Desmoteplase is a novel, highly fibrin-specific "clot-busting" (

thrombolytic Thrombolysis, also called fibrinolytic therapy, is the breakdown (lysis) of blood clots formed in blood vessels, using medication. It is used in ST elevation myocardial infarction, stroke, and in cases of severe venous thromboembolism (massive ...

) drug in development that reached

phase III clinical trials The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases ...

. The

Danish Danish may refer to: * Something of, from, or related to the country of Denmark People * A national or citizen of Denmark, also called a "Dane," see Demographics of Denmark * Culture of Denmark * Danish people or Danes, people with a Danish a ...

pharmaceutical company,

Lundbeck H. Lundbeck A/S (commonly known simply as Lundbeck) is a Danish international pharmaceutical company engaged in the research, development, manufacturing, marketing and sale of pharmaceuticals across the world. The company’s products are targe ...

, owns the worldwide rights to Desmoteplase. In 2009, two large trials (DIAS-3 and DIAS-4) were started to test it as a safe and effective treatment for patients with acute

ischaemic Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems wi ...

stroke. After disappointing results in DIAS-3, DIAS-4 was terminated, and in December 2014 Lundbeck announced that they would stop the development of desmoteplase. Desmoteplase is a recombinant form of the alpha-1 isoform of DSPA ( Desmodus rotundus salivary plasminogen activator).

Mode of action

Desmoteplase, a

chemical A chemical substance is a form of matter having constant chemical composition and characteristic properties. Some references add that chemical substance cannot be separated into its constituent elements by physical separation methods, i.e., w ...

found in the saliva of

vampire bat Vampire bats, species of the subfamily Desmodontinae, are leaf-nosed bats found in Central and South America. Their food source is blood of other animals, a dietary trait called hematophagy. Three extant bat species feed solely on blood: the ...

s, 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, the saliva of the

(''Desmodus rotundus'') was known to lead to interference with the

haemostatic An antihemorrhagic (antihæmorrhagic) agent is a substance that promotes hemostasis (stops bleeding). It may also be known as a hemostatic (also spelled haemostatic) agent. Antihemorrhagic agents used in medicine have various mechanisms of action: ...

mechanism of the host animal. In 1991, the DNA coding of four

plasminogen Plasmin is an important enzyme () present in blood that degrades many blood plasma proteins, including fibrin clots. The degradation of fibrin is termed fibrinolysis. In humans, the plasmin protein (in the zymogen form of plasminogen) is encode ...

activators present in the saliva of the

was completed. Of the four, recombinant ''D. rotundus'' salivary plasminogen activator alpha 1 (rDSPAα1; desmoteplase) was investigated further.

Chemical structure

The structure of desmoteplase is similar to rt-PA (

alteplase Alteplase (t-PA), a biosynthetic form of human tissue-type plasminogen activator (t-PA), is a thrombolytic medication, used to treat acute ischemic stroke, acute ST-elevation myocardial infarction (a type of heart attack), pulmonary embolism a ...

), but it does not contain the plasmin-sensitive cleavage site and the lysine-binding Kringle 2 domain. As a result, desmoteplase, in comparison to rt-PA, has high fibrin selectivity (100,000- v. 550-fold increase in catalytic activity), an absence of

neurotoxicity Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. It occurs when exposure to a substance – specificall ...

, and no apparent negative effect on the blood–brain barrier. Desmoteplase also has a

half-life Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable at ...

of about four hours; rtPA has a terminal plasma half-life of about 5 minutes.

Desmoteplase in acute ischaemic stroke clinical trial program

The two phase II trials DIAS and DEDAS indicated that when intravenous (IV) desmoteplase was administered three to 9 hours after onset of ischaemic

stroke symptoms A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functionin ...

, it was associated with a high rate of reperfusion and a low rate of symptomatic

intracranial The cranial cavity, also known as intracranial space, is the space within the skull that accommodates the brain. The skull minus the mandible is called the ''cranium''. The cavity is formed by eight cranial bones known as the neurocranium that in ...

haemorrhage Bleeding, hemorrhage, haemorrhage or blood loss, is blood escaping from the circulatory system from damaged blood vessels. Bleeding can occur internally, or externally either through a natural opening such as the mouth, nose, ear, urethra, v ...

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 number of patients with a mild stroke at baseline and small mismatch volumes associated with no

vessel occlusion Vascular occlusion is a blockage of a blood vessel, usually with a clot. It differs from thrombosis in that it can be used to describe any form of blockage, not just one formed by a clot. When it occurs in a major vein, it can, in some cases, cau ...

. Post hoc analyses of the DIAS-2 data and the pooled data of the DIAS, DEDAS and DIAS-2 data showed that patients who had a proximal cerebral vessel occlusion or high-grade stenosis on baseline

angiography Angiography or arteriography is a medical imaging technique used to visualize the inside, or lumen, of blood vessels and organs of the body, with particular interest in the arteries, veins, and the heart chambers. Modern angiography is perfor ...

, had a positive response for desmoteplase. In 2009, the DIAS-3 and DIAS-4 phase III trials started, each planning to enroll 400 patients worldwide who had had an acute ischaemic stroke. Participants are treated with desmoteplase as an intravenous bolus dose of 90 μg/kg within three to 9 hours after stroke symptom onset. Patients are selected with occlusion or high-grade stenosis (TIMI 0-1) in proximal cerebral

arteries An artery (plural arteries) () is a blood vessel in humans and most animals that takes blood away from the heart to one or more parts of the body (tissues, lungs, brain etc.). Most arteries carry oxygenated blood; the two exceptions are the pu ...

as assessed by magnetic resonance or computed

tomography Tomography is imaging by sections or sectioning that uses any kind of penetrating wave. The method is used in radiology, archaeology, biology, atmospheric science, geophysics, oceanography, plasma physics, materials science, astrophysics, ...

. Wherever possible, additional perfusion-weighted imaging and diffusion-weighted imaging assessments will be done. The outcomes of DIAS-3 and DIAS-4 studies should tell whether desmoteplase is a breakthrough treatment for acute ischaemic stroke. In June 2014, Lundbeck published a press release about the DIAS-3 study revealing neutral results in an intention-to-treat analysis. The proportion of patients presenting good clinical outcome was comparable in the desmoteplase group (51.3%) and in the placebo group (49.8%). Notably, Lundbeck mentioned that, when analysing per protocol, desmoteplase showed an effect relative to placebo. Publication of the final results is still awaited. After the disappointing results in DIAS-3, the DIAS-4 trial was terminated. In December 2014 Lundbeck announced they would stop the development of desmoteplase and the company made a

write-down A write-off is a reduction of the recognized value of something. In accounting, this is a recognition of the reduced or zero value of an asset. In income tax statements, this is a reduction of taxable income, as a recognition of certain expenses ...

of 309 million Danish crowns.

Significance of the time window

Current standards of treatment allow for IV rt-PA up to 4.5 hours in ischaemic stroke. After this time window, the benefit is typically thought to be outweighed by the risk of

brain haemorrhage Intracerebral hemorrhage (ICH), also known as cerebral bleed, intraparenchymal bleed, and hemorrhagic stroke, or haemorrhagic stroke, is a sudden bleeding into the tissues of the brain, into its ventricles, or into both. It is one kind of bleed ...

. Interarterial approaches are thought to be useful up to six hours. Nevertheless, CT-perfusion scans and

MRI Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio waves ...

-perfusion versus MRI-diffusion demonstrate that even after six hours a significant ischaemic penumbra of brain tissue may be salvageable. Some approaches to this involves mechanical removal of clot (for example the Merci device, the penumbra device and removable

stent In medicine, a stent is a metal or plastic tube inserted into the lumen of an anatomic vessel or duct to keep the passageway open, and stenting is the placement of a stent. A wide variety of stents are used for different purposes, from expandab ...

s like Solitaire). If desmoteplase can extend the IV treatment window to 9 hours, this would allow a much larger percentage of ischaemic stroke patients to receive active thrombolytic treatment – including patients who were delayed in getting to the hospital and neurological assessment. This could make a substantial difference in stroke outcomes. A 9-hour treatment window could also have a major impact on the treatment of "wake-up" strokes - where a patient awoke with symptoms, and is not sure whether the stroke occurred within the past 4.5 hours.

References

External links

* * {{ClinicalTrialsGov, NCT00856661, (DIAS-4) Antithrombotic enzymes Enzymes used as drugs