A novel, recombinant human thrombolytic protein, V10153 is being developed for the potential treatment of acute ischaemic stroke.
- A modified form of human plasminogen
- Only activated to plasmin by the presence of thrombin on newly formed clots
- Unique action, not seen in other thrombolytics
- Long half life allowing persistence of effect and bolus administration
V10153 is a biological molecule, first developed by one of Vernalis’s predecessor companies. V10153 is human plasminogen that has been altered so that it is activated to plasmin by thrombin, rather than by the natural plasminogen activators. This makes V10153 potentially much more location-specific than the drugs currently available to tackle ischaemic stroke, and the blood clots that are its cause.
Activation by thrombin
To deliver localised effect
Most thrombolytics are tissue plasminogen activators, and so can activate plasminogen circulating in the body. Because V10153 is a thrombolytic that is only activated by the presence of thrombin (occurring on the surface of newly formed blood clots) its effect is potentially much more localised.
V10153 has a half-life of 3-4 hours so can persist in the blood as an inactive pro-drug that can be selectively activated at fresh/forming thrombi by the thrombin localised there. A key feature of thrombin-activatable plasminogen is that thrombin is only found at the sites of ongoing clotting. This novel activation mechanism results in localised plasmin generation to remove thrombi and prevent them forming/reforming. Persistence in the circulation may also reduce re-occlusion rates.
Stroke affects the blood vessels supplying the brain and occurs when an artery ruptures or becomes blocked by a blood clot. This deprives the brain of oxygen. Nerve cells in the affected area die within minutes. A severe stroke can be fatal or can leave the victim permanently disabled, as dead brain cells cannot be replaced.
There are two main types of stroke, ischaemic stroke, caused by blockage of a blood vessel, and hemorrhagic stroke, caused by bleeding. Ischaemic stroke accounts for over 80 percent of all strokes. People of all ages, including children, suffer from stroke, and it occurs slightly more commonly in men than women.
Current therapeutic options for ischaemic stroke sufferers are limited since the only current approved therapy, recombinant tissue plasminogen activator (rt-PA), must be administered within a few hours of a stroke occurring. Stroke is the third most common cause of death, behind heart disease and cancer. The market for effective and safe stroke therapeutics is considerable.
A range of studies confirm both the thrombolytic and also the anti-thrombotic effect of V10153. It has comparable thrombolytic activity to rt-PA in inducing reperfusion of occluded arteries. It is better than rt-PA at preventing reocclusion, and achieves thrombolysis with no accompanying increase in bleeding. Thrombolytic efficacy (a summation of the ability of the agent to induce reperfusion and prevent reocclusion) was clearly seen to be superior to rt-PA. V10153 has been shown to be markedly superior to heparin as an antithrombotic.
We’ve successfully completed a number of clinical studies with V10153. These included a Phase I study in healthy volunteers, and a dose escalation Phase IIA safety study in patients with acute ischaemic stroke. We also conducted a study of patients with acute myocardial infarction. With both proof of concept as a thrombolytic and the appropriate dose to study in acute ischaemic stroke established, V10153 is ready to move to the next stage of development.
Pre-clinical studies completed by Vernalis. We’ve also completed Phase I and a number of Phase II clinical studies, again with positive results. V10153 is now ready for partnering and Vernalis welcomes expressions of interest.