1. Field of the Invention
The invention is related to a method of treating stroke with a thrombolytic agent, more particularly, a method of administering tenecteplase in a certain dosing regimen to treat acute ischemic stroke.
2. Description of Related Art
Stroke is a general term for acute brain damage resulting from disease of the blood vessels. This presents a serious problem to society, with about 500,000 people dying from or becoming permanently disabled by stroke in the United States each year. Stroke can be classified into two main categories: hemorrhagic stroke (resulting from leakage of blood outside of the normal blood vessels) and ischemic stroke (cerebral ischemia due to lack of blood supply); this application is concerned with the latter.
Ischemic stroke is responsible for about one third of all deaths in industrialized countries and is the major cause of serious, long-term disability in adults over the age of 45. It stands to reason that there is a need for pharmacotherapy to treat acute ischemic stroke. Considerable insights have been gained into the mechanisms of stroke and the cascade of events that occurs following stroke; there is also an improved understanding of neuronal injury and cell death.
The three main mechanisms of ischemic stroke are thrombosis, embolism, and systemic hypoperfusion (with resultant ischemia and hypoxia). In each of these types of stroke, the area of the brain that dies as a result of the lack of blood supply thereto is called an infarct. Obstruction of a cerebral artery resulting from a thrombus that has built up on the wall of a brain artery is generally called “cerebral thrombosis.” In cerebral embolism, the occlusive material blocking the cerebral artery arises downstream in the circulation (e.g., an embolus is carried to the cerebral artery from the heart). Because it is difficult to discern whether a stroke is caused by thrombosis or embolism, the term “thromboembolism” is used to cover both these types of stroke. Systemic hypoperfusion may arise as a consequence of elevated blood lactate levels, reduced hematocrit, low blood pressure, or inability of the heart to pump blood adequately.
When symptoms of stroke last less than 24 hours and the patient recovers completely, the patient is said to have undergone a transient ischemic attack (TIA). The symptoms of TIA are a temporary impairment of speech, vision, sensation, or movement. Because a TIA is often thought to be a prelude to full-scale stroke, patients having suffered a TIA are candidates for prophylactic stroke therapy with anticoagulation agents (e.g., coumarin, and heparin) or anti-platelet agents (such as aspirin and ticlopidine), for example.
Acute ischemic stroke (AIS) is a heterogeneous disease process; prediction of course, recovery, disability, or death is difficult. It is typically due to an acute thromboembolic arterial occlusive lesion. The location of the arterial occlusive lesion in acute ischemic stroke is relatively heterogeneous. Thrombolytic agents, such as recombinant tissue plasminogen activator (rtPA), have been used in the treatment of thromboembolic stroke, and function by lysing the thrombus causing the ischemia. In fact, intravenous rtPA (alteplase, ACTIVASE®) is the only drug approved for the treatment of acute ischemic stroke. Intravenous rtPA (0.9 mg/kg, maximum 90 mg), with 10% of the dose given as a bolus followed by an infusion lasting 60 minutes, is recommended treatment within 3 hours of onset of ischemic stroke. This drug is believed to be most useful if administered as soon as possible after acute stroke (Gross et al., Neurosurgery, 36:1172-1177 (1995); Ingall et al., Stroke, 35: 2418-2424 (2004); The ATLANTIS, ECASS, and NINDS rt-PA Study Group Investigators, Lancet, 363: 768-774 (2004)), to restore, partially at least, cerebral blood flow in the ischemic region and to sustain neuronal viability. There is additional evidence, however, that administration at later times, by means of other methods, is effective, for example, by use of diffusion-weighted and perfusion MR imaging techniques and CT perfusion technology. Tomsick, J. Vase. Interv. Radiol., 15: S67-S76 (2004). In addition, catheter-based treatment with intra-arterial tissue-plasminogen activator (tPA) or urokinase alone or with adjuvant balloon angioplasty/stenting for those patients ineligible for intravenous treatment of acute ischemic stroke has been successful. Ramee et al., Stroke, 35: e109-e111 (2004). A combined intravenous and intra-arterial tPA approach to recanalization in ischemic stroke patients has also been proposed. The IMS Study Investigators, Stroke, 35: 904-912 (2004).
Thrombolysis, the lysis of a cerebral arterial clot with tPA within hours of symptom onset in ischemic stroke, has been approved for treatment of acute ischemic stroke since 1996. Two other agents, pro-urokinase (intra-arterial administration directly into M1 or M2 arterial thrombus) and intravenous ancrod, a fibrinogen-lowering agent derived from the venom of the Malayan pit viper, have shown therapeutic benefit, and may be available for acute ischemic stroke therapy in the future. The effect of anti-ICAM-1 antibodies in a rabbit embolic stroke model followed by thrombolysis with tPA has also been examined (Bowes et al., Exp. Neurol., 119:215-219 (1993)). Although tPA (30 minutes post-ischemia) and anti-ICAM-1 antibody (five minutes post-ischemia) each separately improved the neurological outcome relative to controls, administration of a combination of the two compounds at the same time was no more effective than administering either compound alone. When thrombolysis was delayed three hours following embolism, neither tPA nor the combination reduced neurological damage. Experiments in rabbits have also shown that tPA (30 minutes post-ischemia) and an anti-CD18 antibody (5 minutes post-ischemia) each separately improved neurological outcome, although administration of the combination of the two compounds at the same time was no more effective than administering either compound alone (Bowes et al., Neurology, 45:815-819 (1995)). The combination of anti-ICAM-1 antibody (15 minutes post-ischemia) and tPA (2 hours post-ischemia) extended the pest-ischemia duration at which the tPA remained effective. That is, the combination was effective in extending the therapeutic window of tPA outside the effective therapeutic window of the tPA when administered alone in a rabbit. This effect has also been seen in rats with tPA and a glycoprotein IIB/IIIA receptor inhibitor. Li et al., Circulation, 107: 2837-2843 (2003). US Pat. Pubs. 2002/0081294 and US 2004/0057951 disclose co-administration of a thrombolytic compound and an anti-CD18 antibody for increasing blood flow in an infarct-related artery in a mammal such as a human (e.g., acute myocardial infarction (AMI) in a mammal with a blocked coronary artery or focal ischemic stroke caused by obstruction of a cerebral artery).
U.S. Pat. No. 6,541,452 discloses a brain-associated inhibitor of tPA and its use in treating stroke. US Pat. Pub. 2004/0176347 discloses a pharmaceutical composition for treating cerebral ischemic diseases comprising an astrocyte-function-improving agent and a thrombolytic agent, preferably tPA, as active ingredients.
Tenecteplase (TNK, TNKASET™, Genentech, Inc., South San Francisco, Calif.) is a genetically engineered variant of human tPA cloned and expressed in Chinese hamster ovary cells. Keyt et al., Proc. Natl. Acad. Sci USA, 91: 3670-3674 (1994). See also Verstraete, Am. J. Med, 109: 52-58 (2000) for an overview of third-generation thrombolytic drugs in general. Approved in the U.S. for a single-bolus administration in patients with AMI, tenecteplase was engineered to have increased fibrin specificity and an increased half-life compared to alteplase.
Tenecteplase and alteplase were equivalent for 30-day mortality when single-bolus tenecteplase was compared with front-loaded alteplase in acute myocardial infarction in the ASSENT-2 double-blind randomized trial. The ease of administration of tenecteplase may facilitate more rapid treatment in and out of the hospital. Van de Werf et al., Lancet, 354: 716-722 (1999). The results of the ASSENT-2 study indicated that total stroke rate and 30-day mortality were lower in female patients over 75 years of age treated with tenecteplase than in those treated with alteplase, albeit that the difference was statistically not significant. The authors concluded that female patients and patients over 75 years of age will probably benefit more from a thrombolytic agent that is given according to a weight-adjusted close regimen, e.g., tenecteplase. Vermeer, Thrombosis Research, 103: Supplement 1, S101-S104 (Sep. 30, 2001). Other thrombolytic drugs that may be useful in treating AMI include streptokinase, urokinase, anistreplase, alteplase, saruplase, reteplase, lanoteplase, staphylokinase, fibrolase, prourokinase, and vampire bat plasminogen activator. Iqbal, Clinical and Applied Thrombosis/Hemostasis, 6/1: 1-13 (2000). Follow-up data with tenecteplase indicate that it shows overall efficacy and tolerability profiles similar to those of alteplase, with comparable mortality after one year of follow-up. Tenecteplase has an apparent advantage over alteplase in reduced mortality in patients receiving late treatment and reduced incidence of non-cerebral bleeding complications in ASSENT-2. Dunn and Goa, Am J Cardiovasc Drugs 1 (1), 51-66 (2001).
Callahan et al., HeartDrug 1/5: 281-290 (2001) is a review stating that both r-PA and tenecteplase are effective in treating AMI when given as bolus therapy, a feature that may facilitate earlier treatment initiation as well as lower treatment costs. In a later study it was found that the thrombolytic drugs (reteplase, tenecteplase, alteplase, and streptokinase) appear to be of similar efficacy in reducing mortality, and the apparent benefits of accelerated alteplase in GUSTO-I are consistent with this. Dundar et al., QJM, 96: 103-113 (2003). Tenecteplase was found to be effective in treating AMI in combination with the low-molecular-weight heparin enoxaparin (ENOX) or unfractionated heparin in the prehospital setting in a trial called ASSENT-3 PLUS. The combination of tenecteplase with ENOX reduces early ischemic events, but lower doses of ENOX need to be tested in elderly patients. Wallentin et al., Circulation, 108: 135-142 (2003); U.S. Pat. No. 7,084,118.
In the treatment of ischemic stroke, Jonas et al., Annals of the New York Academy of Sciences, 939: 257-267 (2001) discloses the predictive value of animal models in assessing the failure of neuronal protective agents versus the success of thrombolysis. Agents claimed to be neuroprotective in animal stroke models have all failed in human trials. Thrombolysis has been reported as beneficial in animal and human stroke. In animals the effect of neuroprotective agents and of thrombolytic agents on infarct size is time-dependent: early initiation of treatment works best; and benefit is progressively—and eventually totally—lost with increasing delay of time of first treatment. The animal data also show that, overall, the beneficial effects of the neuroprotective agents are weaker, and are totally lost sooner, than those of thrombolytics. The human data show that the failed trials of the neuroprotective agents had entry windows that went far beyond the windows of (any) success seen in tests of these agents in animals. By contrast, human thrombolysis trials uniformly restricted time of entry to windows in which these agents have shown beneficial effect in animals. In clinical stroke trials, neuroprotective agents failed to produce benefit because their effects at best are too weak, and they were used at times predictable from the animal models as too late. Thrombolytic therapy, such as tenecteplase and urokinase, which has a stronger-effect than neuroprotective agents in animal models, was used clinically during the early window of optimal effectiveness, and produced beneficial results.
The field of intravenous and intra-arterial thrombolysis for the treatment of acute ischemic stroke is rapidly advancing. Limitations of existing thrombolytic agents have prompted the development of new thrombolytic agents over the last decade, called third-generation thrombolytics. Two of the several third-generation thrombolytic agents have been investigated for the treatment of acute ischemic stroke and include tenecteplase and reteplase. By virtue of structural modifications, third-generation thrombolytics have longer half-lives and greater penetration into the thrombus matrix. The first prospective human clinical trial evaluated the safety and efficacy of intra-arterial reteplase in 16 patients with ischemic stroke who were poor candidates for intravenous alteplase therapy. Near complete or complete recanalization was observed after treatment in 88% of the patients. The development and use of third-generation thrombolytics is expected to increase the rate of recanalization and clinical recovery in patients with ischemic stroke. Qureshi et al., Current Opinion in Investigational Drugs 3(12): 1729-1732 (2002).
For example, monteplase, a modified rtPA, reduces infarct volume and hemorrhagic transformation in rat model of embolic stroke. Muramatsu et al., Neurological Research, 24: 311-316 (2002). Other such third-generation drugs include lanoteplase, plasmin, or a truncated form of plasmin (microplasmin), a direct-acting thrombolytic with non-thrombolytic-related neuroprotective, therapeutic activities, recombinant desmodus rotundus salivary plasminogen activator (rDSPA) alpha-1, and a mutant fibrin-activated human plasminogen (BB10153; British Biotech Inc.). These areas of drug discovery and development are reviewed in Lapchak, Expert Opinion on Investigational Drugs 11: 1623-1632 (2002).
A multi-center, randomized, double-blinded sequential dose-escalation clinical trial called the CLEAR stroke study is now being conducted to evaluate the safety of eptifibatide, an intravenous cyclical heptapeptide that selectively blocks the platelet glycoprotein IIb/IIIa receptor, in combination with low-dose rtPA in acute ischemic stroke treated within three hours.
It has been proposed that tenecteplase may be neuroprotective following a stroke because of its increased fibrin specificity over alteplase, its resistance to PAI-1, and its increased biological half-life (18 vs. 10 minutes for alteplase), features that could lead to fewer cerebral hemorrhages than alteplase in stroke patients.
A pilot study of tenecteplase was made in 88 acute ischemic stroke patients enrolled over 2000 to 2003 using four dose tiers of tenecteplase: 0.1, 0.2, 0.4, and 0.5 mg/kg. There were no symptomatic intracranial hemorrhages (ICHs) in the first three tiers. Two of 13 patients had symptomatic ICH at 0.5 mg/kg, and there were increasing ICHs with increasing doses (8%-38%), with outcomes similar to the alteplase group in the earlier acute ischemic stroke trial. Tenecteplase is currently being tested in a randomized controlled Phase IIb clinical study in acute ischemic stroke patients using 0.1 mg/kg tenecteplase, 0.4 mg/kg tenecteplase, and 0.9 mg/kg rtPA.
In an early animal study, the activity of tenecteplase was compared with that of alteplase in rabbit models of embolic stroke and peripheral bleeding. Infusion of alteplase or bolus administration of the tenecteplase resulted in dose-dependent clot lysis. The tenecteplase was found to be an order of magnitude more potent than alteplase on a milligram-per-kilogram basis. Unlike alteplase, tenecteplase caused less systemic activation of plasminogen and fewer hemorrhagic transformations in this model. The tenecteplase did not extend template bleeding times. The authors state that by combining increased fibrin specificity with decreased plasma clearance, it is possible to produce a thrombolytic agent (tenecteplase) that is more convenient and more potent than wild-type tPA. According to the authors, the significant reduction in hemorrhagic conversions may be attributable to the conservation of systemic plasminogen seen with this molecule. Thomas et al., Stroke, 25: 2072-2078 (1994).
In another animal study, tenecteplase in a dose of using 0.6 mg/kg or 1.5 mg/kg was compared with wild-type tPA in a rabbit embolic stroke model. Both wild-type tPA and tenecteplase caused thrombolysis in most subjects, and did not differ from each other. Neither tenecteplase nor tPA affected the size of the hemorrhages. Tenecteplase shows comparable rates of recanalization compared with wild-type tPA in a model of embolic stroke. While tPA increases hemorrhage rate, the hemorrhage associated with tenecteplase treatment is not statistically different compared with controls or the tPA group. The authors suggested that tenecteplase shows promise as an alternative thrombolytic treatment for stroke, but they could not demonstrate improved safety compared with wild-type tPA. Chapman et al., Stroke, 32: 748-52 (2001).
More recent studies in humans indicate many parallels with animal studies, not only in the nature of events following ischemia, but also in their time course. Callaway, Current Neuropharmacology, 2/3: 277-294 (2004). Co-administration of NXY-059 (100 mg/kg) and tenecteplase (0.9 mg/kg) six hours following embolic strokes in rabbits improves clinical rating scores. Lapchak et al., Experimental Neurology 188: 279-285 (August 2004); Comment in Exp Neurol., 188: 195-199 (August 2004). Wagner and Jauch Experimental neurology 188 (2): 195-199 (2004); Comment on Exp Neurol. 188(2) 279-85(2004) discloses the window for acute stroke treatment of thrombolytics such as tenecteplase plus central-nervous-system (CNS)-protective therapies such as free-radical scavengers, NXY 059, and nitrogen oxides. Lapchak et al., Experimental Neurology, 185: 154-159 (2004) discloses a comparison of tenecteplase with alteplase on clinical rating scores following small-clot embolic strokes in rabbits. The rabbit small clot embolic stroke model (RSCEM) was used for a dose-response profile analysis of tenecteplase (0.1 mg/kg-3.3 mg/kg) and alteplase (0.9 mg/kg-3.3 mg/kg) given intravenously 1 hour following embolization.
In additional studies, tenecteplase (0.9 mg/kg) or alteplase (3.3 mg/kg) was administered 3 (or 6) hours following embolization to determine the therapeutic window for the thrombolytics. For both studies, behavioral analysis was conducted 24 hours following embolization, allowing for the determination of the effective stroke dose (P50) or clot amount (mg) that produces neurological deficits in 50% of the rabbits.
This study indicates that tenecteplase has a wide therapeutic range, a therapeutic window of at least 3 hours, and a durable effect. Moreover, the safety profile for tenecteplase is similar to that of alteplase. Tenecteplase does not increase the rate of intracerebral hemorrhage (ICH) above that produced by alteplase. However, the therapeutic range and window for alteplase is more limited than that for tenecteplase. These preclinical studies suggest that tenecteplase has a better pharmacological profile than alteplase and supports further investigation of tenecteplase in randomized double-blinded clinical trials in stroke patients. Sec also Araujo et al., Society for Neuroscience Abstract Viewer and Itinerary Planner, Volume: 2003, Page: Abstract No. 102.2 (2003) Conference: 33rd Annual Meeting of the Society of Neuroscience, New Orleans, La., USA, Nov. 8-12, 2003.
There is a need to provide a method for improving clinical outcome in acute ischemic stroke, such as by increasing cerebral blood flow and/or reducing infarct size, using tenecteplase.