact suggested that 5 percent to 10 percent of dialysis patients fall into the hypo-responder category, yet account for 30 percent of ESA use.

"So any restriction for these patients could be commercially meaningful," he said.

FDA panelist Frederick J. Kaskel, a physician at Children's Hospital at Montefiore in New York, argued that setting a single target hemoglobin could add to the problem of physicians frequently changing dosages of ESAs for patients, or cycling, which could increase a patient's risk of cardiovascular events.

He suggested that the FDA work with Amgen and Ortho Biotech to develop dosing algorithms for ESAs.

John Jenkins, director of FDA's Office of New Drugs, told reporters that the FDA hopes to make a decision on any labeling changes for ESAs within "weeks," and not months.

Jenkins said that the agency's goal is to incorporate suggestions made by Tuesday's panel and the FDA's Oncologic Drugs Advisory Committee, which met in May, into one labeling change. However, he said, it may be necessary to make the labeling changes separately.

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