Washington Editor

WASHINGTON - A week after Ortho Biotech Products LP announced that 42 patients had died in a German study of epoetin alfa in stroke patients, the FDA Friday issued its own alert. In a so-called "Early Communication," drug regulators said that three months after the start of the study, 16 percent of the patients who had received Eprex, the epoetin alfa version sold in Europe by Johnson & Johnson subsidiary Janssen-Cilag, had died compared with 9 percent of those who did not receive the drug.

Researchers at the Max Planck Institute for Experimental Medicine in Munich, Germany, had been investigating whether Eprex could improve the neurological functioning of patients who have experienced a stroke, an indication not yet approved for epoetin alfa.

Bridgewater, N.J.-based Ortho Biotech, a J&J subsidiary that markets epoetin alfa in the U.S. as Procrit, released brief details last week about the deaths "because of the potential safety implications for patients," a spokesman said. (See BioWorld Today, Sept. 19, 2008.)

Epoetin alfa, which also is marketed in the U.S. by Thousand Oaks, Calif.-based Amgen Inc. as Epogen, belongs to a class of drugs known as erythropoiesis-stimulating agents (ESAs), which are bioengineered forms of a protein made in the kidneys that is critical to red-blood cell production. ESAs are approved in the U.S. to treat anemia in patients with kidney disease and HIV and in cancer patients with chemotherapy-induced anemia.

The FDA noted that most of the patients enrolled in the German study were not anemic and were administered high dosages of Eprex. The trial was a double-blind, placebo-controlled, multicenter investigation in 522 adult patients with an MRI-confirmed ischemic stroke in the middle cerebral artery, the FDA said. Patients were randomized to receive either placebo or Eprex at an intravenous dosage of 40,000 units daily for three days - a dosage that is considerably higher than what is recommended by the FDA for anemia.

A recombinant tissue-type plasminogen activator (rtPA), or clot buster, also was used in the German study when clinically indicated.

Roughly half of all deaths in both groups occurred within the first seven days after starting Eprex, drug regulators said. Death from intracranial hemorrhage, or bleeding in the brain, occurred in about 4 percent of patients compared with 1 percent in the placebo group, the FDA noted.

The German institute's Hannelore Ehrenreich, the study's lead investigator, argued that the increased death rate in the intent-to-treat population was restricted to patients who received systemic thrombolytic therapy with the rtPA.

In an e-mail last week to BioWorld Today, she contended that the study's results were "promising" and that use of epoetin alfa in stroke patients may be "less dangerous and more beneficial than thrombolysis." Last week, Ehrenreich had called Ortho Biotech's alert "premature," and said an article that German researchers planned to publish would clarify the study's results. She did not respond before deadline to questions about the FDA's alert.

Regulators said the finding of increased deaths in the German study "suggests the need to closely monitor patients enrolled in other ongoing trials for adverse outcomes and to evaluate whether the potential benefits for enrolled patients outweigh the risks in these trials." The agency said it is aware of other trials using epoetin alfa for potential neuroprotective effects of improving the functional outcomes of patients after stroke.

Stem Cell Therapeutics Corp. last week said U.S. and Canadian regulators asked the Calgary, Alberta-based firm to temporarily halt its Phase IIb stroke trial of its neuroregenerative therapy NTx-265 because the study uses a regimen that includes epoetin alfa.

Health Canada and the FDA last week provided few details for the basis of their request, only stating that it was based on concern over a foreign trial. But CEO Alan Moore told BioWorld Today Friday that regulators now had confirmed that the request to halt SCT's trial, which uses a dosage of 30,000 units of epoetin alfa, stemmed from the German study. "Once there is a deeper understanding of the German study, then hopefully things will get resolved," Moore said, adding that he expected there to be a "simple solution."

The FDA said Friday it will work with ESA manufacturers and other study sponsors to evaluate the clinical parameters of the risks and benefits associated with the investigational uses of ESAs as potential neuroprotective agents.

The agency said it currently is analyzing additional data from the German study and anticipates results of those analyses "within the next several weeks," and will communicate its conclusions and recommendations to the public.

Regulators noted that the agency's early communication reflects the FDA's current analysis of available data concerning epoetin alfa and that its alert "does not mean that the FDA has concluded there is a cause-and-effect relationship" between the drug and the emerging safety issue. "Nor does it mean that FDA is advising health care professionals to discontinue prescribing these products," the agency said.

In a research note, analyst Michael Aberman, of Credit Suisse Securities LLC, reiterated again this week that since ESAs are not approved for stroke or used for that indication - "in fact we believe this was a risky trial to run in the first place" - that the FDA's warning would have "no commercial impact whatsoever."

Zerhouni to Step Down as NIH Chief

National Institutes of Health Director Elias A. Zerhouni announced last week that he plans to step down at the end of October to pursue writing projects and explore other professional opportunities. Zerhouni, a physician scientist known for his discovery of various radiology devices, served as executive vice dean of the Johns Hopkins University School of Medicine before taking the top job at NIH in 2002.

He led a major restructuring project at NIH, known as the Roadmap for Medical Research, which brought together all of the agency's 27 institutes and centers to fund research initiatives that no single institute could tackle alone and led a key reform of the translational and clinical research system in the U.S. Zerhouni also launched new programs at NIH to encourage high-risk innovative research and focused on the need to support new investigators and foster their independence.

In February 2005, Zerhouni announced a set of ethics regulations to address outside consulting between some NIH employees and representatives of the pharmaceutical and biotechnology sectors.

A replacement for Zerhouni has not been named.