News
11/13/1987

<TITLE>TPA Approval -- Blood Clot Dissolver</TITLE>
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TPA Approval -- Blood Clot Dissolver

P87-32                                      Food and Drug Administration
FOR IMMEDIATE RELEASE                       Faye Peterson - (301) 443-3285

    The Food and Drug Administration today approved a genetically engineered
blood clot dissolver for preventing permanent heart damage immediately
following a heart attack.  The product is called alteplase, a tissue
plasminogen activator commonly called TPA.
    A heart attack occurs, typically, after a blood clot develops in one of 
the arteries to the heart, blocking oxygen-rich blood to that part of the 
heart muscle.  The greater the blockage and the longer it continues, the
more of the heart muscle that is likely to die.  And death of substantial 
amounts of heart muscle can lead to heart failure and death.
    But FDA said today that TPA has been shown to dissolve clots in 71
percent of patients injected with the product within six hours -- with
improved heart function documented in a study of patients administered TPA
within four hours.
    The approved labeling advises the administration of alteplase, or TPA,
"as soon as possible after the onset of symptoms."
    HHS Assistant Secretary for Health Robert E. Windom and FDA Commissioner
Frank E. Young -- both physicians -- joined in announcing the approval of 
TPA, while also noting the recent relabeling of another clot dissolver
called streptokinase for intravenous administration.  The physicians
encouraged people who suspect they are having a heart attack to get care
without delay.
    They emphasized that TPA and streptokinase are each much more effective 
if begun quickly after symptoms appear.  For example, streptokinase injected
within an hour of a heart attack was shown in one study to reduce deaths 47 
percent -- a reduction that declined to 26 percent if administered in the 
                                   


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first three hours and further declined to 17 percent if administered in 
three to six hours. 
    Dr. Windom estimated that "one out of every four or five people will
feel the pain and constriction of a heart attack
-- pressure and pain in their chest or pain in their left arm -- sometime in
their lives.  My message to them is this:  Don't waste time hoping against
hope that the pain will go away.  You will greatly increase the chances that
you will continue to live an active, productive life, if you get help 
quickly." 
    Dr. Windom said that diet, anti-smoking campaigns and other factors have
helped reduce age-adjusted death rates from heart disease by 46 percent.
"Yet," he said, "it remains America's number one killer, responsible for
about 768,000 deaths each year -- or about a third of all deaths. 
    Dr. Young said, "Of the 800,000 people a year who have a first heart
attack, 250,000 die within a month -- 100,000 before they are (or can be) 
hospitalized.  Early treatment may help reduce these deaths, but it may be
even more important to many of us that early treatment can improve the
QUALITY of the years remaining.  Today only one-third of the survivors of 
initial heart attacks completely recover.  Many of the rest live limited, 
circumscribed lives as a result of heart damage.  By limiting damage to the 
heart, early use of TPA can reduce heart damage and thus help ensure the
continued enjoyment of the vigor and pleasures of life. 
    "TPA is a dramatic example of the benefits of biotechnology in helping
to improve medical care.  It is a natural product of the body -- now
available, thanks to biotech production, in sufficient quantity to use as a 
treatment.  I am enthusiastic about the prospects for this and future 
biotech-derived products to improve the quality of life for all of us.  It
should usher in a new era of pharmaceutical development." 
    Dr. Young said the list of genetically engineered or "biotech advances" 
includes human insulin (1982); human growth hormone (1985 and 1987); two
alpha interferon products for treating a rare form of leukemia, OKT*3 
(monoclonal antibody) to reverse acute kidney transplant rejections 
and the first genetically engineered vaccine, for hepatitis B (all in 1986);
and monoclate, a purified antihemophilic agent, approved earlier this year. 
                                   


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    TPA is a genetically engineered copy of a natural protein -- tissue 
plasminogen activator -- produced in the body.  The amount produced in the
human body is minute.  Before recombinant DNA technology there was no way to
produce the material in quantities needed to treat patients.
    Genetically produced (recombinant) TPA is made by introducing the human 
gene that codes for TPA production into Chinese hamster ovary cells.  These 
cells are thereby "programmed" to consistently produce large quantities of
the drug. 
    TPA has been used in clinical trials supported by the National
Institutes of Health and other institutions here and abroad.  It will be
marketed by Genentech Inc. of South San Francisco, Calif., under the brand
name Activase.
    Arterial blood clots are thought to be the primary cause of heart tissue
damage in about 80 percent of heart attack victims.  Scientists in Belgium
in l979 first purified and characterized TPA and showed that it could 
dissolve large clots in experimental animals.  Genentech in l981 undertook
development of the drug using recombinant biotechnology techniques to 
produce sufficient quantities of TPA to be tested therapeutically.
    Clinical trials of TPA began in l984.  One of the largest studies,
sponsored by the National Heart, Lung and Blood Institute, was known as the 
Thrombolysis in Myocardial Infarction trial.  In all, TPA has been tested in
more than 4,000 patients in the United States.
    Recombinant TPA can be used to treat the vast majority of heart attack
victims, but should not be given to patients at high risk of hemorrhaging.
This includes patients with active internal bleeding, a recent stroke,
surgery or a major injury, long-standing uncontrolled high blood pressure or
a bleeding disorder.  The drug also should be used with caution in people 
over 75, pregnant women and under any other circumstances where bleeding is 
a significant hazard. 
    Intracranial bleeding was one of four issues on which an advisory 
committee May 29 asked FDA to obtain more data before TPA was approved. 
Subsequent data showed the problem occurred at higher doses but was unlikely
to occur frequently at the recommended 100 milligrams.  At this dose it 

                                   



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occurred in only about 0.4 percent of patients. 
    The safe and effective dose level was the second issue resolved.
    The committee of outside experts also asked FDA to obtain and review
data on 1) whether a change in manufacturing procedures at Genentech made 
any difference in the resultant product's safety and effectiveness, and 2)
whether TPA's ability to dissolve clots did, as theorized, limit heart
damage.  As a result of additional data submitted by the manufacturer, the
answer to first question is in the negative and the second in the 
affirmative.
    The final data submission by the company was Sept. 29, 1987 -- seven
weeks ago.  During this period, to aid in the evaluation of the data, FDA 
used outside experts to ensure that the medical community's views were fully
represented.
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