h. lundbeck a/s slide 1 desmoteplase in stroke scientific background & protocol

H. Lundbeck A/S slide 1

Desmoteplase in StrokeDesmoteplase in Stroke

Scientific Background Scientific Background &&

ProtocolProtocol

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


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


Fibrinolysis Cascade


Structure

AlteplaseDesmoteplase

Desmoteplase has 72% structural homology to human t-PA (Alteplase)

Essential Difference: Absence of Kringle 2 in desmoteplase

K2EGF

EGF

K1

K1

PP

F F


rt-PA

Cleavage

Fibrin

Plasminogen

rt-PA

Tissue Plasminogen Activator – Mechanism of Action


rt-PA

Cleavage

Fibrin

Plasminogen

Intrinsic activity

Plasminogen

rt-PA

rt-PAOther scaffolds (e.g. endothelialannexin II)

Plasmin

rt-PA

PDGF-CC

Various targets ...blood brain barrier

Tissue Plasminogen Activator – Mechanism of Action


SAE Related to rt-PA Use in Acute Isehcmic Stroke

• Disrupts the BBB

• Neurotoxic

• Β-amyloid activates rt-PA


Fibrin

ogenogenPlasminDSPAPlasminogen

Cleavage

Desmoteplase: No physiological function in humans


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 Fibrinogen550x over absence

Yes

12,900x over Fibrinogen105,000x over absence

No

Lower bleeding risk

Activation by

ß-Amyloid

Yes No Lower bleeding risk inthe elderly

Administration i.v. infusion Single bolus, i.v. Ease of administration

Half life 3-5 min About 4.5h Positive impact onre-occlusion rate andformation of micro-emboli


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


Agenda

• DesmoteplaseDesmoteplase– Compound and nonclinical dataCompound and nonclinical data

• Previous stroke studies– DIAS/DEDAS– DIAS-2– Post-hoc analyses & rationale for DIAS-3/DIAS-4


Desmoteplase in Stroke Studies: Overview

>20% Penumbra(MRI or CT)NIHSS: 4-24Age: 18-85

90, 125 µg/kg+ Placebo

Phase III Confirmatory n= 186

DIAS-2(2009)

>20% Penumbra (MRI) NIHSS 4-20Age: 18-85

90, 125 µg/kg+ Placebo

Phase IIDose-finding n= 37

DEDAS(2006)

>20% Penumbra (MRI) NIHSS: 4-20Age: 18-85

Part 1: 25, 37.5, 50 mgPart 2: 62.5, 90, 125 µg/kg+ Placebo

Phase IIDose-finding n= 102

DIAS(2005)

InclusionDosesPhase & Sample size

Study


n= 8

29 11 27 18 24

DIAS/DEDAS: Promising results

0

10

20

30

40

50

60

70

Reperfusion Recovery

%

no drug 90 µg/ kg 125 µg/ kg

Recovery = D90 mRS 0-2


n= 8

DIAS-2: Unexpected results (1)

05

101520253035404550

Recovery

%



DIAS-2: Unexpected results (2)

• Low response of 125 µg/kg desmoteplase (36% versus 60%)

• High placebo response (46% vs. 20-25%)

• 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%

0

10

20

30

40

50

60

70

Reperfusion Recovery

%


05

101520253035404550

Recovery

%


DIAS/DEDAS

DIAS-2


Symptomatic ICH DIAS-2

Desmoteplase

Placebon=63

90 g/kgn=57

125 g/kgn=66

sICH within 24 h

n (%) 0 2 (3.5%)* 1 (1.5%)

sICH within 72 h

n (%) 0 2 (3.5%)* 3 (4.5%)

* One patient had baseline ICH present prior to receiving study medication


Mortality over time DIAS-2

0 20 40 60 80

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Day Since Treatment

Su

rviv

al R

ate

DSP 125ug/kgDSP 90ug/kgPlacebo

Kaplan-Meier Estimate of Survival Curve by Treatment Group

10

10 of 14 unrelated (Investigator assessment) 10 of 14 late (after day 10)


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)


• 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


Major Protocol Violations DIAS-2

Placebo 90 µg/kg 125 µg/kg

n % n % n %

Presence of ICH or SAH 0 0.0 1 1.8 0 0.0

AV malformation, cerebral aneurysm or cerebral neoplasm

1 1.6 0 0.0 0 0.0

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 1.5

No infarct or no ischemia 3 4.8 0 0.0 3 4.5

Baseline glucose >200 mg/dl and no post-anti-diabetic medical treatment performed

0 0.0 1 1.8 0 0.0

Baseline glucose 200 mg/dl and a post-anti-diabetic med’s glucose of 200 mg/dl

2 3.2 3 5.3 3 4.5

Baseline systolic blood pressure >185 0 0.0 1 1.8 0 0.0

Baseline diastolic blood pressure >110 0 0.0 0 0.0 1 1.5


Efficacy Per Protocol analysis: ITT vs. PP Population

ITT PP

Sample Size

Responder Rate (%)

Sample Size

Responder Rate (%)

Placebo 63 46.0 50 46.0

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


DIAS/DEDAS & DIAS-2:Were they different?

Placebo 90 µg/kg 125 µg/kg

DIAS/ DEDAS

DIAS-2 DIAS/ DEDAS

DIAS-2 DIAS/ DEDAS

DIAS-2

BL NIHSS median 12 9 11 9 11 9

BL Lesion Volume (cc, median) 24 12 28 8 22 11

3-6h post stroke (%) 66

99

320

59

41

49

478

27

21

114

393

54

33

52

506

26

63

130

241

59

36

66

531

36

Absolute Mismatch Volume (cc, median)

Relative Mismatch (%, median)

BL TIMI 0-1 (%)


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


Stroke severity (NIHSS)

Mismatchvolume

Vessel Patency (TIMI)

DIAS-2DIAS-2 DIAS/DEDASDIAS/DEDAS

.

0

3

Large

Small

Shift in overall pattern of study populations

4 24

Investigator Meeting DIAS-4, Chicago, 2011.

Does desmoteplase have an effect?

DIAS-2

TIMI 0-1 TIMI 2-3

Responder Rate

(mRS 0-2)

%

Responder Rate

(mRS 0-2)

%

Placebo 18 56.0

90 µg/kg 36 50.0

125 µg/kg 27 40.0


Clinical response in TIMI 0-1 patients: DIAS/DEDAS vs DIAS-2

-5

5

15

25

35

45

55

65

Placebo 90 µg/ kg 125 µg/ kg

Resp

on

der

Rate

(%

)

DIAS/ DEDAS DIAS-2 Combined

Absolute effect

90 µg/kg: 22%

*

*


Mismatch versus Vessel Occlusion: DIAS-2

020406080

100120140160180200220240260

TIMI 0-1 Overall

degree of patency (TIMI)

pati

en

ts (

n)

mismatch screen fail mismatch violator eligible

33% No MM

15% No MM


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: 98-104


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


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.

h. lundbeck a/s slide 1 desmoteplase in stroke scientific background & protocol

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