Stemgen Effective For PBPC Mobilization, Not For Aphereses Reduction

Amgen's Stemgen data support an indication for the stimulation of peripheral blood progenitor cells for autologous stem cell transplants in cancer patients, but not for reduction in time to neutrophil engraftment or reduction in leukaphereses, FDA's Biological Response Modifiers Advisory Committee agreed July 30.

The committee voted 10-1 that Stemgen (ancestim) has an "appropriate risk benefit ratio for approval to increase the proportion of patients that are able to obtain a target CD34+ count that permits transplantation."

The recommendation, however, falls short of the full indication being sought by Amgen for the stem cell growth factor and raises the question of whether Stemgen may be approved at all based on what FDA considers a surrogate endpoint.

Amgen is seeking an indication for use of Stemgen in combination with granulocyte colony stimulating factor Neupogen (filgrastim) to increase the number of peripheral blood progenitor cells capable of engraftment, to increase the proportion of patients reaching a PBPC target, and to reduce the number of leukaphereses required to collect the PBPC target for stem cell transplants in cancer patients.

FDA Office of Therapeutic Research & Review Director Jay Siegel, MD, pointed out that increased CD34 "is not an endpoint...identified in any of the studies" and is only a "surrogate for benefit, not a real measure of benefit." FDA would like input on "an indication [for which] clinical significance is known," Siegel said. "We can't simply say it does this thing....We need to draw some sort of presumption that there is a benefit from it."

The Stemgen BLA, submitted April 14, 1997, contains studies comparing Stemgen plus Neupogen to Neupogen alone in breast cancer, lymphoma and myeloma patients. In the one Phase III study with long-term follow-up, 204 breast cancer patients were randomized to either 20 mcg/kg per day subcutaneous SCF plus 10 mcg/kg per day G-CSF or G-CSF alone.

The percent of patients who reached the target number of cells (5 x 106 CD34+ cells/kg) by the fifth apheresis day was 60% for the SCF/G-CSF group compared to 46% for G-CSF alone. The difference was not statistically significant. The mean number of aphereses required was reduced from 3.7 for SCF/G-CSF to 3.3 for G-CSF.

The median time to neutrophil engraftment (average neutrophil count (500/microliter) was 10 days for the SCF/G-CSF arm and nine days for G-CSF alone, a statistically significantly longer time for the combination arm.

In questions to the committee, FDA raised the point that "if a new drug mobilized CD34+ cells which were less effective or ineffective at promoting engraftment, the higher cell count would nonetheless lead to fewer leukaphereses but drug benefit would be uncertain."

Seigal noted that the neutrophil engraftment delay, demonstrated across the Stemgen trials, "raises a question about the quality of the cells mobilized with stem cell factor." Committee Chair Julie Vose, MD, University of Nebraska, disagreed, calling the neutrophil engraftment delay, though statistically significant, not "clinically significant."

The committee voted 9-1 (with one abstention) that Stemgen's potential to reduce the average number of leukaphereses does not outweigh the drug's associated risk of anaphylaxis and related toxicities.

"The issue of whether it takes .4 or .6 or 1 fewer aphereses is in some ways irrelevant. That's an issue of patient convenience and some modest issue of cost," committee member Virginia Broudy, MD, University of Washington, said, suggesting that Amgen "drop the claim" for a decreased number of aphereses.

Clinical trials demonstrated a 5% incidence of anaphylaxis-syndrome, dropping to 3% for patients receiving prophylactic premedication with H1 and H2 blockers and an inhaled beta-agonist bronchodilator.

Amgen maintained that the anaphalactoid symptoms were treatable and "resolved within 24 hours." FDA expressed concern that the syndrome may be more severe in the general population. "Part of our concern is not just what we've seen, but whether we have yet to see the full spectrum of the severity," Siegel declared.

Adverse reactions associated with the combination Stemgen/Neupogen regimen included injection-site reactions such as erythema, pruritus and urticaria (84%), and dermatologic symptoms distant from the injection site such as pruritus, rash and urticaria (18%). Also reported were mild-to-moderate respiratory symptoms including pharyngitis, dyspnea and cough (25%) and musculoskeletal symptoms (48%).