Washington Editor

SILVER SPRING, Md. - Members of the FDA's Oncologic Drug Advisory Committee on Thursday agreed to some degree with recent label changes to Amgen Inc.'s blockbuster EPO products, but also suggested a few further steps, proposing more studies and stricter guidelines on prescribing the red blood cell boosters.

Clearly, the latter recommendation stands to roil sales, as the FDA typically follows the advice of its panels, and a more conservative label could dampen further already slowing EPO use. Amgen's stock (NASDAQ:AMGN) dropped 9.1 percent Thursday, or $5.77, to $57.33, not far off the two-year low the shares hit last month.

Richard Pazdur, the director of the FDA's Office of Oncology Drug Products, declined to specify when another label change could come for the products in question, known as erythropoiesis-stimulating agents (ESAs).

Committee members voted 15-2 that the products' continued marketing warrants some further label changes, and 17-0 that additional safety studies are needed. Among suggested boundaries, they voted 12-5 that labeling should restrict ESA use in certain cancers such as breast, non-small-cell lung and head and neck, given existing data. In addition, they voted 15-2 that labeling should set a hemoglobin level to begin ESA use in asymptomatic patients, and 16-1 for discontinuing ESA use after chemotherapy.

"There certainly are some more restrictions on the horizon," said Dhesh Govender, an analyst with Monness, Crespi, Hardt & Co. Inc. in New York. Expecting patients to end ESA treatment "much quicker," he boldly forecasted a sales erosion of up to 25 percent for Aranesp (darbepoetin alfa), which would amount to about $1 billion. Govender, whose firm does not make a market in Amgen's stock, predicted the negative outcome earlier this week.

In addition to Aranesp, the products also include Epogen (epoetin alfa) and Johnson & Johnson's Procrit (epoetin alfa). Approved as supportive-care drugs to treat anemia in patients on chemotherapy and those with chronic kidney failure, a number studies have since shed light on safety issues showing that higher-than-recommended doses can lead to multiple complications.

However, the committee members voted 11-6 against targeting a hemoglobin level lower than 12 g/dL, which seemingly contrasts with their other suggestions.

That left Chris Raymond, an analyst with Robert W. Baird & Co. in Chicago, feeling more sanguine about drastic sales slumps. As a result, he's modeling a $100 million slippage in Aranesp sales this year compared to last year's $4.1 billion in sales, and down $300 million more next year, before beginning to climb again.

"I found it odd that the panel would completely brush by that upper-limit issue [beyond 12 g/dL], which is where all the controversy and safety issues exist," Raymond told BioWorld Today, though he later added that the committee consensus would "give the FDA a little more confidence if they really want to get very restrictive."

Still, he said the agency would presumably need more concrete data than are currently available to make sweeping changes.

Pazdur promised "internal discussions" to come at the FDA.

The central question before the committee related to whether problems associated with excessive ESA administrations signal the potential for worrisome outcomes when the products are dosed within the limits of their label. Both FDA staffers and Amgen officials presented a range of evidence to back up their respective cases.

FDA medical officer Vinni Juneja outlined data from six studies that point to decreased survival, increased tumor promotion and higher numbers of thrombovascular events in patients with several types of cancers. In those trials, ESAs were administered to target hemoglobin levels that exceed 13 g/dL, a higher threshold than that recommended in the products' labels, or received by patients not getting chemotherapy.

"ESAs do not increase survival and may promote tumor growth," Juneja said, so in light of those risks, coupled with a better reputation for blood transfusions than when ESAs first received approval, he urged a "reconsideration" of their risk-to-benefit profile in cancer patients.

Juneja also warned against using meta-analyses to elucidate safety signals.

On the other hand, Amgen's executive vice president of research and development, Roger Perlmutter, noted that despite a longstanding acknowledgement of thrombovascular events due to ESAs, he said their benefits in this setting "are substantial and unambiguous."

In particular, he and other supporters noted the 50 percent reduction in blood transfusions in patients treated with ESAs, beneficial to their overall health outcomes and quality of life, as well as the nation's always-short blood supply. Further, Perlmutter said the erythropoietin receptor gene is not an oncogene and therefore not driving tumor growth. Other data point to a neutral survival effect for ESAs.

Urging panelists to review the totality of evidence from many more studies than the FDA cited, he stressed that ESAs have "no demonstrable effect" on overall survival or tumor progression when used in accordance with their label.

Additional committee ideas included corrective advertisements that amend prior promotions that suggest the products' beneficial impact on fatigue, an outcome that's not on their label, as well as placebo-controlled safety studies. A skeptical Govender told BioWorld Today that it would be "almost impossible" to prod Amgen into completing such testing, though Raymond noted inherent recruitment difficulties for those types of trials, given the longstanding use of ESAs.

His firm makes a market in Amgen's stock.

The products' recently revised labeling includes more conservative prescribing instructions to advise doctors to monitor hemoglobin and adjust doses to maintain the lowest level necessary to avoid blood transfusions. The change is underscored by a black box warning that ESAs increase the risk of death and cardiovascular problems when dosed to target hemoglobin levels above 12 g/dL.

Perlmutter said Amgen does not advocate exceeding such a threshold.

Aranesp, Epogen and Procrit are manufactured by the Thousand Oaks, Calif.-based company, though Procrit is sold by Johnson & Johnson, of New Brunswick, N.J. The products' first-quarter sales dipped in light of the surge in safety concerns of late, with lower reimbursement limits reflecting the recent label changes but also leading to patient access problems.

In that background, many members of Congress are exploring whether to decrease Medicare reimbursement as well.

Additional pressure on the products could come from a potential competitor, CERA (continuous erythropoietin receptor activator), which Basel, Switzerland-based F. Hoffmann-La Roche Ltd. is positioning to enter the market.

An FDA advisory committee will meet this fall to discuss the safety of ESA dosing in anemic renal failure patients, Pazdur said.