Stuart R. Gallant, MD, PhD
In the first part of this post, we looked at urokinase. In the second part, we will look at tissue plasminogen activator (tPA)—urokinase’s more successful cousin.
A Tale of Two Kinases—Second Chapter: Tissue Plasminogen Activator
In 1979, Professor Désiré Collen of University of Leuven was the first person to isolate and purify significant quantities of tPA to study its function, and ultimately, to treat patients. His tPA was, however, not recombinant. Without expression in a characterized cultured cellular expression system, tPA would be just as problematic as urokinase was as a commercial product. The dual problems of concern over possible contamination and problems scaling up production to meet the medical need would limit the utility of tPA from tissue culture, whatever the source the source of the cells.
Fortunately, a scientist from Genentech, Diane Pennica, was undaunted by the challenge of expressing tPA. Professor Collen has described the beginning of his collaboration with Dr. Pennica and with Genentech [1]:
| “At the Fifth Congress on Fibrinolysis in Malmo, Sweden (1980), where our first results with t-PA were presented, Dr. D. Pennica from the Department of Molecular Biology at Genentech Inc. approached us. Collaborations devoted to the cloning and expression of the t-PA gene ensued, with results reported at the Sixth Congress on Fibrinolysis in Lausanne, Switzerland (1982), and published in Nature in January 1983. Nowadays the cloning and expression of t-PA would be a relatively trivial accomplishment, but in 1982 this was quite an achievement for which D. Pennica deserves most of the credit.” |
Collen and Pennica worked together to express tPA in Chinese hamster ovary cells, the first commercial product licensed in CHO cells. Importantly, the collaboration with Collen had an additional benefit, other than the technical expertise he provided. The patent from the University of Leuven, granted in 1988 in the US, was the cornerstone of Genentech’s intellectual property defense of the tPA franchise [2]. Upon patent approval, Genentech immediately filed suit block a competing project sponsored by Burroughs Wellcome Inc. and Genetics Institute.
tPA in the Clinic and the Market
tPA would be the subject of a number of clinical trials, but one study in particular focuses attention on how lucky and perceptive Genentech was in developing tPA. Below is a table from the Thrombolysis In Myocardial Infarction trial (TIMI) sponsored by the National Heart, Lung, and Blood Institute [3]:
Upon reviewing the table, one thing stick out. At every time point, tPA substantially outperforms streptokinase. Short (1 hr) or long (>7 hr) term, a patient’s chance of reperfusion (expressed in % columns) essentially doubles if receiving tPA, compared to receiving streptokinase. Successful reperfusion leads to saving heart muscle and improved patient outcomes. Based on this table, in the hospital in 1988, a patient could be told by their cardiologist that the most likely outcome of their heart attack was reperfusion (62%) if they were given tPA. In contrast, the streptokinase patients would most likely not to be successfully reperfused. This one table explains why tPA is the standard of care in the US, while streptokinase is no longer offered in US hospitals.
From the very beginning, tPA sold like hot cakes [4]. At the time of launch in 1988, a dose of tPA sold for $2,200. In contrast, streptokinase sold for between $100 and $500, depending on the manufacturer and distribution channel. In spite of the price differential, Gerard M. McKeegan, director of pharmacy at Williamsport Hospital and Medical Center in Pennsylvania was quoted in 1988 as saying, ”They’ve done a tremendous job of pre-marketing this drug, so that the cardiologists are salivating.”
Time has passed, and the market for clot busters has matured. As of 2012, the following products were on the market [7]:
Given the strength of the US market alone, the world market will probably support a few more products, either biosimilars or innovator drugs [6]:
| Indication | US Annual Market |
| Central venous catheter clearance | $330 million/yr |
| Pulmonary embolism | $90 million/yr |
| Peripheral thrombosis | $760 million/yr |
| Stroke | $580 million/yr |
| Total | $1.76 billion/yr |
Innovator companies could, perhaps, tweak one of the existing molecules to deliver improved performance. Biosimilar companies could compete based on price. (tPA is a complex molecule, so there has not been a stampede of biosimilars coming to the US market since Genentech’s patent coverage expired. Development of tPA biosimilars will be limited to companies with a high degree of technical expertise. As an example, Generium, a Russian pharma company, has a biosimilar Revelise for the Russian market.)
While tPA has generally done well in pharmaceutical economic cost-effective analysis, the price has trended up. Below is a graph of the price per mg paid by Center for Medicare and Medicaid Services for tPA [7]:
Additional biosimilar products would slow this rate of growth. However, before we are excessively critical of the price of this pharmaceutical, it might make sense to end with a cautionary tale.
Even a highly successful pharmaceutical company may find the task of developing and maintaining a portfolio of products a challenging task. In the 1970s and 1980s, Genentech had a string of technical and commercial successes. Three of these have been discussed by PharmaTopo (insulin, Factor VIII, and tissue plasminogen activator). Another important molecule that should not be forgotten and may be the subject of a future post is human growth hormone. During this period, Genentech enjoyed tremendous sales revenue; however, drug development is a highly capital-intensive undertaking. In the late 1980s, Genentech found itself short on cash and vulnerable to take over. Genentech sold the Factor VIII project to Bayer to raise cash. In 1990, Genentech founder Robert Swanson was forced to resign from his position as CEO. At the same time, Hoffmann-La Roche stepped in to purchase 60 percent of Genentech and stabilize the company financially.
In the pharmaceutical business, any company is dependent on the power of its ideas (i.e., how strong its pharmaceutical pipeline is) and the power of its fund-raising abilities. If it falters in either endeavor, it can fail.
[1] Collen, D. and Lijnen, H.R. “The Tissue-Type Plasminogen Activator Story,” Arterioscler Thromb Vasc Biol. 29(8):1151-5 (2000).
[2] Pollack, A. “Genentech Gets Patent For Drug for Blood Clots,” New York Times, June 22, 1988, Section D, Page 1.
[3] Chesebro, J.H., et al. “Thrombolysis in Myocardial Infarction (TIMI) Trial, Phase I: A comparison between intravenous tissue plasminogen activator and intravenous streptokinase. Clinical findings through hospital discharge.” Circulation. 76:142-154 (1987).
[4] Pollack, A. “Fast Start for Bioengineered Drug,” New York Times, January 5, 1988, Section D, Page 1.
[5] Sidawy, A.N., et al. Rutherford’s Vascular Surgery and Endovascular Therapy, 9th Edition.
[6] Microbix. KINLYTIC. Non Confidential Information Presentation, Nov 2019.
[7] Kleindorfer, D., et al. “Cost of Alteplase Has More Than Doubled Over the Past Decade,” Stroke Volume 48, Issue 7, Pages 2000-2002 (2017).
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