Presentation on theme: "Desmoteplase in Stroke Scientific Background & Protocol"— Presentation transcript:
1 Desmoteplase in Stroke Scientific Background & Protocol H. Lundbeck A/S slide 1
2 Previous stroke studies AgendaDesmoteplaseCompound and nonclinical dataPrevious stroke studiesDIAS/DEDASDIAS-2Post-hoc analyses & rationale for DIAS-3/DIAS-4
3 Desmoteplase: Where from? Plasminogen activator (DSPA1)From the saliva of the vampire bat Desmodus rotundus living in South AmericaFood source: Blood from mammals‘Victims‘ blood should be prevented from the natural clotting response
8 SAE Related to rt-PA Use in Acute Isehcmic Stroke Disrupts the BBBNeurotoxicΒ-amyloid activates rt-PA
9 Desmoteplase: No physiological function in humans CleavageogenogenDSPAPlasminogenPlasminFibrin
10 Desmoteplase advantages Potential AdvantagesAlteplaseDesmoteplaseDesmoteplase advantagesAdministration time after stroke onset0-3h3-9hBroader time-window larger patient potentialNeurotoxicityYesNoSurvival of brain tissueFibrin selectivityFibrin specificityBBB damage72x over Fibrinogen550x over absence12,900x over Fibrinogen105,000x over absenceLower bleeding riskActivation byß-AmyloidLower bleeding risk in the elderlyAdministrationi.v. infusionSingle bolus, i.v.Ease of administrationHalf life3-5 minAbout 4.5hPositive impact on re-occlusion rate and formation of micro-emboli
11 Summary - Desmoteplase Desmoteplase may have advantages over rtPA (Alteplase)Data suggest that Desmoteplase is a safer compound compared with AlteplaseEasier to administerLong half-life
12 Previous stroke studies AgendaDesmoteplaseCompound and nonclinical dataPrevious stroke studiesDIAS/DEDASDIAS-2Post-hoc analyses & rationale for DIAS-3/DIAS-4
16 DIAS-2: Unexpected results (2) DIAS/DEDASLow response of 125 µg/kg desmoteplase (36% versus 60%)High placebo response (46% vs %)Overall mortality rate (11.3 %) in line with rates in stroke. However, mortality in 125 µg/kg was higher than in other groups125 µg/kg: 21%90 µg/kg: 5%Placebo: 6%DIAS-2
17 Symptomatic ICH DIAS-2 Desmoteplase Placebo n=63 90 g/kg n=57 sICH within 24 hn (%)2 (3.5%)*1 (1.5%)sICH within 72 h3 (4.5%)* One patient had baseline ICH present prior to receiving study medication
18 Mortality over time DIAS-2 10 of 14 unrelated (Investigator assessment)10 of 14 late (after day 10)
19 Adjudication by DMC and SC Chairs 14 deaths in the 125 µg/kg groupCauses:Index stroke (incl. 3 sICH) 4 casesRecurrent stroke and its complications 4 casesMiscellaneous (others) 6 casesRelated to study drug:3 sICH (related)1 recurrent stroke (unlikely related)
20 Mortality Conclusions Overall Day 90 mortality in line with reportsNo complete explanation for relatively higher death rate in the 125 µg/kg group compared to the other 2 study groups
21 Major Protocol Violations DIAS-2 Placebo90 µg/kg125 µg/kgn%Presence of ICH or SAH0.011.8AV malformation, cerebral aneurysm or cerebral neoplasm1.6No distinct penumbra of at least 20%812.7610.5913.6Extensive early infarction188.8.131.52No infarct or no ischemia4.84.5Baseline glucose >200 mg/dl and no post-anti-diabetic medical treatment performedBaseline glucose 200 mg/dl and a post-anti-diabetic med’s glucose of 200 mg/dlBaseline systolic blood pressure >185Baseline diastolic blood pressure >110
22 Efficacy Per Protocol analysis: ITT vs. PP Population Sample SizeResponder Rate (%)Placebo6346.05090 µg/kg5747.44346.5125 µg/kg6636.45339.6Sample size decreased but overall outcome identical
24 TIMI Grading in DIAS 4 CT angiography MR angiography 0 = Complete occlusion represented by lack of contrast filling of a vascular segment1 = Near complete occlusion represented by a severe or critical stenosis of a vascular segment. This assessment is independent of distal flow characteristics.2 = Mild to moderate stenosis of a vascular segment, with normal distal flow.3 = Normal open vascular segments. MR angiography 0 = Complete occlusion represented by lack of flow signal of a vascular segment and distal vessels1 = Near complete occlusion represented by a severe or critical stenosis of a vascular segment. Distal to stenosis there is significantly reduced flow signal.2 = Mild to moderate stenosis of a vascular segment, with normal distal flow signal.3 = Normal open vascular segments
25 Shift in overall pattern of study populations DIAS DIAS/DEDASLargeVessel Patency (TIMI)MismatchvolumeSmall3424Stroke severity (NIHSS).
26 Does desmoteplase have an effect? DIAS-2TIMI 0-1TIMI 2-3Responder Rate(mRS 0-2)%Placebo1856.090 µg/kg3650.0125 µg/kg2740.0.
27 Clinical response in TIMI 0-1 patients: DIAS/DEDAS vs DIAS-2 Absolute effect90 µg/kg: 22%**
28 Mismatch versus Vessel Occlusion: DIAS-2 33% No MM15% No MM
29 Patients without penumbra: Lyse/Do not lyse? Studies investigating patients with versus without penumbra up to 6-9hrs (DEFUSE, EPITHET, DIAS-2) did not show a worse outcome in those without penumbraSeemingly infarct growth occurs with equal probability in patients with and without mismatchNo agreement on how to identify penumbra: Which method? Which perfusion threshold? Which volume is relevant?Inclusion on penumbra does not ensure ’a clot’ for a thrombolytic agent to exert its effectSelecting and treating patients based on presence of occlusion/stenosis is a biologically plausible and more practicalAlbers et al. 2006; Ann Neurol 60:508–517; Davis et al. 2008; Lancet Neurol 7:299–309; Rivers et al. 2006; Stroke 37:
30 Therefore…In DIAS 3 and DIAS 4 we enrol patients with proximal cerebral vessel occlusion or high grade stenosis and will ensure safety by:limiting the size of the core infarct (<1/3 MCA territory)using a product with possibly better safety profile than standard treatmentchoosing desmoteplase 90 µg/kg which showed the best benefit/risk profile in the previous studies
31 Lundbeck has obtained worldwide rights to desmoteplase from PAION AG in Germany. PAION has been supporting in the planning of the DIAS 3&4 trials.