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Executive Summary

Centocor's Myoscint should be approved as an imaging agent for the detection of heart tissue death resulting from myocardial infarction, FDA's Biological Response Modifiers Advisory Committee recommended at its Nov. 26 meeting. In a unanimous vote, the committee agreed that Myoscint (imciromab pentetate) is effective "as an adjunct for diagnosis of myocardial necrosis associated with ischemic heart disease." Standard diagnostic techniques include electrocardiograms and enzyme tests. Myoscint is the first monoclonal-based radiolabeled imaging agent to come before an FDA advisory committee for any indication. A PLA for Myoscint was submitted in April 1988. Myoscint is Centocor's second monoclonal antibody product to gain a unanimous approval recommendation from an FDA panel. Centoxin cleared FDA's Vaccines & Related Biologics Advisory Committee in September ("The Pink Sheet" Sept. 9, p. 14). The monoclonal imaging agent is "a clinically useful advance over other non-invasive imaging techniques," committee consultant James Weiss, MD, Johns Hopkins University, said. Myoscint could complement current diagnostic methods, including the most widely used cardiac imaging agent, DuPont-Merck's Thallium-201, suggested John McAfee, MD, George Washington University. "As I see it," McAfee said, "this agent would be most valuable in problem cases where the other diagnostics are inconclusive or negative." Myoscint is a murine monoclonal antibody Fab fragment bound to DTPA (diethylenetriaminepentaacetic acid) radiolabeled with indium-111 that binds with high specificity to myosin, the protein that is exposed in necrotic myocardial cells. Centocor estimates that there are 1.5 mil. people annually who experience a heart attack, of whom 1 mil. survive. Some 20% to 30% of the diagnoses following a myocardial infarction may be equivocal, the company said. Phase III efficacy data from 16 U.S. centers and nine European centers of 578 patients (497 evaluable) were presented by Centocor Cardiology Director Harlan Weisman, MD. Patients received a Myoscint dose consisting of 0.5 mg antimyosin antibody labeled with 2 milliCuries of indium-111 and were scanned using planar imaging. Myoscint had an 88% detection rate of necrotic tissue in patients with definitive myocardial infarction and a 95% specificity in excluding patients who did not have heart attack or unstable angina. Location of the myocardial necrosis determined by Myoscint imaging agreed 91% of the time with electrocardiogram assessments. No patients in the clinical trials experienced severe adverse reactions to Myoscint administration, and there were no cases of Human Anti-Mouse Antibody to the murine monoclonal. In addition, the extent of tissue death as detected by Myoscint was found to predict the risk of future cardiac events. Patients with extensive necrotic areas (10 or more segments as determined by single-photon emission computed tomography or SPECT) on a Myoscint scan were five times more likely to experience cardiac death or nonfatal myocardial infarctions compared to patients with nonextensive (10 segments or fewer) small areas of dead tissue. While committee members agreed that Myoscint should be indicated for determining presence and location of myocardial necrosis, they were more skeptical about how accurately the monoclonal imaging agent measures extent of the infarct area. "The agent may provide a qualitative assessment of [infarct size], but not a quantitative one," said Committee Chairman Jerome Groopman, MD, New England Deaconess Hospitals. Several committee consultants noted that quantitative assessments of extent would be possible only with three-dimensional SPECT imaging, which is available only in major medical and academic centers. Some committee consultants also raised concerns about data from a repeat- and delayed-injection trial that showed positive images indicating acute myocardial infarction many months after administration of Myoscint. Because positive readings persisted for up to 12 months, the consultants were concerned that the detection of a new myocardial infarction in the same location could be obscured. Centocor's Weisman assured the committee that the issue would be addressed in the precaution and warning sections of labeling. A lesser concern was expressed about the waiting period for Myoscint scans. They are not available until 24 hours following injection, because it takes that long for the agent to clear the body. The committee urged Centocor to conduct further studies with Myoscint to determine its usefulness in unstable angina and left ventricular hypertrophy. The panel also recommended that Myoscint be tested in conjunction with the imaging agent Thallium-201, which binds to normal tissue. "I think Thallium and Myoscint are going to prove to be complementary agents," committee consultant McAfee commented, especially in detecting "stunned" or hibernating myocardium. Centocor said that studies are currently underway with the two agents. FDA is developing a "working paper" on study endpoints for a new field of monoclonal imaging agents, FDA Lab of Cell and Molecular Biology Chief Philip Noguchi, MD, told the committee. "When a product license is submitted, the manufacturer needs to be able to define the indications for the test, interpretations of the results, and the clinical utility of the information," Noguchi said. Monoclonal imaging agents may be equivalent or complementary to other imaging techniques. However, if the "value of a test is unclear, . . . further tests of studies should be done to define the usefulness of this test with emphasis on clinical application or the information," Noguchi noted. If a monoclonal diagnostic possesses a certain toxicity, then the company "may, in fact, need to demonstrate an actual outcome on the patient," he observed. CBER's Thomas Hoffman, chairman of the Myoscint review committee within FDA, said that an "active review of manufacturing is ongoing." Centocor's facility was inspected in May, and "the report on that inspection is in the final stages of preparation." Hoffman also noted that discussions between the agency and the company are proceeding on the issues of "limits for the immunoelectrophoresis determination of the purity of the product; . . . particulates and their removal." FDA's MYOSCINT QUESTIONS TO NOV. 26 SESSION OF BIOLOGICAL RESPONSE MODIFIERS ADVISORY COMMITTEE 1. Please comment on the clinical utility of indium-111 antimyosin scans and please make a recommendation concerning licensure of indium-111 antimyosin as an adjunct for the diagnosis of myocardial necrosis associated with ischemic heart disease. 2. Please comment on the adequacy of the indium-111 antimyosin data to support a claim for determining the extent (or size) of myocardial necrosis. 3. Please comment on the type of study that should be performed to evaluate the clinical utility of dual imaging with indium-111 antimyosin and thallium 201 (or other myocardial perfusion agents) to identify MI subjects at high risk for additional ischemic cardiac events.

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