Plasmin (Human) Administration in Acute Middle Cerebral Artery Ischemic Stroke: Phase 1/2a, Open-Label, Dose-Escalation, Safety Study
Introduction
Acute ischemic stroke (AIS) is one of the leading causes of death and disability across the globe.1, 2, 3 Rapid recanalization of occluded vessels, whether by systemic pharmacological fibrinolysis or intra-arterial mechanical clot retrieval, is crucial for achieving better outcomes. However, there are important limitations to both approaches.
Currently, the only regulatory-approved form of fibrinolytic therapy is systemic, intravenous (IV) tissue plasminogen activator (tPA), given up to 3.0-4.5 hours after stroke onset.4 The systemic route of administration allows rapid treatment start but disseminates the active fibrinolytic agent throughout the body. Consequently, low, diluted lytic concentrations are achieved at the targeted clot, and IV tPA only successfully recanalizes 4%-32% of target large-vessel cerebral occlusions.5 In addition, systemic distribution incurs risk for adverse bleeding events in nontarget organs and nonischemic brain. IV tPA is associated with symptomatic intracerebral hemorrhage in up to 6% of cases.6
Mechanical clot retrieval achieves higher rates of reperfusion but also has constraints. At the time of design of the current trial, the first-generation mechanical thrombectomy devices in use achieved only modest recanalization.7, 8, 9 Randomized trials comparing these mechanical thrombectomy devices to the best medical therapy did not show they were beneficial.10, 11, 12, 13 Subsequently, second-generation devices, including stent retrievers, were shown to have substantially greater recanalization efficacy and safety,14, 15, 16 and were demonstrated to improve patient outcome compared with medical therapy in multiple randomized trials.7, 8, 14, 15, 16, 17 However, even in the pivotal trials, second-generation thrombectomy devices were unable to substantially recanalize 20%-41% of target proximal occlusions. In addition, the devices are unable to safely reach more distal potential target occlusions and are associated with fragmentation and distal embolization of thrombi to new arterial territories.
Intra-arterial administration of fibrinolytics is a promising recanalization therapy that could potentially complement IV fibrinolysis and mechanical thrombectomy. Randomized trials have investigated several plasminogen activators, including tPA, urokinase, and prourokinase.18, 19, 20, 21, 22, 23 Results of individual trials have suggested and meta-analysis of all trials has confirmed benefit.24 However, the use of plasminogen activators as the treatment agent in all of the randomized trials may have limited treatment efficacy. Plasminogen activators convert plasminogen into the active lytic molecule plasmin. In the low or no flow region of an occlusive thrombus, the local supply of plasminogen may be completely consumed, and further instillation of plasminogen activators may not result in further lytic treatment activity. For these reasons, direct-acting fibrinolytic agents, such as plasmin itself, may be advantageous in intra-arterial delivery strategies.
Since the 1950s, plasmin—a direct fibrinolytic enzyme that degrades fibrin without requiring the intermediate actions of plasminogen activators—has been proposed as a thrombolytic agent that can potentially dissolve an ischemic thrombus without increasing bleeding risk.23 The possible advantages of using catheter-delivered plasmin over systemic tPA infusion are attributable to high target thrombus activity and curtailed activity at other sites. High activity at the target occlusion may be expected from its direct mode of lytic action, not requiring local endogenous plasminogen. Limited off-target activity arises from the ability of endogenous α-2-antiplasmin (A2AP) to rapidly neutralize plasmin.25, 26 When delivered by catheter directly to a thrombus, plasmin is shielded from A2AP in the circulation while it carries out thrombolysis. Once released from the thrombus, plasmin is neutralized quickly by A2AP, therefore preventing unwanted bleeding at distal vascular injury sites. In preclinical investigations, plasmin showed higher in vitro fibrinolytic activity in retracted clots than tPA27 and was superior to tPA for in vivo thrombolysis and flow restoration in a rabbit model.28, 29 In a rat model of transient ischemic stroke, a recombinant plasmin derivative with similar functions to native plasmin demonstrated a superior intracranial hemorrhage safety profile compared to recombinant tPA.30 Furthermore, plasmin was just as effective as tPA at dissolving cerebral thromboemboli retrieved from patients with AIS31 and has demonstrated the ability to dissolve clots across multiple species, including rabbit, dog, sheep, pig, bovine, and human.32, 33
In the clinical setting, plasma-derived plasmin (Plasmin [Human], TAL-05-00018; Grifols Therapeutics Inc., Research Triangle Park, NC) has been evaluated in 3 clinical studies for 2 different intravascular thrombosis indications: hemodialysis graft occlusion and peripheral arterial occlusion. Results from early phase studies in peripheral arterial occlusion34 and hemodialysis graft occlusion35, 36 showed that plasmin doses ranging from 1 to 175 mg were safe and well tolerated. There was improved thrombolysis observed with the higher doses (125-175 mg) as compared to the lower doses (25-100 mg), but no increase in adverse events (AEs), serious adverse events (SAEs), or bleeding events was observed with escalating doses.34
The present study describes the first evaluation of plasmin as an intra-arterial thrombolytic treatment for AIS caused by MCA occlusion. The objectives of the present study were to evaluate the safety of plasmin in patients with acute middle cerebral artery (MCA) ischemic stroke, given in escalating doses within 9 hours of stroke symptom onset, and to determine treatment efficacy as measured by partial or full recanalization of the occluded vessel. The rationale for this approach was that intrathrombus administration of plasmin would allow it to bind to fibrin, based on delivery to the targeted clot, and, presumably, to protect it from the action of circulating inhibitors. The potential advantages of delivering directly to the clot for intra-arterial thrombolysis (IAT) administration over the IV route would potentially include (1) the potential for faster and more complete recanalization compared to IV therapy, (2) a longer treatment window, (3) the assessment of clot lysis by arteriography during treatment, and (4) a reduction of thrombolytic dose volume with an associated reduction of hemorrhagic complications.37, 38
Section snippets
Patient Population
Male and female patients 18-85 years old were recruited from multiple centers across Europe and Australia. The study was conducted between February 2010 and February 2014. Eligible patients must have had a new focal, potentially disabling, neurological deficit clinically localized to the MCA distribution (characterized by complete occlusion or contrast penetration with minimal perfusion of the M1 segment, M2 segment, M2 division, or combinations of these segments as assessed by arteriography)
Results
Fifty-eight patients were screened; 18 failed to meet the eligibility criteria. A total of 40 patients were enrolled at 13 investigative centers in 7 countries (Australia, n = 5; Austria, n = 1; France, n = 7; Germany, n = 4; Serbia, n = 10; Slovakia, n = 5; and Spain, n = 8) (Fig 3). Plasmin doses of 20, 40, or 80 mg were administered for a median time of .33-.55 hours across the 5 treatment cohorts: cohort 1 (20 mg, .5 mL/min), cohort 2a (40 mg, .05 mL/min), cohort 2b (40 mg, .33 mL/min),
Discussion
Plasmin treatment was generally safe at doses as high as 80 mg and did not present additional safety risks in the present study. Cerebral bleeding is considered the most likely safety risk of thrombolytic therapy. However, no major intracerebral bleeding events and no SICH events were reported in this study. Five patients (12.5%) experienced asymptomatic cerebral bleeding events. No relationship was observed between the plasmin dose and the incidence or severity of cerebral or systemic bleeding
Acknowledgments
The authors would like to thank Tam Nguyen-Cao, PhD, of Grifols for medical writing assistance under the direction of the authors. We also wish to thank the following investigators for their participation in this trial: Olav Jansen of Universitätsklinikum Schleswig-Holstein Campus Kiel, Germany; Jaime Masjuan of Hospital Universitario Ramón y Cajal, Spain; Mikael Mazighi of Hôpital Bichat-Claude Bernard, France; Milan Savić of Specijalna Bolnica za Cerebrovaskularne Bolesti “Sveti Sava,”
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Cited by (3)
Microscale structural changes of individual fibrin fibers during fibrinolysis
2022, Acta BiomaterialiaCitation Excerpt :One clinical approach to resolving an occluded blood vessel is to administer enzymes from outside the thrombus in a process called thrombolysis. While recombinant tPA is the standard thrombolytic agent used to treat strokes [3], a phase 1/2a safety study has shown potential for using plasmin as a thrombolytic [4]. Clinical studies have shown a limited time window for the safe administration of tPA treatments for stroke (within 4.5 h after symptom onset) [5], and recanalization of the occluded blood vessel is often not achieved in thrombolytic treatments [6,7].
Alpha2-Antiplasmin: The Devil You Don't Know in Cerebrovascular and Cardiovascular Disease
2020, Frontiers in Cardiovascular MedicineChoosing of suitable animal model of arterial thrombosis to test new recombinant thrombolytic agent — modified human plasminogen
2020, Russian Cardiology Bulletin
Grant support: This study was funded by Grifols, the sponsor of this clinical trial.
Conflict of interest: Kecia L. Courtney is an employee of Grifols, the sponsor of this study. Jeffrey L. Saver is an employee of the University of California and has served as an unpaid site investigator in multicenter trials run by Medtronic and Stryker for which the UC Regents received payments on the basis of clinical trial contracts for the number of subjects enrolled. Dr. Saver received stock options for services as a scientific consultant regarding trial design and conduct to Cognition Medical. Dr. Saver receives funding for services as a scientific consultant regarding trial design and conduct to Grifols, Medtronic, Stryker, Neuravi, BrainsGate, and Boehringer Ingelheim (prevention only). Dr. Saver serves as an unpaid consultant to Genentech, advising on the design and conduct of the PRISMS trial; neither the University of California nor Dr. Saver received any payments for this voluntary service. The University of California has patent rights in retrieval devices for stroke.
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Dr. Marder passed away before the writing of this manuscript was initiated on January 29, 2015. However, he played a crucial role in the design of this study and served as an active, key leader on the advisory committee of this study for 6 of the 7 years in which the program was being developed and conducted.