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Amgen Inc.'s latest bad news regarding Aranesp comes in the form of Phase III data from breast-cancer patients on chemotherapy with hemoglobin levels above the range already specified on the Aranesp label, and interim results from the ongoing study seemed to affirm safety concerns that surfaced earlier.

Wall Street responded accordingly, nipping but not clobbering the company's shares (NASDAQ:AMGN), which closed Monday at $55.09, down 16 cents. The stock traded as low as $53.67 in reaction to the news, disclosed after the market closed Friday.

"I don't know if there is an appreciation as to how much Aranesp is used in breast cancer," said Christopher Raymond, with Robert Baird & Co. in Chicago. "It's a pretty big driver."

The most recent survey by Baird found that ESA use in the indication has been dropping, but doctors report that about half - 49 percent of Stage II/III and 55 percent of Stage IV breast cancer patients - still get an ESA, and the latest news of interim data from the PREPARE study, though not shattering for Amgen, is incrementally unfavorable.

"Is it going to make it go away completely tomorrow? No," Raymond said. "But does it make a physician think twice? Absolutely."

Examining the worst-case scenario, Raymond estimated a complete loss of the breast-cancer market would mean 20 percent to 30 percent of Aranesp use in treating chemo-induced amenorrhea (stoppage of menstrual bleeding) could go away. By 2009, the loss would take away about $260 million in revenue from Baird's worldwide forecast of $3.25 billion and, all other things being equal, about 17 cents from the $4.87 in earnings per share.

Regulators might want results from PREPARE included in labels, just as similar results with a trial called BEST were included, Raymond told BioWorld Today, and the data could influence whether Amgen can get reimbursement guidelines changed for ESAs.

Amgen still is trying to overturn a decision made in July by the Centers for Medicare & Medicare Services to restrict payments for ESAs in patients with cancer to those whose hemoglobin levels decrease to less than 10 g/dL.

"The bull case [for Amgen] seems to be increasingly dependent on CMS revisiting that decision," Raymond said, adding that he finds little interest among politicians to push for ESA payback parameters more favorable to the company.

PREPARE includes 733 patients, and is designed to try sequential preoperative therapy with a chemo regimen of epirubicin, paclitaxel and CMF (cyclophosphamide, methotrexate, 5-fluorouracil), compared to epirubicin and cyclophosphamide, followed by paclitaxel. Patients in both arms are randomized to get Aranesp (darbepoetin alfa) or placebo, as a way of showing whether the erythropoietin-stimulating agent (ESA) helps the chemo work better.

So far, it doesn't. Interim results showed no significant difference in tumor response during treatment - and as of the end of October, patients getting Aranesp had a higher mortality rate (50 out of 356, or 14 percent), compared to those given placebo (37 out of 377, or 10 percent). The BEST trial came up with a higher four-month mortality rate in the ESA arm (8.7 percent) vs. control (3.4 percent) in metastatic breast cancer patients.

Started in 2002, PREPARE was developed, conducted and analyzed by the independent German Gynecological Oncology Study Group and the German Breast Group. A formal statistical analysis of survival is expected in early 2009, and Amgen cautioned against drawing firm conclusions until long-term follow-up of the final study is done.

But that didn't stop analysts. Joel Sendek at Lazard Capital Markets wrote in a research report that his firm's physician consultant found the results "very worrisome in a patient population with a potentially curable cancer." Bret Holley, though, at CIBC World Markets, expects sales of Aranesp and Epogen to stabilize after the end of this year, and pointed to Amgen's "solid pipeline" in calling the firm undervalued. Amgen's lead candidate is denosumab for osteoporosis and cancer treatment-induced bone loss.

Last month, the FDA strengthened black-box warnings added last March to ESAs, widely used for anemia. ESAs are marketed in the U.S. by Thousand Oaks, Calif.-based Amgen as Epogen (epoetin alfa) and Aranesp, and by Bridgewater, N.J.-based Ortho Biotech Products LP as Procrit (epoetin alfa). (See BioWorld Today, Nov. 9, 2007.)

The drugs all are approved to treat anemia in patients with chronic kidney disease and anemia caused by chemo in certain patients with cancer. Epogen and Procrit also are cleared for anemia in patients slated for major surgery to reduce blood transfusions during or shortly after their procedures, as well as for anemia caused by zidovudine therapy in HIV patients.

ESA labels warn that the drugs can boost the risk of death and cardiovascular events, cut the time to tumor progression in patients with advanced head and neck cancer who got radiation therapy and shortened overall survival while increasing deaths because of disease progression at four months in metastatic breast cancer patients on chemo.

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