Thrombotic Disease: V10153
Summary
V10153 is a novel thrombolytic protein which is being developed for the treatment of acute ischaemic stroke. Ischaemic stroke is the most common type of stroke, accounting for over 80 per cent of all strokes and occurs when a blood clot forms and blocks blood flow in an artery supplying blood to a part of the brain (as distinct from a haemorrhagic stroke which is caused by bleeding). Current therapeutic options for stroke sufferers are limited since the only current approved therapy, recombinant tissue plasminogen activator (rtPA), must be administered within the first three hours after a stroke has occurred.
Vernalis has conducted a multi-centre Phase IIa clinical study of V10153 to determine whether this novel thrombolytic can safely benefit patients who have recently experienced an acute ischaemic stroke if administered up to nine hours after the stroke has occurred. The study has successfully identified 5mg/kg as a safe and potentially efficacious dose of V10153 to be evaluated in future studies.
Trials undertaken to date demonstrate that V10153’s safety profile has the potential to extend thrombolytic treatment in the other major thrombotic diseases, including AMI, peripheral arterial occlusion, pulmonary embolism and deep vein thrombosis. Each of these is under-treated because of the risk of induction of bleeding, and particularly intracranial haemorrhage (ICH) in the case of stroke, by treatment with current thrombolytic agents.
Vernalis contracted the process development, scale-up and cGMP manufacturing of V10153 to Diosynth Biotechnology who have now completed drug substance manufacturing for use in the Phase III stroke trials.
Vernalis retains world-wide right to V10153.
Background
Stroke is a leading cause of death and long-term disability in the developed world. According to the American Heart Association, stroke accounts for more than one in every fifteen deaths in the United States and ranks no 3 amongst all causes of death, behind diseases of the heart and cancer. It is a public health problem that costs the U.S. healthcare system over $50B each year with more than two million strokes occurring each year in the world's major industrialised countries, about 750,000 of which occur in the U.S.
The leading product for stroke is rtPA, which, due to its treatment restrictions, is used to treat fewer than 5% of stroke patients in the US annually, accounting for approximately $200 million in annual sales. A drug with an extended window of opportunity that can be administered up to 9 hours after stroke without significant safety concerns could be used to treat a substantially broader population of stroke victims.
Stroke affects the blood vessels that supply blood to the brain and occurs when a blood vessel that brings oxygen and nutrients to the brain bursts or is blocked by a blood clot. This deprives the brain of oxygen and nerve cells in the affected area of the brain die within minutes. The devastating effects of a severe stroke are often permanent as dead brain cells are not replaced.
There are two main types of stroke, ischemic stroke which is caused by blockage of a blood vessel, and hemorrhagic stroke which is caused by bleeding. Ischemic stroke is the most common type and accounts for over 80 percent of all strokes. It occurs when a blood clot (thrombus) forms and blocks blood flow in an artery bringing blood to part of the brain. Blood clots usually form in arteries damaged by fatty build-ups (atherosclerosis). People of all ages, including children, suffer from stroke, and it occurs slightly more commonly in men than women.
V10153
V10153 is a modified version of human plasminogen which has been altered so that it is activated to plasmin by thrombin, rather than by the natural plasminogen activators. Thrombin-activatable plasminogen is a new approach to thrombolysis in which thrombin, the key enzyme involved in blood clot formation, is utilised to initiate clot destruction (Dawson et al). Although the coagulation cascade and the fibrinolytic systems are functionally separate, thrombin-activatable plasminogen circumvents the physiological haemostatic mechanisms and selectively induces lysis of newly forming thrombi, effectively hijacking the natural blood clotting system to initiate the destruction of blood clots.
V10153 has a half-life of 3-4 hours which enables it to persist in the blood as an inactive pro-drug which can be selectively activated at fresh/forming thrombi by the thrombin which is localised there. A key feature of the thrombin-activatable plasminogen concept is that it takes advantage of the fact that active 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. Therefore, in addition to lysis of an existing thrombus, V10153 may reduce the re-occlusion rates.
The anticipated clinical profile of V10153 is compared below against that of the "ideal" thrombolytic and three of the currently marketed agents. If the potential of V10153 is fulfilled it will have significant advantages over the competition and go a long way towards the profile of the "ideal".
|
rt-PA |
SK |
reteplase |
"ideal" |
V10153 | |
|---|---|---|---|---|---|
|
Efficacy | |||||
| Induction of reperfusion |
++++ |
+++ |
+++/+ |
+++++ |
++++ |
| Reocclusion |
Yes |
Yes |
Yes |
No |
No/Reduced |
|
Safety | |||||
|---|---|---|---|---|---|
| Haemorrhage/ICH |
Yes |
Yes |
Yes |
No |
No/Reduced |
|
Pharmacokinetics | |||||
|---|---|---|---|---|---|
| Bolus dosing |
No |
No |
Yes |
Yes |
Yes |
| Prolonged activity (hours) |
No |
No |
No |
Yes |
Yes |
| Antigenicity |
No |
Yes |
No |
No |
No |
Pre-clinical Studies
V10153 has comparable thrombolytic activity to rt-PA in inducing reperfusion of occluded arteries. However, it is markedly superior in preventing reocclusion, and achieved thrombolysis without an 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 markedly superior efficacy as an antithrombotic than heparin, especially in arterial thrombosis. Additional advantages are bolus administration and thrombus selectivity, the latter resulting in antithrombotic activity without bleeding.
Clinical Studies
V10153 was initially evaluated in a typical escalating dose safety study, tolerability and PK study in healthy volunteers. Safety was good at all dose levels tested (up to 4.8 mg/kg) and the half life was confirmed to be 3-4 hours. It was then tested by a consortium of cardiologists in the US and Europe (the TIMI Study Group) in a Phase IIa ascending-dose study to establish proof-of concept (i.e. that it can dissolve clots and restore coronary bloodflow) in patients who have suffered acute myocardial infarction (AMI). Data showed that V10153 was well tolerated throughout the dose range of 1–10 mg/kg in patients with AMI. Restoration of bloodflow was observed in blocked coronary arteries in up to 40 per cent of patients after 60 minutes following doses of 5 mg/kg and greater. These results are comparable to the efficacy reported for other marketed thrombolytic therapies using a similar experimental protocol. V10153 was found to be safe in the range of doses tested.
Vernalis has subsequently completed a multi-centre Phase IIa clinical study of V10153 to determine whether this novel thrombolytic can safely benefit patients who have recently experienced an acute ischaemic stroke if administered up to nine hours after the stroke has occurred. The study was designed to identify a safe and potentially efficacious dose of V10153.
Patients with ischaemic stroke who presented at the trial centres within the permitted timeframe were assessed for eligibility in the study. Patients who would potentially benefit from therapy and who had an identifiable blockage in a cerebral blood vessel, assessed by CT angiogram, receive a single bolus injection of V10153. Two hours later the effects of the drug on the patency of the vessel were assessed by a repeat scan, with the aim of identifying whether blood flow had been restored. Patients were monitored intensively for 48 hours, and thereafter for 3 months during which time their recovery is assessed. The study was the first to employ serial CT angiograms to assess the potential efficacy of a novel thrombolytic drug.
A Drug Safety Monitoring Board comprising two independent physicians and a statistician was convened to provide an ongoing review of safety during the trial and to advise on dose progression.
Four dose levels (1 mg/kg; 2.5 mg/kg; 5 mg/kg and 7.5 mg/kg) have been completed and a total of 49 patients have been treated. Ten patients received each of the first two dose levels of 1 mg/kg and 2.5 mg/kg and 20 patients received the third dose level of 5 mg/kg. Nine patients received the top dose level of 7.5 mg/kg of which three experienced a clinically significant bleed. Although such bleeds occur relatively frequently in ischaemic stroke patients, the possibility that the bleeds were treatment-related cannot be ruled out. It has been agreed, in consultation with the Study Steering Committee and Data Safety Monitoring Board, that the study has met its objectives and consequently enrolment in the study has been closed.
The Data Safety Monitoring Board has confirmed that the 5mg/kg dose is safe and well tolerated. Several patients at this dose level have demonstrated positive clinical outcomes with those patients who entered the trial with better prognostic characteristics, such as those that were treated earlier and/or those with smaller clots, responded particularly well to V10153.