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Desmoteplase in Stroke Scientific Background & Protocol

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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
Agenda Desmoteplase Compound and nonclinical data Previous stroke studies DIAS/DEDAS DIAS-2 Post-hoc analyses & rationale for DIAS-3/DIAS-4

3 Desmoteplase: Where from?
Plasminogen activator (DSPA1) From the saliva of the vampire bat Desmodus rotundus living in South America Food source: Blood from mammals ‘Victims‘ blood should be prevented from the natural clotting response

4 Fibrinolysis Cascade

5 Structure Desmoteplase has 72% structural homology to human t-PA (Alteplase) Essential Difference: Absence of Kringle 2 in desmoteplase Desmoteplase Alteplase P P K1 K2 EGF K1 EGF F F

6 Tissue Plasminogen Activator – Mechanism of Action
rt-PA Cleavage rt-PA Plasmin ogen Fibrin

7 Tissue Plasminogen Activator – Mechanism of Action
rt-PA rt-PA Intrinsic activity PDGF-CC rt-PA Plasmin ogen Other scaffolds (e.g. endothelial annexin II) Cleavage Various targets ...blood brain barrier rt-PA Plasmin ogen Plasmin Fibrin

8 SAE Related to rt-PA Use in Acute Isehcmic Stroke
Disrupts the BBB Neurotoxic Β-amyloid activates rt-PA

9 Desmoteplase: No physiological function in humans
Cleavage ogen ogen DSPA Plasmin ogen Plasmin Fibrin

10 Desmoteplase advantages
Potential Advantages Alteplase Desmoteplase Desmoteplase advantages Administration time after stroke onset 0-3h 3-9h Broader time-window larger patient potential Neurotoxicity Yes No Survival of brain tissue Fibrin selectivity Fibrin specificity BBB damage 72x over Fibrinogen 550x over absence 12,900x over Fibrinogen 105,000x over absence Lower bleeding risk Activation by ß-Amyloid Lower bleeding risk in the elderly Administration i.v. infusion Single bolus, i.v. Ease of administration Half life 3-5 min About 4.5h Positive 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 Alteplase Easier to administer Long half-life

12 Previous stroke studies
Agenda Desmoteplase Compound and nonclinical data Previous stroke studies DIAS/DEDAS DIAS-2 Post-hoc analyses & rationale for DIAS-3/DIAS-4

13 Desmoteplase in Stroke Studies: Overview
>20% Penumbra (MRI or CT) NIHSS: 4-24 Age: 18-85 90, 125 µg/kg + Placebo Phase III Confirmatory n= 186 DIAS-2 (2009) >20% Penumbra (MRI) NIHSS 4-20 Phase II Dose-finding n= 37 DEDAS (2006) NIHSS: 4-20 Part 1: 25, 37.5, 50 mg Part 2: 62.5, 90, 125 µg/kg+ Placebo Dose-finding n= 102 DIAS (2005) Inclusion Doses Phase & Sample size Study

14 DIAS/DEDAS: Promising results
Recovery = D90 mRS 0-2 8 n=

15 DIAS-2: Unexpected results (1)
8 n=

16 DIAS-2: Unexpected results (2)
DIAS/DEDAS Low 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 groups 125 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 h n (%) 2 (3.5%)* 1 (1.5%) sICH within 72 h 3 (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 group Causes: Index stroke (incl. 3 sICH) 4 cases Recurrent stroke and its complications 4 cases Miscellaneous (others) 6 cases Related to study drug: 3 sICH (related) 1 recurrent stroke (unlikely related)

20 Mortality Conclusions
Overall Day 90 mortality in line with reports No 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
Placebo 90 µg/kg 125 µg/kg n % Presence of ICH or SAH 0.0 1 1.8 AV malformation, cerebral aneurysm or cerebral neoplasm 1.6 No distinct penumbra of at least 20% 8 12.7 6 10.5 9 13.6 Extensive early infarction 2 3.2 3 5.3 1.5 No infarct or no ischemia 4.8 4.5 Baseline glucose >200 mg/dl and no post-anti-diabetic medical treatment performed Baseline glucose  200 mg/dl and a post-anti-diabetic med’s glucose of  200 mg/dl Baseline systolic blood pressure >185 Baseline diastolic blood pressure >110

22 Efficacy Per Protocol analysis: ITT vs. PP Population
Sample Size Responder Rate (%) Placebo 63 46.0 50 90 µg/kg 57 47.4 43 46.5 125 µg/kg 66 36.4 53 39.6 Sample size decreased but overall outcome identical

23 DIAS/DEDAS & DIAS-2: Were they different?
Placebo 90 µg/kg 125 µg/kg DIAS/ DEDAS DIAS-2 DIAS/ DEDAS BL NIHSS median 12 9 11 BL Lesion Volume (cc, median) 24 28 8 22 3-6h post stroke (%) 66 99 320 59 41 49 478 27 21 114 393 54 33 52 506 26 63 130 241 36 531 Absolute Mismatch Volume (cc, median) Relative Mismatch (%, median) BL TIMI 0-1 (%)

24 TIMI Grading in DIAS 4 CT angiography MR angiography
0 = Complete occlusion represented by lack of contrast filling of a vascular segment 1 = 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 vessels 1 = 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/DEDAS Large Vessel Patency (TIMI) Mismatch volume Small 3 4 24 Stroke severity (NIHSS) .

26 Does desmoteplase have an effect?
DIAS-2 TIMI 0-1 TIMI 2-3 Responder Rate (mRS 0-2) % Placebo 18 56.0 90 µg/kg 36 50.0 125 µg/kg 27 40.0 .

27 Clinical response in TIMI 0-1 patients: DIAS/DEDAS vs DIAS-2
Absolute effect 90 µg/kg: 22% * *

28 Mismatch versus Vessel Occlusion: DIAS-2
33% No MM 15% 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 penumbra Seemingly infarct growth occurs with equal probability in patients with and without mismatch No 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 effect Selecting and treating patients based on presence of occlusion/stenosis is a biologically plausible and more practical Albers 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 treatment choosing 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.


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