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By Donna Young
Washington Editor
Amgen Inc. and Ortho Biotech Products LP preempted an FDA advisory panel review of Aranesp, Epogen and Procrit by strengthening the anemia drugs' black-box warnings with new safety language about the risks of using the products in patients with breast and cervical cancers.
The FDA's Oncologic Drugs Advisory Committee (ODAC) is set to meet Thursday to discuss new safety concerns from two recent studies about the drugs, known as erythropoiesis-stimulating agents (ESAs).
The same panel Wednesday will review safety concerns of Amgen's experimental blood-clotting disorder drug Nplate (romiplostim, AMG531). Amgen is seeking approval to sell the drug to treat chronic immune thrombocytopenia purpura.
The news had little impact Monday on Thousand Oaks, Calif.-based Amgen's stock, with shares (NASDAQ:AMGN) up 50 cents, to close at $44.68.
The black-box warning, which was modified in November to alert prescribers and patients that ESAs caused tumor growth and shortened survival in patients with advanced breast, non-small-cell lung, head and neck and lymphoid cancers when dosed to target a hemoglobin of greater than 12 g/dL., was expanded again Friday to include all breast cancers, rather than just advanced, and cervical cancer. (See BioWorld Today, Nov. 9, 2007.)
The newly updated labeling includes interim results from the Preoperative Epirubicin Paclitaxel Aranesp, or PREPARE, study in neoadjuvant breast cancer and data from GOG-191, a study of advanced cervical cancer patients conducted by the Gynecologic Oncology Group with support from Bridgewater, N.J.-based Ortho Biotech, a subsidiary of Johnson & Johnson.
Amgen disclosed in December that it was in discussions with the FDA to update the labeling based on PREPARE and GOG-191.
Both studies were designed to evaluate the efficacy of maintaining hemoglobin levels greater than 12 g/dL and observed lower survival in patients being treated with ESAs. However, neither study showed a statistically significant effect on survival or tumor outcomes, the firms argued.
"These studies are consistent with results from previous studies demonstrating that ESAs should not be used to enhance the response to chemotherapy or radiotherapy, and should be administered to achieve a hemoglobin level of less than 12 g/dL," Craig Tendler, Ortho Biotech's vice president of medical affairs for oncology and nephrology, said in a statement.
The latest ESA labeling revision is the third in the past year. The black-box originally was added in March 2007 after results of two randomized controlled studies showed an increased cardiovascular risk and death in patients when targeting a hemoglobin of greater than 12 g/dL. (See BioWorld Today, March 12, 2007.)
Analyst Christopher Raymond said in a research note that he was surprised that the FDA approved the latest labeling revision just days before its ODAC panel is set to meet to discuss the safety ESAs, which will include a review of the safety of Mircera (methoxy polyethylene glycol-epoetin beta), F. Hoffmann-La Roche Ltd.'s ESA approved in November.
While the new language stops short of specifically excluding use in certain tumor types, namely breast cancer, he cautioned that further action could come out of the ODAC review.
Analyst Mark Schoenebaum of Bear Sterns said he viewed the labeling changes as minor, since cervical cancer accounts for an "extremely small part of Aranesp sales," about 1 percent, and the labeling already contains negative survival time-to-progression data from other breast cancer trials.
But, he warned, further labeling restrictions "are possible" based on the outcome of Thursday's ODAC meeting.
Analyst Michael Aberman, of Credit Suisse Securities LLC, said some might view the timing of the labeling update ahead of the ODAC panel as a potential positive sign, "specifically believing that perhaps the FDA will not ask for anything more than these modest label changes."
But, he said in a research note, "that is wishful thinking."
The briefing documents for the meeting, expected to be released Tuesday, may present a "grim safety assessment of the ESAs in light of these new trials and potentially argue the case for removal of cancer indication in its entirety."
However, Aberman said he does not believe that the ODAC panel will recommend "such a drastic move, and instead seek to restrict ESA use further, particularly in indications like breast cancer, where data have shown an increased harm."
Briefing documents released Monday by the FDA ahead of ODAC's Wednesday meeting to review Amgen's Nplate contained "no surprises," Aberman said.
As previously disclosed in medical presentations, he noted, the safety risks include reticulin deposition in the bone marrow, malignancy risk, particularly given increased blasts seen in myelodysplastic syndrome trials, thrombosis risk given increases in platelets and effect on intrinsic thrombopoietin and the potential rebound after discontinuation of the drug and immunogenicity.
While the list of safety concerns seems long, Aberman said he thinks the FDA and the ODAC panel will determine that the benefits of the drug outweigh its risks, given the high unmet need and the drug's strong efficacy results in treating patients with immune thrombocytopenia purpura, or ITP.
About 16,000 new cases of ITP are reported every year in the U.S. Available treatments include a splenectomy, or removal of the spleen, a vital organ to the immune system, or giving corticosteroids, which can cause serious adverse effects.
In two pivotal studies, Nplate was effective in about half of the patients, or 49.4 percent, compared with 2.4 percent of patients on placebo. | 
