Desmoteplase

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.

Mode of action

Desmoteplase is a chemical found in the saliva of vampire bats 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 saliva of the vampire bat (Desmodus rotundus) leads to interference with the haemostatic mechanism of the host animal.^[1] 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.^[2]

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 neurotoxicity, and no apparent negative effect on the blood-brain barrier. Desmoteplase also has a half-life of about 4 hours;^[3] 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.^[4][5] 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 stenosis on baseline angiography, then a positive response for desmoteplase was shown.^[6]

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.

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 ischemic 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.

External links

• ClinicalTrials.gov (DIAS-3)
• ClinicalTrials.gov (DIAS-4)
• Review article about stroke

References

1. ^ "Hawkey C. Inhibitor of platelet aggregation present in saliva of the vampire bat Desmodus rotundus. Br J Haematol.1967;13(6):1014-20.". 
2. ^ "Schleuning WD. Vampire Bat plasminogen activator DSPA-alpha-1 (desmoteplase): a thrombolytic drug optimized by natural selection. Haemostasis. 2001;31(3-6):118-122.". 
3. ^ "Paciaroni M, Medeiros E, Bogousslavsky J. Desmoteplase. Expert Opin Biol Ther. 2009;9(6):773-778.". 
4. ^ "Hacke W, Albers G, Al Rawi Y, et al. The Desmoteplase in Acute Ischemic Stroke Trial (DIAS): a phase II MRI-based 9-hour window acute stroke thrombolysis trial with intravenous desmoteplase. Stroke. 2005;36(1):66-73.". 
5. ^ "Furlan AJ, Eyding D, Albers G. W, et al. Dose Escalation of Desmoteplase for Acute Ischemic Stroke (DEDAS): evidence of safety and efficacy 3 to 9 hours after stroke onset. Stroke. 2006;37(5):1227-1231.". 
6. ^ "Hacke W, Furlan AJ, Al Rawi Y, et al. Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion-diffusion weighted imaging or perfusion CT (DIAS-2): a prospective, randomised, double-blind, placebo-controlled study. Lancet Neurol. 2009(2):141-150.".