The dual-therapy regimen will be compared to high-dose tPA monotherapy, the standard of care, in patients with distal blood clots post-stroke.
Diederik Dippel, MD, PhD
Thrombolytic Science has announced its initiation of a phase II clinical trial of a dual treatment regimen of low-dose tissue plasminogen activator (tPA) and the company’s mutant prourokinase (HisproUK) in patients who have experienced an ischemic stroke.
The trial will be led by Diederik Dippel, MD, PhD, the co-director of the Erasmus MC Stroke Center in Rotterdam, The Netherlands. The dual-therapy regimen will be compared to high-dose tPA monotherapy, the standard of care, in patients with distal blood clots post-stroke. It will have a prospective, randomized, open, blinded end-point (PROBE) design. The primary safety endpoint will be any intracranial hemorrhage, as assessed by MRI, while the efficacy endpoints will include NIH Stroke Scale at 24 hours, and follow-up infarct volume on MRI.
“Timely and rapid clot dissolution is key to treating ischemic stroke, especially when the clots are distal, a situation that asks for medical treatment with a next-generation thrombolytic drug to minimize complications and maximize chances of [a] good outcome,“ explained Dippel in a statement.1 “That makes this phase II trial particularly important, as we hope to show that sequential dual-therapy with low-dose tPA and HisproUK can initiate thrombolysis safely and effectively.”
The trial follows a phase I exploration of the clot-dissolving therapy, which assessed the therapy in in 26 men, administering either a single dose of HisproUK or low-dose tPA followed by infusion of HisproUK. There were no instances of change in coagulation indicative of safety issues. Alexis C. Wallace, MScENG, MBA, the chief executive officer and co-founder of TSI, said in September 2017 that due to the dual therapy’s induction rapid clot dissolution using both smaller and safer doses than monotherapy, he expected the treatment would “fundamentally alter the therapeutic paradigm for patients with acute ischemic stroke.”2
"There is a strong pathophysiological basis for the concept that treatment with HisproUK will lead to less hemorrhage," Dippel told NeurologyLive. "The point is that activation by a small amount of tPA is necessary. When this is out of the circulation again after several minutes, the risk of bleeding is strongly diminished. So my thoughts about the dual regimen are quite favorable, the more so because stroke doctors are used to treating their stroke patients with a small bolus of alteplase, anyway."
The treatment of ischemic stroke patients with alteplase, Dippel noted, leads to a considerably high risk of intracerebral hemorrhage, upward of 10-fold the risk in patients treated for myocardial infarction. "One of the most terrible things that can happen to patients and their doctor is sudden neurological deterioration because intracerebral hemorrhage occurred during treatment with IV alteplase. If we can reduce this risk by half, we will certainly have fulfilled an unmet need," he said.
HisproUK was developed via recombinant technology, intended to control the highly intrinsic activity of proUK, which has historically led to bleeding in clinical studies. After the process of thrombolysis is initiated and the tPA activates plasminogen into plasmin, HisproUK then activates a duo of additional plasminogen binding sites on the degraded clot surface to hasten thrombolysis.
The 2 enzymes, tPA and proUK, have complementary functions, and both required for a full fibrinolytic effect, according to Victor Gurewich, MD, the chief scientific officer of TSI. He referred to the dual-therapy regimen as “Nature's clot-dissolving design.”
“Initiation of our Phase II trial in ischemic stroke is an important milestone for TSI, the medical community, and patients, as we take a step closer to possibly treating ischemic stroke faster, safely, and with greater confidence,” said Wallace in a statement. “Having been greatly encouraged by the favorable results from our Phase I trial of low-dose tPA and HisproUK, we are confident that the Phase II study will further characterize the clinical utility of this next-generation clot-dissolving regimen. We look forward to exploring potential partnerships with pharmaceutical companies as we continue to advance the clinical development program for this promising dual-therapy.”
The company also announced that it will be beginning a second phase II trial of the dual-treatment regimen pre-hospitalization in patients who have experienced myocardial infarction, set to begin in 2019.
1. Thrombolytic Science Initiates Phase 2 Clinical Trial of its Novel Treatment Regimen for Ischemic Stroke [press release]. Cambridge, MA: TSI. Published September 5, 2018. businesswire.com/news/home/20180905005211/en/Thrombolytic-Science-Initiates-Phase-2-Clinical-Trial. Accessed September 5, 2018.
2. TSI Completes Phase 1 Clinical Trial of Novel Clot-dissolving Therapy, TS01 [press release]. Cambridge, MA: TSI. Published September 18, 2017. prnewswire.com/news-releases/tsi-completes-phase-1-clinical-trial-of-novel-clot-dissolving-therapy-ts01-300521248.html. Accessed September 5, 2018.