Desmoteplase
Encyclopedia
Desmoteplase is a novel, highly fibrin-specific thrombolytic agent in phase III of clinical development. In 2009, 2 large trials (DIAS-3 and DIAS-4) were started, and the results of these studies will determine whether desmoteplase will gain marketing authorization as a safe and effective treatment for patients with acute ischaemic stroke. Filing with health authorities is estimated in the second quarter of 2012. The Danish
pharmaceutical company, H. Lundbeck
A/S (commonly known as Lundbeck
), owns the worldwide rights to desmoteplase.
of vampire bat
s that has the effect of catalysing the conversion of plasminogen to plasmin, which is the enzyme responsible for breaking down fibrin blood clots.
of the vampire bat
(Desmodus rotundus) leads to interference with the haemostatic mechanism of the host animal. In 1991, the DNA coding of 4 plasminogen activators present in the saliva of the vampire bat
was completed. Of the 4 plasminogen activators, recombinant Desmodus rotundus salivary plasminogen activator alpha 1 (rDSPAα1; desmoteplase) was investigated further.
, and no apparent negative effect on the blood-brain barrier. Desmoteplase also has a half-life of about 4 hours; rtPA (alteplase) has a terminal plasma half-life of about 5 minutes.
on baseline angiography, then a positive response for desmoteplase was shown.
In 2009, the DIAS-3 and DIAS-4 phase III trials started, each planning to enrol 400 patients worldwide who had had an acute ischaemic stroke. Participants will be treated with desmoteplase as an intravenous bolus dose of 90 µg/kg within 3 to 9 hours after stroke symptom onset. Patients are selected with occlusion or high-grade stenosis (TIMI 0-1) in proximal cerebral arteries as assessed by magnetic resonance or computed tomography
angiography. Wherever possible, additional perfusion-weighted imaging and diffusion-weighted imaging assessments will be done.
The outcomes of DIAS-3 and DIAS-4 studies will tell whether desmoteplase is a breakthrough treatment for acute ischaemic stroke.
stroke (ECASS-3 Study NEJM 2008). After this time window, the benefit is typically thought to
be outweighed by the risk of brain hemorhage. Interarterial approaches are thought to be useful
up to 6 hours. Nevertheless, CT-Perfusion scans,
and MRI-Perfusion (think Penumbra) versus MRI-Diffusion (think "dead" brain),
demonstrate that even after 6 hours there can sometimes be a significant
ischemic penumbra of brain tissue that may be salvageable. Some approaches
to this involves mechanical removal of clot (for example the : Merci
device,
the Penumbra device and removable stents). Many stroke patients present with
a stroke upon waking. It is unclear how much time has elapsed since onset of their
stroke so they may be beyond the time window for rTPA. (Studies are underway
to specifically examine rTPA treatment of wake-up strokes of unknown onset).
(Other approaches use perfusion imaging (CT-Perfusion,or MRI-Perfusion versus DWI)
to directly decide on whether to thrombolyse, but this approach has not been confirmed
by a large scale RCT).
IF desmoteplase can extend the IV treatment window to 9 hours, this would
allow a much larger percentage of ischemic stroke patients to receive active
thrombolytic treatment - including patients with "wake-up" strokes, and patient
who were delayed in getting to the hospital and neurological assessment.
This could make a substantial difference in stroke outcomes.
Denmark
Denmark is a Scandinavian country in Northern Europe. The countries of Denmark and Greenland, as well as the Faroe Islands, constitute the Kingdom of Denmark . It is the southernmost of the Nordic countries, southwest of Sweden and south of Norway, and bordered to the south by Germany. Denmark...
pharmaceutical company, H. Lundbeck
Lundbeck
H. Lundbeck A/S is a Danish international pharmaceutical company engaged in the research and development, production, marketing, and sale of drugs for the treatment of disorders in the central nervous system , including depression, schizophrenia, Alzheimer’s disease, Parkinson’s disease,...
A/S (commonly known as Lundbeck
Lundbeck
H. Lundbeck A/S is a Danish international pharmaceutical company engaged in the research and development, production, marketing, and sale of drugs for the treatment of disorders in the central nervous system , including depression, schizophrenia, Alzheimer’s disease, Parkinson’s disease,...
), owns the worldwide rights to desmoteplase.
Mode of action
Desmoteplase is a chemical found in the salivaSaliva
Saliva , referred to in various contexts as spit, spittle, drivel, drool, or slobber, is the watery substance produced in the mouths of humans and most other animals. Saliva is a component of oral fluid. In mammals, saliva is produced in and secreted from the three pairs of major salivary glands,...
of vampire bat
Vampire bat
Vampire bats are bats whose food source is blood, a dietary trait called hematophagy. There are three bat species that feed solely on blood: the Common Vampire Bat , the Hairy-legged Vampire Bat , and the White-winged Vampire Bat .All three species are native to the Americas, ranging from Mexico to...
s that has the effect of catalysing the conversion of plasminogen to plasmin, which is the enzyme responsible for breaking down fibrin blood clots.
Discovery of desmoteplase
As early as in 1932, it was known that the salivaSaliva
Saliva , referred to in various contexts as spit, spittle, drivel, drool, or slobber, is the watery substance produced in the mouths of humans and most other animals. Saliva is a component of oral fluid. In mammals, saliva is produced in and secreted from the three pairs of major salivary glands,...
of the vampire bat
Vampire bat
Vampire bats are bats whose food source is blood, a dietary trait called hematophagy. There are three bat species that feed solely on blood: the Common Vampire Bat , the Hairy-legged Vampire Bat , and the White-winged Vampire Bat .All three species are native to the Americas, ranging from Mexico to...
(Desmodus rotundus) leads to interference with the haemostatic mechanism of the host animal. In 1991, the DNA coding of 4 plasminogen activators present in the saliva of the vampire bat
Vampire bat
Vampire bats are bats whose food source is blood, a dietary trait called hematophagy. There are three bat species that feed solely on blood: the Common Vampire Bat , the Hairy-legged Vampire Bat , and the White-winged Vampire Bat .All three species are native to the Americas, ranging from Mexico to...
was completed. Of the 4 plasminogen activators, recombinant Desmodus rotundus salivary plasminogen activator alpha 1 (rDSPAα1; desmoteplase) was investigated further.
Chemical structure
The structure of desmoteplase is similar to rtPA (alteplase), but it does not contain the plasmin-sensitive cleavage site and the lysine-binding Kringle 2 domain. As a result, desmoteplase, in comparison to rtPA, has high fibrin selectivity (100,000- v. 550-fold increase in catalytic activity), an absence of neurotoxicityNeurotoxicity
Neurotoxicity occurs when the exposure to natural or artificial toxic substances, which are called neurotoxins, alters the normal activity of the nervous system in such a way as to cause damage to nervous tissue. This can eventually disrupt or even kill neurons, key cells that transmit and process...
, and no apparent negative effect on the blood-brain barrier. Desmoteplase also has a half-life of about 4 hours; rtPA (alteplase) has a terminal plasma half-life of about 5 minutes.
Desmoteplase in Acute Ischaemic Stroke (DIAS) clinical trial program
The 2 phase II trials DIAS and DEDAS indicated that when intravenous desmoteplase was administered 3 to 9 hours after onset of ischaemic stroke symptoms, it was associated with a high rate of reperfusion and a low rate of symptomatic intracranial haemorrhage at doses up to 125 µg/kg. In the subsequent DIAS-2 trial, the same benefit could not be shown. This could be explained by the inclusion of a substantial amount of patients with a mild stroke at baseline and small mismatch volumes associated with no vessel occlusion. Post hoc analyses of the DIAS-2 data showed that when patients had a proximal cerebral vessel occlusion or high-grade stenosisStenosis
A stenosis is an abnormal narrowing in a blood vessel or other tubular organ or structure.It is also sometimes called a stricture ....
on baseline angiography, then a positive response for desmoteplase was shown.
In 2009, the DIAS-3 and DIAS-4 phase III trials started, each planning to enrol 400 patients worldwide who had had an acute ischaemic stroke. Participants will be treated with desmoteplase as an intravenous bolus dose of 90 µg/kg within 3 to 9 hours after stroke symptom onset. Patients are selected with occlusion or high-grade stenosis (TIMI 0-1) in proximal cerebral arteries as assessed by magnetic resonance or computed tomography
Tomography
Tomography refers to imaging by sections or sectioning, through the use of any kind of penetrating wave. A device used in tomography is called a tomograph, while the image produced is a tomogram. The method is used in radiology, archaeology, biology, geophysics, oceanography, materials science,...
angiography. Wherever possible, additional perfusion-weighted imaging and diffusion-weighted imaging assessments will be done.
The outcomes of DIAS-3 and DIAS-4 studies will tell whether desmoteplase is a breakthrough treatment for acute ischaemic stroke.
Significance of the 3 to 9 hour time window : Wake-up strokes.
Current standards of treatment allow for IV rTPA up to 4.5 hours in ischemicstroke (ECASS-3 Study NEJM 2008). After this time window, the benefit is typically thought to
be outweighed by the risk of brain hemorhage. Interarterial approaches are thought to be useful
up to 6 hours. Nevertheless, CT-Perfusion scans,
and MRI-Perfusion (think Penumbra) versus MRI-Diffusion (think "dead" brain),
demonstrate that even after 6 hours there can sometimes be a significant
ischemic penumbra of brain tissue that may be salvageable. Some approaches
to this involves mechanical removal of clot (for example the : Merci
Merci
Merci is a Czech company selling and manufacturing laboratory equipment, devices, and many other things used in laboratories, like hoods, glassware, chemicals.It is also a huge laboratory furniture producer....
device,
the Penumbra device and removable stents). Many stroke patients present with
a stroke upon waking. It is unclear how much time has elapsed since onset of their
stroke so they may be beyond the time window for rTPA. (Studies are underway
to specifically examine rTPA treatment of wake-up strokes of unknown onset).
(Other approaches use perfusion imaging (CT-Perfusion,or MRI-Perfusion versus DWI)
to directly decide on whether to thrombolyse, but this approach has not been confirmed
by a large scale RCT).
IF desmoteplase can extend the IV treatment window to 9 hours, this would
allow a much larger percentage of ischemic stroke patients to receive active
thrombolytic treatment - including patients with "wake-up" strokes, and patient
who were delayed in getting to the hospital and neurological assessment.
This could make a substantial difference in stroke outcomes.