FDA Panel Recommends Stemgen Approval

BETHESDA, Md--The Food and Drug Administration’s Biological Response Modifiers Advisory Committee voted to recommend approval of Stemgen (amcestim, r-metHuSCF), in combination with Neupogen (filgrastim, G-CSF), for use in mobilizing peripheral blood progenitor cells in cancer patients who undergo autologous stem-cell transplants in conjunction with high-dose chemotherapy. Both drugs are manufactured by Amgen, Inc.

In a 10-to-1 vote, the panel said the two drugs have an appropriate risk-to-benefit ratio for use in raising patient’s stem cell counts to target levels for autologous stem cell transplant. However, in making this recommendation, the committee rejected its own 1994 criteria for approval of mobilizing agents--ie, that such agents must either improve engraftment or reduce the number of aphereses needed for equivalent engraftment--criteria that, the panel said, the Stemgen-Neupogen combination did not meet.

Jay P. Siegel, MD, director of therapeutics research and review at FDA’s Center for Biologics Evaluation and Research, indicated that after further review of the data and consultation with Amgen, the FDA might bring the issue back to the committee for further clarification of its recommendation before deciding whether to approve the drug combination.

After the vote, Amgen chairman and CEO Gordon Binder said, "We are encouraged that the committee has recognized that Stemgen can give patients a chance to receive more effective stem cell transplants and, we believe, more successful cancer treatment. We are looking forward to our continued discussions with the FDA and to the approval of Stemgen in the United States."

Neupogen is Amgen’s recombinant form of granulocyte colony stimulating factor (G-CSF) that the FDA has approved for five specific uses in reducing neutropenia and mobilizing peripheral blood progenitor cells prior to transplant.

Stemgen is an early-acting blood cell growth factor and major regulator of blood stem cells. It can significantly increase the number of CD34+ cells, which, the company contends, serve as surrogate markers for stem cells.

Five Studies

Amgen presented data from five studies. In its pivotal study--an open-label, multicenter, randomized phase III trial of 203 breast cancer patients--104 women received Neupogen alone and 99 got Stemgen plus Neupogen.

The sponsor’s analysis showed 63% of the women receiving the combination achieved the target number of CD34+ cells--5 million/kg of body weight--compared with 47% of patients who got Neupogen alone. The company argued that this indicated the drug combination increased the percentage of women able to benefit from autologous stem cell transplant.

The company’s analyses also showed that women receiving Stemgen required a median of two fewer aphereses than the Neupogen-only group. FDA Reviewer Richard Steffen, MD, argued that the mean is statistically superior to the median in calculating aphereses reduction. He put the mean reduction in aphereses in the Stemgen-Neupogen group at 0.5 and questioned whether this was a clinically significant reduction.

Engraftment Results

The study showed mixed results on engraftment. While platelet engraftment was similar in the women getting the drug combination, average time to neutrophil engraftment lagged in this group by nearly one day when compared to the Neu-pogen-only patients. The company argued that this difference was not clinically significant. An FDA staff analysis contended, however, that the neutrophil findings suggest that "cells mobilized with Stemgen are less effective in supporting rapid neutrophil engraftment."

Amgen presented data that more than 500 women had received the Stemgen-Neupogen combination without a single life-threatening adverse event. People with allergies were excluded from these studies, and patients were premedicated with antihistamines and a bronchodilator to prevent or minimize reactions related to histamine release.

 Systemic Allergic-Like Reactions

The most frequent side effects, while mostly mild to moderate, stemmed from mast cell activity. The most common were injection-site reactions, but 3% to 4% of the patients experienced what Amgen called "systemic allergic-like reactions."

Amgen and several clinicians who helped conduct the trials said the allergic-like reactions occurred about 5.5 hours after Stemgen-Neupogen injection; symptoms developed slowly and were easily controlled; and none of the patients suffered shock.

The FDA, however, had serious concerns about these reactions. Dr. Siegel suggested that the studies contained too few patients to get a complete determination of the extent of the risk. "Part of our concern is not just what we’ve seen, but that we have not seen the whole spectrum," he said.

Updating the Criteria

In the committee’s discussion, Hugh Auchincloss, Jr., MD, associate professor of surgery, Harvard Medical School, voiced strong disagreement with the 1994 approval criteria for mobilizing agents, which the FDA had asked the panel to consider. He told the FDA representatives, "You are not going to get superior times to engraftment and who cares if you have two or three aphereses per patient. What I would pick as an endpoint for these studies is the marker you don’t believe in, which is the number of patients who achieve a target stem cell count."

Dr. Auchincloss said that Amgen had shown that adding Stemgen to Neupogen boosted the number of women who reached the number of stem cells targeted in the study protocol, and he felt this warranted approval of the combination.

The FDA asked the committee whether the risk-to-benefit profile of Stemgen warranted approval based on the documented adverse events and data on engraftment and number of aphereses required. The committee voted 8 to 1, with one abstention, against recommending approval of the drug combination on that basis.

Then the panel asked if it could take another vote considering other benefits not specified by the FDA. Subsequently, the committee voted 8 to 1 to recommend approval of Stemgen, based on the premise that with use of the two-drug combination, a larger percentage of women would generate enough stem cells for transplantation, compared with use of Neupogen alone.

Concerns about the allergy-like reactions caused Abbey S. Meyers of the National Organization for Rare Disorders, the panel’s consumer representative, to cast the lone dissenting vote on whether Stemgen had demonstrated a risk-to-benefit relationship suitable for approval.