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Executive Summary

Cytogen's OncoScint was unanimously recommended for approval as an adjunct in determining the location and extent of ovarian and colorectal carcinoma in "selected subsets of patients" by FDA's Biological Response Modifiers Advisory Committee on Jan. 16. In a summary of the committee's recommendations, Chairman Jerome Groopman, MD, New England Deaconess Hospital, stated that OncoScint would be most useful in "patients with potentially recurrent ovarian disease for whom other usual diagnostic modalities are equivocal or negative and in patients with colorectal carcinoma who appear to have a negative workup and particularly patients with a rising CEA [carcinoembryonic antigen]." Although the committee recommendation appears to restrict use of OncoScint to several subgroups of patients with ovarian and colorectal cancer, the company indicated that it is "totally comfortable" with the committee's conclusions. Cytogen acknowledged that OncoScint would not be used as a first-line screening agent and would probably be used in conjunction with computerized tomography (CT) scans for recurrent disease. OncoScint, tradenamed OncoScint OV103 and OncoScint CR103 for the different indications, is on track to be the first product marketed in the U.S. by Cytogen. FDA medical reviewer Gerald Marti noted that "arrangements for prelicensing site inspections are being made" by the agency. Cytogen markets OncoScint in seven European countries. OncoScint is composed of a monoclonal antibody (B72.3), developed by National Cancer Institute researcher Jeffrey Schlom, that targets tumor cells. Cytogen used its proprietary linking technology (GYK-DTPA) to chelate Indium-111 to the monoclonal antibody. The company is in Phase I clinicals using the same monoclonal antibody in therapeutic products for ovarian and gastrointestinal cancers. Schlom is currently working on a second generation monoclonal antibody targeted at tumors. Data presented by Cytogen Clinical Investigations Director Robert Maguire, MD, showed that OncoScint had a 69% sensitivity and 76% specificity in determining the location and extent of disease in 174 patients with suspected colorectal carcinomas. When compared to computerized tomography, OncoScint was equally effective in detecting disease. Results from a questionnaire given to physicians monitoring the study showed that the clinicians thought OncoScint was of clear clinical benefit to 25% of the patients. Maguire presented data on 103 patients being screened for ovarian carcinoma. Overall sensitivity of the test in these patients was 68% and specificity was 55%. OncoScint was found to be more sensitive than CT scan in patients with recurrent disease (69% versus 44%), and more likely to detect carcinomatosis (widespread disease) than CT (71% versus 45%). OncoScint received a beneficial rating for 27% of the patients from the monitoring physicians. In both studies, OncoScint was given as a single 1 mg infusion with 5 milliCuries of Indium-111 and imaged by gamma camera 48 to 72 hours post-infusion, with follow-up imaging at seven days. OncoScint is the second MAb-imaging agent to reach an FDA advisory review since the agency outlined its views on such products at a Biological Response Modifiers Advisory Committee meeting in November. At that meeting, FDA presented a working document entitled "Clinical Endpoints for Monoclonal Antibody Imaging Agents." The committee also reviewed Centocor's Myoscint monoclonal cardiac imaging agent, which received an approval recommendation ("The Pink Sheet" Dec. 2, p. 3). As a result of the discussion at the November meeting, Cytogen Director of Regulatory Science Melvin Fisher noted that the company had tailored its presentation of OncoScint data to address FDA's interest in seeing evidence of the clinical utility of the imaging agent. Cytogen consultant Earl Surwit, MD, University of Arizona, told the committee that OncoScint could reduce the number of extensive surgical procedures used to detect disease in patients with recurrent ovarian cancer. Following OncoScint imaging, ovarian disease was confirmed in those patients by laparoscopy rather than the more invasive laparotomy. Laparoscopies can be performed during a short hospital stay or on an outpatient basis, whereas laparotomies require a longer hospital stay and cost up to $10,000. "In the recurrent ovarian population, I think this is a useful diagnostic imaging complement...and might potentially spare patients from more invasive procedures," Janice Gabrilove, MD, Memorial Sloan-Kettering Cancer Center, said. She recommended that "additional work needs to be done regarding false positive [results]," which occurred in a number of the ovarian cancer patients. She added that "it should be very clear [in the package insert] that [OncoScint] is useful in a restricted setting and not something that could be depended upon in the day-to-day management of patients receiving ongoing treatment for advanced ovarian cancer." Committee member Fred Appelbaum questioned the 25%-27% benefit of OncoScint as assessed by the studies' monitoring physicians. "I think there is a strong suggestion that this product would be of some utility [but] I think 25% overstates the issue," Appelbaum said. "There are some patients for which this is the only means for detecting or locating residual pockets of tumor. In those 10%- 15% of patients, this is of some clinical utility," he noted. The advisory committee's major concern about the safety of OncoScint regarded a human anti-mouse antibody response in 40% of the patients in clinical studies. Although the number of patients positive for HAMA dropped to 20% a year after the OncoScint infusion, the committee was concerned with how HAMA might affect the clearance of OncoScint and other cancer antigen assays. The committee was particularly concerned with how the HAMA response might interfere with the efficacy of multiple injections of the imaging agent. In a multicenter repeat administration study of 69 patients being conducted by Cytogen, HAMA positive patients were found to have a significantly increased plasma clearance of OncoScint. Cytogen's Maguire said that the effect of the increased OncoScint clearance is not yet clear. The presence of HAMA can also interfere with site immunoassays such as CEA and CA-125, Maguire said. However, Cytogen has found a method to remove HAMA from samples so that it will not affect the assays, he said. The committee recommended that Cytogen submit results from the multiple injection study as soon as possible. "A great deal of attention has to be paid to the issue of HAMA," Committee Chairman Groopman remarked. "Patients who have been previously treated with murine monoclonal antibodies and test positive for HAMA are not likely to benefit from diagnostic evaluation with OncoScint....and therapy with OncoScint could prejudice a patient from receiving future therapy with other murine monoclonal products," Groopman maintained. "A patient who has been treated with OncoScint in whom a repeat scan is being considered should be followed for a sufficiently long period of time until the HAMA becomes negative," Groopman suggested. The OncoScint kit will cost $350, Cytogen said. The entire procedure could cost anywhere from $600-$1,000, which is comparable to a CT scan, the company noted. OncoScint will be comarketed by Knoll, which will add about 50 sales reps to Cytogen's 25 rep marketing force. There are close to 180,000 new cases of ovarian and colorectal cancer annually. Cytogen is planning a physician education program on the proper use and interpretation of OncoScint imaging.

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