Thrombotic disease

Unique mode of action

The main objective when treating thrombotic diseases such as stroke is to unblock the blood vessel as quickly as possible. However, all thrombolytic agents currently available do not always offer an optimal solution as they normally take too long to dissolve the clot and are often associated with significant complications such as unwanted bleeding (hemorrhage). Microplasmin’s mode of action differs from most other thrombolytics in development and on the market; it is a direct acting thrombolytic while most other thrombolytics are plasminogen activators (PAs), which convert plasminogen into plasmin, its active form. PAs rely on the presence of plasminogen in the thrombus and in the blood, and therefore their action depends on multiple factors. Direct acting thrombolytics do not suffer from these potential drawbacks. This difference in mode of action is thought to be particularly critical in older clots, which can become resistant to indirect acting thrombolytics as the amount of plasminogen decreases in these clots. The Company believes that this direct mode of action will enable microplasmin to dissolve clots more predictably, efficiently and quickly than indirect thrombolytics.

Stroke

The Company has conducted a Phase II clinical trial with microplasmin in stroke with the goal of investigating the safety, tolerability and initial activity of microplasmin. The study was a multicentre, randomized, double-blinded, placebo-controlled, ascending-dose clinical trial evaluating the safety and preliminary efficacy of the intravenous administration of microplasmin in 40 patients, 4 to 12 hours after onset of acute ischemic stroke, a timeframe for which currently none of the thrombolytic drugs has been approved. The trial investigated three dose regimens of microplasmin (2, 3, and 4 mg/kg total dose) compared to placebo. Clinical outcomes were assessed at seven days and 30 days post-treatment, and at each of these visits neurological assessments were performed.
The study found that microplasmin was generally well tolerated with no evidence of increased bleeding risk compared to placebo. In addition, the study provided some interesting preliminary efficacy results. Approximately 25% of patients treated with microplasmin had reperfusion (restoration of blood flow) within eight hours of being treated, this compares with 10% of placebo-treated patients. Moreover, of the patients who had more severe vascular blockages, 33% of patients treated with microplasmin achieved reperfusion compared with 14% of placebo-treated patients. Due to the small number of patients in this study, neither of these end points were statistically significant. However, the study also showed that microplasmin-treated patients had a statistically significant improvement in the level of damage to the blood brain barrier compared to placebo-treated patients, measured using the marker of matrix metalloproteinase (MMP). MMP activation plays a crucial role in the pathogenesis of brain edema and hemorrhagic transformation after ischemic stroke.

ThromboGenics is now looking for a partner to continue the promising development of microplasmin for the stroke indication.

For an overview of the different trials, please visit www.clinicaltrials.gov