SMITHLKINE BEECHAM EMINASE IS SAFE AND EFFECTIVE, FDA AND ADVISORY COMMITTEE AGREE; GENENTECH SCIENTIST RAISES PLASMINOGEN ANTIBODY ISSUE

"FDA has no outstanding questions about the safety and efficacy" of Eminase (anistreplase), the agency's Division of Blood & Blood Products Director Joel Solomon, MD, reported at an Oct. 31 advisory committee meeting. The regulatory review of the manufacturing process for the SmithKline Beecham thrombolytic (also known as APSAC) is also at an advanced stage. An agency background paper prepared for the Oct. 31 meeting of the Blood Products Advisory Committee notes that "the manufacturing of anistreplase has already been addressed in the licensing review process." FDA did not ask the advisory committee for further comments on manufacturing information. Based on the evidence of a favorable FDA review at the Oct. 31 meeting and the positive reception for the application by the committee members, Eminase appears on track for a 1989 approval. The advisory committee was not asked by FDA to vote on approval of the drug. However, it unanimously agreed that Eminase is safe and effective for the treatment of acute myocardial infarction. Specifically, the committee concurred with data that establish that the agent reduces mortality in comparison to placebo, and improves left ventricular function and infarct size in comparison to conventional heparin therapy. FDA's Cardio-Renal Drugs Advisory Committee, in reviewing data for streptokinase and Genentech's TPA in 1987, recommended that approval of thrombolytic agents be based on a demonstration of improvement in either myocardial function or mortality. Eminase mortality data was derived from the APSAC intervention mortality study (AIMS), which was discontinued when interim results found that the agent resulted in a 47% reduction in 30-day mortality compared to placebo. Data on infarct size and left ventricular function was obtained from the French APSIM study, which found that Eminase resulted in a 31% reduction in infarct size over heparin and a 6% improvement in left ventricular function (left ventricular ejection fraction was 0.53 in the Eminase group and 0.47 in the heparin group). Safety information on the agent includes data on 5,275 patients. The adverse reaction of greatest concern is intracerebral bleeding, which occurred in 0.57% of patients. FDA reviewer Deborah Beebee, PhD, told the committee: "So far, from all the information we have, the incidence of intracerebral bleeding [with Eminase] is well within the range of other thrombolytic agents." Intracerebral bleeding rates for both streptokinase and TPA are in the 0.4% range. Discussing other safety issues, Beebee reported that hypotension rates were similar to streptokinase and that bolus dosing "does not increase the incidence of hypotension." Beebee noted that FDA reviewed the viral safety of Eminase "in great detail" and is "fairly confident in the safety of this product." The vapor heat purification process for the live plasminogen component of the product was shown to remove a cumulative 21 logs of HIV and studies demonstrated no cases of transmission of non-A, non-B hepatitis (hepatitis C). The advisory committee discussion of Eminase proceeded quickly. The committee asked few questions before voting on safety and efficacy of the product. The entire session, including presentations by FDAers and the company, was less than three hours long. At the beginning of the meeting, Solomon explained that Eminase was being brought to the committee despite FDA's positive assessment of the safety and efficacy. "Because it is a new product, and because other related products were reviewed by [an advisory] committee," the FDAer said, "we believe it is appropriate to seek your concurrence with our satisfaction with the safety and efficacy data submitted by the manufacturer." The decision to bring the drug before an advisory committee may also have been influenced by TPA manufacturer Genentech, which lobbied for a committee review. On behalf of the company, Sen. Wilson (R-Calif.) wrote FDA Commissioner Young in late July requesting an advisory committee review of the product. "It is my understanding that the rigorous review process required of Genentech is not being applied by the FDA to a pending application by Beecham Research for Eminase, a potentially competing thrombolytic agent developed outside the United States by Beecham Labs, a foreign pharmaceutical firm," Wilson wrote. "I am very concerned about this seemingly inconsistent treatment of foreign pharmaceutical companies . . . and the apparent inconsistency the FDA seems to be showing in its review of new thrombolytic therapies," he said. TPA (Activase) was reviewed by FDA's Cardio-Renal Drugs Advisory Committee in May 1987. The committee, which has a reputation as a thorough and demanding group, initially recommended against approval and suggested that additional data be gathered. The drug was approved five months later, on Nov. 13. Genentech attempted to raise several issues about the Eminase data package under review by FDA. During an open session of the blood product committee's review of Eminase, Genentech Director of Clinical Research David Stump noted that Genentech has submitted data to FDA showing that Eminase may produce antibodies to native human plasminogen. "We've had access to the plasma of patients who've been participating in clinical trials conducted in Europe comparing recombinant TPA to APSAC and surprisingly, at least to me, have in very preliminary data, which has been submitted to the agency, learned that there is an incidence, not yet precisely defined, but not zero, of acquired antibodies in the seven-to-10 day post-treatment period to native human plasminogen," Stump said [EDITORS' NOTE: See box below for a transcript of Stump's comments to the advisory committee.] SmithKline Beecham says it is not aware of the antibody data. The company stated in response: "There is no reason to believe we are introducing any novel antigenic determinants when we introduce the live plasminogen." FDA reviewers noted that all protein products would have the same concern regarding antibodies, and that antibody production has not been a problem with those products. FDA's report to the committee appears to dismiss the antibody issue. "The plasminogen portion of the product is a human plasma-derived protein that is not likely to invoke an antibody response, as opposed to a recombinant protein such as alteplase [TPA], particularly with one use," the document states. FDA explains: "Since the normal mechanism of streptokinase is to complex with circulating plasminogen in vivo and since there has been no evidence of antibody development to the circulating complex, the formation of a 'neo-antigen' by the complexed plasminogen does not appear to be a problem. Furthermore, it has been shown that the plasminogen does not exchange with circulating plasminogen during the time course of administration and subsequent removal. Hence, the availability of free plasminogen for eliciting an immune response would be minimal." Beecham filed the product license application for Eminase in June 1988. The product is currently approved for marketing in 11 countries. In the U.S., Eminase will be marketed by SmithKline Beecham and Upjohn. The combined marketing effort will put over 1,000 reps behind the product. TPA, which is being promoted by Genentech and Boehringer Ingelheim, has 600-700 reps behind it. Eminase may be priced under Activase, which is sold for roughly $ 2,000/dose. Eminase may also have an administration advantage: the product is injected over a period of up to five minutes, whereas streptokinase is administered over an hour and TPA is given over three hours. GENENTECH SCIENTIST ADDRESSES FDA ADVISORY COMMITTEE: QUESTIONS ON EMINASE ANTIBODIES The transcript below is taken from a tape recording of remarks made by Genentech Director of Clinical Research David Stump during an open session of FDA's Oct. 31 Blood Products Advisory Committee. Stump has not had an opportunity to edit or review his comments prior to publication. . . . Since joining Genentech I've been aware of a long-term commitment to the investigation of possible immunological sequelae of large molecular compounds. We, in trying to meld that with an interest in hemostasis, have been looking at the potential for unanticipated immunologic sequelae of the administration of certain compounds such as Eminase. We've had access to plasma of patients who have been participating in clinical trials conducted in Europe comparing recombinant TPA to APSAC, and surprisingly, at least to me, have in very preliminary data, which has been submitted to the agency, learned that there is an incidence, not yet precisely defined, but not zero, of acquired antibodies in the seven-to-10 day post-treatment period to native human plasminogen. I don't personally feel the scientific data is available to comment on the relevance of that, but I would propose the following questions to the committee for discussion: 1) Is there data available regarding the risk of generating antiplasminogen antibodies in patients receiving Eminase? 2) If so, what is the exact incidence in large, large numbers of so-screened patients? 3) What is its duration when it occurs? 4) What is the short-term effect, particularly on laboratory parameters of fibrinolysis as well as short-term thrombotic events? We certainly know that acquired auto-antibodies to other key components of the hemostatic system can translate into significant clinical outcome . . . 5) What is the long-term effect in patients who do acquire such antibodies? Specifically, are there thrombotic events which can be associated with deficient fibrinolysis, such as deep venous thrombosis, which has been previously reported in the literature. [Asked by the committee how many patients were looked at, Stump continued:] We have obtained seven samples of Eminase-treated patients and have found significantly measurable titers in an ELISA system, where native human plasminogen is coated into a microtiter dish and bound quantitated antibodies are determined with a conjugated substrate. We have seen no such antibodies in 11 of our TPA patients but are certainly looking at more of these to see if the phenomenon exists. Interestingly, we did (as a positive control to the assay) look at antistreptokinase antibodies, specifically generated, and found antibodies. There was a much higher frequency of acquired streptokinase antibodies, not only in the TPA but in the APSAC patients, not distinguishable between the two groups. Thus, I think what is clear is that these antibodies can occur to plasminogen. We have yet to see [plasminogen antibodies] in TPA patients.