Desmoteplase

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Salivary plasminogen activator alpha 1
UniProt
P98119
Other data
EC number3.4.21.68
ChromosomeUnplaced: 1.98 - 2.01 Mb
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Desmoteplase is a novel, highly

ischaemic 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.[1]

Desmoteplase is a

Desmodus rotundus
salivary plasminogen activator).

Mode of action

Desmoteplase, a

chemical found in the saliva of vampire bats
, 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

plasminogen activators present in the saliva of the vampire bat was completed. Of the four, recombinant D. rotundus salivary plasminogen activator alpha 1 (rDSPAα1; desmoteplase) was investigated further.[3]

Chemical structure

The structure of desmoteplase is similar to rt-PA (

half-life of about four hours;[4]
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

vessel occlusion.[7] 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, had a positive response for desmoteplase.[8]

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

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 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.[9] 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.[10] In December 2014 Lundbeck announced they would stop the development of desmoteplase and the company made a

write-down of 309 million Danish crowns.[1]

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

MRI-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 stents like Solitaire).[12][13]

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

  1. ^
    H Lundbeck A/S (2014-12-18). "BRIEF-Lundbeck discontinues development of desmoteplase and narrows 2014 profit guidance"
    . Reuters.
  2. PMID 6075437
    .
  3. PMID 11910176
    .
  4. PMID 21627637
    .
  5. PMID 15569863
    .
  6. PMID 16574922
    .
  7. PMID 19097942
    .
  8. PMID 22474060
    .
  9. ^ "Lundbeck provides update on the development program for desmoteplase". 27 June 2014. Archived from the original on 1 August 2014.
  10. ^ Clinical trial number NCT00856661 for "Efficacy and Safety Study of Desmoteplase to Treat Acute Ischemic Stroke (DIAS-4)" at ClinicalTrials.gov
  11. PMID 20472172
    .
  12. PMID 23626646
    .
  13. PMID 22454778
    .

External links
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