BETHESDA, Md--The Food and Drug Administrations 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 patients 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
FDAs 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 Amgens 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.
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
The sponsors 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 companys 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.
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 weve seen, but that we have not seen
the whole spectrum," he said.
Updating the Criteria
In the committees 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 dont 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 panels
consumer representative, to cast the lone dissenting vote on whether
Stemgen had demonstrated a risk-to-benefit relationship suitable for approval.