Presentation is loading. Please wait.

Presentation is loading. Please wait.

H. Lundbeck A/S slide 1 Desmoteplase in Stroke Scientific Background & Protocol.

Similar presentations


Presentation on theme: "H. Lundbeck A/S slide 1 Desmoteplase in Stroke Scientific Background & Protocol."— Presentation transcript:

1 H. Lundbeck A/S slide 1 Desmoteplase in Stroke Scientific Background & Protocol

2 Investigator Meeting DIAS-4, Chicago, 2011 Agenda Desmoteplase –Compound and nonclinical data Previous stroke studies –DIAS/DEDAS –DIAS-2 –Post-hoc analyses & rationale for DIAS- 3/DIAS-4

3 Investigator Meeting DIAS-4, Chicago, 2011 Desmoteplase: Where from? Plasminogen activator (DSPA1) 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 Investigator Meeting DIAS-4, Chicago, 2011 Fibrinolysis Cascade

5 Investigator Meeting DIAS-4, Chicago, 2011 Structure AlteplaseDesmoteplase Desmoteplase has 72% structural homology to human t-PA (Alteplase) Essential Difference: Absence of Kringle 2 in desmoteplase K2 EGF K1 P P F F

6 Investigator Meeting DIAS-4, Chicago, 2011 rt-PA Cleavage Fibrin Plasmin ogen rt-PA Tissue Plasminogen Activator – Mechanism of Action

7 Investigator Meeting DIAS-4, Chicago, 2011 rt-PA Cleavage Fibrin Plasmin ogen Intrinsic activity Plasmin ogen rt-PA Other scaffolds (e.g. endothelial annexin II) Plasmin rt-PA PDGF-CC Various targets...blood brain barrier Tissue Plasminogen Activator – Mechanism of Action

8 Investigator Meeting DIAS-4, Chicago, 2011 SAE Related to rt-PA Use in Acute Isehcmic Stroke Disrupts the BBB Neurotoxic Β-amyloid activates rt-PA

9 Investigator Meeting DIAS-4, Chicago, 2011 Fibrin ogen Plasmin DSPA Plasmin ogen Cleavage Desmoteplase: No physiological function in humans

10 Investigator Meeting DIAS-4, Chicago, 2011 Potential Advantages AlteplaseDesmoteplaseDesmoteplase advantages Administration time after stroke onset 0-3h3-9hBroader time-window larger patient potential Neurotoxicity YesNoSurvival of brain tissue Fibrin selectivity Fibrin specificity BBB damage 72x over Fibrinogen 550x over absence Yes 12,900x over Fibrinogen 105,000x over absence No Lower bleeding risk Activation by ß-Amyloid YesNoLower bleeding risk in the elderly Administration i.v. infusionSingle bolus, i.v.Ease of administration Half life 3-5 minAbout 4.5hPositive impact on re-occlusion rate and formation of micro-emboli

11 Investigator Meeting DIAS-4, Chicago, 2011 Summary - Desmoteplase 1.Desmoteplase may have advantages over rtPA (Alteplase) 2.Data suggest that Desmoteplase is a safer compound compared with Alteplase 3.Easier to administer 4.Long half-life

12 Investigator Meeting DIAS-4, Chicago, 2011 Agenda

13 Investigator Meeting DIAS-4, Chicago, 2011 Desmoteplase in Stroke Studies: Overview >20% Penumbra (MRI or CT) NIHSS: 4-24 Age: , 125 µg/kg + Placebo Phase III Confirmatory n= 186 DIAS-2 (2009) >20% Penumbra (MRI) NIHSS 4-20 Age: , 125 µg/kg + Placebo Phase II Dose-finding n= 37 DEDAS (2006) >20% Penumbra (MRI) NIHSS: 4-20 Age: Part 1: 25, 37.5, 50 mg Part 2: 62.5, 90, 125 µg/kg+ Placebo Phase II Dose-finding n= 102 DIAS (2005) InclusionDosesPhase & Sample size Study

14 Investigator Meeting DIAS-4, Chicago, 2011 n= 8n= DIAS/DEDAS: Promising results Recovery = D90 mRS 0-2

15 Investigator Meeting DIAS-4, Chicago, 2011 n= 8n= 8 DIAS-2: Unexpected results (1)

16 Investigator Meeting DIAS-4, Chicago, 2011 DIAS-2: Unexpected results (2) 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/DEDAS DIAS-2

17 Investigator Meeting DIAS-4, Chicago, 2011 Symptomatic ICH DIAS-2 Desmoteplase Placebo n=63 90 g/kg n= g/kg n=66 sICH within 24 h n (%)02 (3.5%)*1 (1.5%) sICH within 72 h n (%)02 (3.5%)*3 (4.5%) * One patient had baseline ICH present prior to receiving study medication

18 Investigator Meeting DIAS-4, Chicago, 2011 Mortality over time DIAS-2 10 of 14 unrelated (Investigator assessment) 10 of 14 late (after day 10)

19 Investigator Meeting DIAS-4, Chicago, 2011 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 Investigator Meeting DIAS-4, Chicago, 2011 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 Mortality Conclusions

21 Investigator Meeting DIAS-4, Chicago, 2011 Major Protocol Violations DIAS-2 Placebo90 µg/kg125 µg/kg n%n%n% Presence of ICH or SAH AV malformation, cerebral aneurysm or cerebral neoplasm No distinct penumbra of at least 20% Extensive early infarction No infarct or no ischemia Baseline glucose >200 mg/dl and no post-anti- diabetic medical treatment performed Baseline glucose 200 mg/dl and a post-anti- diabetic meds glucose of 200 mg/dl Baseline systolic blood pressure > Baseline diastolic blood pressure >

22 Investigator Meeting DIAS-4, Chicago, 2011 Efficacy Per Protocol analysis: ITT vs. PP Population ITTPP Sample Size Responder Rate (%) Sample Size Responder Rate (%) Placebo µg/kg µg/kg Sample size decreased but overall outcome identical

23 Investigator Meeting DIAS-4, Chicago, 2011 DIAS/DEDAS & DIAS-2: Were they different? Placebo90 µg/kg125 µg/kg DIAS/ DEDAS DIAS-2DIAS/ DEDAS DIAS-2DIAS/ DEDAS DIAS-2 BL NIHSS median BL Lesion Volume (cc, median) h post stroke (%) Absolute Mismatch Volume (cc, median) Relative Mismatch (%, median) BL TIMI 0-1 (%)

24 Investigator Meeting DIAS-4, Chicago, 2011 TIMI Grading in DIAS 4 CT 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 Investigator Meeting DIAS-4, Chicago, 2011 Stroke severity (NIHSS) Mismatch volume Vessel Patency (TIMI) DIAS-2DIAS/DEDAS DIAS-2 DIAS/DEDAS. 0 3 Large Small Shift in overall pattern of study populations 424

26 Investigator Meeting DIAS-4, Chicago, Does desmoteplase have an effect? DIAS-2 TIMI 0-1TIMI 2-3 Responder Rate (mRS 0-2) % Responder Rate (mRS 0-2) % Placebo µg/kg µg/kg2740.0

27 Investigator Meeting DIAS-4, Chicago, 2011 Clinical response in TIMI 0-1 patients: DIAS/DEDAS vs DIAS-2 Absolute effect 90 µg/kg: 22% * *

28 Investigator Meeting DIAS-4, Chicago, 2011 Mismatch versus Vessel Occlusion: DIAS-2 33% No MM 15% No MM

29 Investigator Meeting DIAS-4, Chicago, 2011 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 Investigator Meeting DIAS-4, Chicago, 2011 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 Investigator Meeting DIAS-4, Chicago, 2011 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.


Download ppt "H. Lundbeck A/S slide 1 Desmoteplase in Stroke Scientific Background & Protocol."

Similar presentations


Ads by Google