[PPT] - Recent Advances In the Recent Advances In the Management of ITP PowerPoint Presentation

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Recent Advances In the Recent Advances In the Management of ITP Management of ITP

Prof Gregory Cheng Prof Gregory Cheng

Prof. Gregory Cheng
Prof. Gregory Cheng

SLIDE 2

Immune thrombocytopenia (ITP) is a

Immune thrombocytopenia (ITP) is a disease characterized by accelerated disease characterized by accelerated destruction of platelets by anti destruction of platelets by anti-platelet platelet destruction of platelets by anti destruction of platelets by anti platelet platelet antibodies antibodies

SLIDE 3

Treatment is therefore primarily

Treatment is therefore primarily directed at reducing destruction of directed at reducing destruction of antibody antibody-coated platelets coated platelets antibody antibody coated platelets coated platelets

SLIDE 4

Thrombopoietic Factors in ITP: Thrombopoietin Receptor (TPOr)- Thrombopoietin Receptor (TPOr) Targeted Therapy

Platelet production may be decreased in

Platelet production may be decreased in a substantial fraction of patients with ITP a substantial fraction of patients with ITP a substantial fraction of patients with ITP , a substantial fraction of patients with ITP , especially those with refractory disease especially those with refractory disease

SLIDE 5

Impaired platelet production p p p

gpIIb

gpIIb-IIIa and gpIb IIIa and gpIb-IX) are co IX) are co-expressed expressed

gpIIb

gpIIb IIIa and gpIb IIIa and gpIb IX) are co IX) are co expressed expressed

n platelets, megakaryocytes and
n platelets, megakaryocytes and

megakaryocyte precursors megakaryocyte precursors

Recognized by auto

Recognized by auto-

antibodies and may

antibodies and may g y g y y lead to impaired megakaryopoiesis, lead to impaired megakaryopoiesis, maturation and platelet release. maturation and platelet release.1

ITP

ITP – –Plasma containing autoantibodies Plasma containing autoantibodies against gpIb and gpIIb against gpIb and gpIIb IIIa significantly IIIa significantly against gpIb and gpIIb against gpIb and gpIIb-IIIa significantly IIIa significantly suppresed megakaryopoiesis in vitro. suppresed megakaryopoiesis in vitro.2

1. McMillan R, et al 2000;37:239‐248 2. Chang M, et al 2003;102:887‐95

SLIDE 6

Thrombopoietin (TPO) levels are

Thrombopoietin (TPO) levels are inappropriately low (near normal) in inappropriately low (near normal) in thrombocytopenic ITP patients thrombocytopenic ITP patients thrombocytopenic ITP patients thrombocytopenic ITP patients

SLIDE 7

TPO levels are TPO levels are inappropriately low inappropriately low in in ITP ITP ITP ITP

Kosugi et al. Br J Haematol1996;93:704–706

SLIDE 8

Stimulation of platelet production may

Stimulation of platelet production may be especially useful in patients not be especially useful in patients not responsive to currently available responsive to currently available responsive to currently available responsive to currently available treatment. treatment.

SLIDE 9

Eltrombopag is an oral,

Eltrombopag is an oral, p g , p g , non non-

peptide, small

peptide, small molecule thrombopoietin molecule thrombopoietin receptor agonist receptor agonist receptor agonist receptor agonist

Does not cause activation

Does not cause activation and aggregation and aggregation

Less immunogenic than

Less immunogenic than thrombopietin and other thrombopietin and other tid l t tid l t peptidyl agents peptidyl agents

SLIDE 10

Thrombopoietin Receptor (TPOr) Thrombopoietin Receptor (TPOr)

TPOr = cMpl

TPOr

cMpl TPOr cMpl –a member of the type I a member of the type I hematopoietic growth factor receptor hematopoietic growth factor receptor hematopoietic growth factor receptor hematopoietic growth factor receptor family family –A homodimer with a transmembrane A homodimer with a transmembrane –A homodimer with a transmembrane A homodimer with a transmembrane domain and an intracellular domain domain and an intracellular domain

SLIDE 11

Selectively activates TPOr

Selectively activates TPOr and the

and the

Selectively activates TPOr

Selectively activates TPOr and the

and the JAK/STAT signaling pathway JAK/STAT signaling pathway

–Oral bioavailability is 89% in monkey Oral bioavailability is 89% in monkey Oral bioavailability is 89% in monkey Oral bioavailability is 89% in monkey / human / human

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Eltrombopag Phase I Study: Eltrombopag Phase I Study: Platelet Platelet-Count Change from Count Change from

160

e

R d i d R d i d

Platelet Platelet Count Change from Count Change from Baseline in Healthy Subjects Baseline in Healthy Subjects

120 140 160

m baseline

Randomized

Randomized placebo controlled placebo controlled phase I trial in 73 phase I trial in 73

80 100

change fro

phase I trial in 73 phase I trial in 73 healthy male healthy male subjects subjects

40 60

uL(x1000) c

Oral capsules:

nce a day, for 10
nce a day, for 10

d

20 placebo 5mg 10mg 20mg 30mg 50mg 75mg

Platelets/u

days days

Doses :

Doses : 5 10 20 30 50 5 10 20 30 50

p g g g g g g

Eltrombopag Dose x 10 days

5, 10, 20, 30, 50, 5, 10, 20, 30, 50, 75 mg 75 mg

Jenkins, J, et al. 2004; Blood (ASH Abstracts); 104: 2916.

SLIDE 13

In two 6

In two 6-

week placebo

week placebo-

controlled

controlled

1 2 1 2

p trials trials1,2

1,2 (N >200), eltrombopag

(N >200), eltrombopag significantly increased platelet counts significantly increased platelet counts reduced clinical bleeding in ITP reduced clinical bleeding in ITP reduced clinical bleeding in ITP reduced clinical bleeding in ITP patients and had a favorable safety patients and had a favorable safety profile profile

N Engl J Med 2007; 357:2237 - 47 Lancet 2009;373:641 – 8

SLIDE 14

Response to Eltrombopag: Primary Endpoint (Phase II): % with Plts ≥50,000/µL after 42 Days (Baseline

p<0.001* p<0.001* OR 38 82 OR 38 82

90 90 100 100

rs rs

) , /µ y ( Platelets <30,000/µL)

p<0.001* p<0.001* OR=21.96 OR=21.96 OR=38.82 OR=38.82

70 70 80 80

esponder esponder

p = 0 07 p = 0 07

40 40 50 50 60 60

ge of Re ge of Re

p = 0.07 p = 0.07 OR=3.09 OR=3.09

20 20 30 30 40 40

Percenta Percenta

10 10 20 20

Placebo Placebo 30mg 30mg 50mg 50mg 75mg 75mg

P

OR = Odds ratio treatment relative to placebo OR = Odds ratio treatment relative to placebo * = Indicates significance under closed testing procedure * = Indicates significance under closed testing procedure Placebo Placebo 30mg 30mg 50mg 50mg 75mg 75mg N Engl J Med 2007; 357:2237 - 47

SLIDE 15

Phase II Study: Median Platelet Counts Over Time (25% & 75% Counts Over Time (25% & 75% Quartiles; Observed Analysis)

50mg 75mg

LOCF Analysis

5 g

SLIDE 16

Eltrombopag in Chronic ITP Phase 2 Results: Increased Platelet Results: Increased Platelet Production, Decreased Bleeding

180000 200000

nt

16 18

nts

Platelet count Bleeding events

100000 120000 140000 160000

atelet coun

10 12 14

(%) of on- eding even

40000 60000 80000 100000

Median pla

4 6 8

Incidence erapy blee

20000 40000

Placebo 30 mg 50 mg 75 mg

M

2

I the

g g g

Dosage of eltrombopag: once daily for 6 weeks

N Engl J Med 2007; 357:2237 - 47

SLIDE 17

RAISE is a phase III, placebo

RAISE is a phase III, placebo-

controlled,

controlled, p , p p , p , double double-

blind trial of eltrombopag

blind trial of eltrombopag treatment treatment

To evaluate the efficacy and safety of

To evaluate the efficacy and safety of up to 6 months of treatment with up to 6 months of treatment with lt b i ti t ith h i ITP lt b i ti t ith h i ITP eltrombopag in patients with chronic ITP eltrombopag in patients with chronic ITP

SLIDE 18

Adult patients with chronic ITP who

Adult patients with chronic ITP who had a platelet count <30,000/µL and had a platelet count <30,000/µL and had received ≥1 prior ITP therapies had received ≥1 prior ITP therapies had received ≥1 prior ITP therapies had received ≥1 prior ITP therapies were eligible for RAISE were eligible for RAISE

Patients were randomized 2:1

Patients were randomized 2:1 (eltrombopag:placebo) and stratified (eltrombopag:placebo) and stratified (eltrombopag:placebo) and stratified (eltrombopag:placebo) and stratified by splenectomy status, concomitant by splenectomy status, concomitant ITP medication use, and platelet count ITP medication use, and platelet count , p , p ≤15,000/µL 15,000/µL

SLIDE 19

Eltrombopag (or matching placebo) was

Eltrombopag (or matching placebo) was initiated at 50 mg once daily initiated at 50 mg once daily

Screening period Follow-up period BL 1 2 3 4 5 6 10 14 18 22 26FU 1 FU 2 FU 4

Study week

BL, baseline; FU, follow-up .

SLIDE 20

Study Design y g

Permit eltrombopag dose changes P it d ti Screening period Follow-up period Permit reductions in concomitant ITP medications BL 1 2 3 4 5 6 10 14 18 22 26FU FU FU 1 2 4

Study week

BL, baseline; FU, follow-up .

SLIDE 21

Primary Efficacy Endpoint Primary Efficacy Endpoint

The odds of responding with a platelet

Primary Efficacy Endpoint Primary Efficacy Endpoint

The odds of responding with a platelet

The odds of responding with a platelet count of 50,000 to 400,000/ count of 50,000 to 400,000/µL at least L at least

nce during the treatment period
nce during the treatment period
nce during the treatment period
nce during the treatment period

SLIDE 22

Secondary Efficacy Endpoint Secondary Efficacy Endpoint

Median platelet counts

Total cumulative weeks of response

Longest period of continuous response

Durable response

Response greater than 75% assesment

SLIDE 23

Secondary Endpoints Secondary Endpoints Secondary Endpoints Secondary Endpoints

Incidence and severity of bleeding

Incidence and severity of bleeding symptoms were measured using the symptoms were measured using the World Health Organization (WHO) World Health Organization (WHO) World Health Organization (WHO) World Health Organization (WHO) Bleeding Scale Bleeding Scale –Grade 0, no bleeding; grade 1, mild Grade 0, no bleeding; grade 1, mild Grade 0, no bleeding; grade 1, mild Grade 0, no bleeding; grade 1, mild bleeding; grade 2, moderate bleeding; bleeding; grade 2, moderate bleeding; grade 3, gross bleeding; grade 4, grade 3, gross bleeding; grade 4, g , g g; g , g , g g; g , debilitating blood loss debilitating blood loss

SLIDE 24

Secondary Endpoints Secondary Endpoints

Proportion of patients who discontinued

r achieved a sustained reduction in the
r achieved a sustained reduction in the

dose of concomitant ITP medication dose of concomitant ITP medication dose of concomitant ITP medication dose of concomitant ITP medication from baseline from baseline

Safety and tolerability parameters,

Safety and tolerability parameters, including adverse event reporting and including adverse event reporting and including adverse event reporting and including adverse event reporting and clinical laboratory tests clinical laboratory tests

SLIDE 25

Secondary Endpoints Secondary Endpoints

Quality of life was measured at baseline

Quality of life was measured at baseline and at weeks 6 14 and 26 or upon and at weeks 6 14 and 26 or upon and at weeks 6, 14, and 26 or upon and at weeks 6, 14, and 26 or upon discontinuation of study medication discontinuation of study medication using the acute recall version of the using the acute recall version of the using the acute recall version of the using the acute recall version of the Short Form Short Form-

36, version 2 (SF

36, version 2 (SF-

36v2)

36v2) questionnaire.14 The impact of questionnaire.14 The impact of questionnaire.14 The impact of questionnaire.14 The impact of bleeding on quality of life was assessed bleeding on quality of life was assessed using a 6 using a 6-

item subset from the

item subset from the g Functional Assessment of Cancer Functional Assessment of Cancer Therapy Therapy-

Thrombocytopenia (FACT

Thrombocytopenia (FACT-

Th6)

Th6) questionnaire. questionnaire.

SLIDE 26

Patient Demographic

Placebo Placebo Eltrom bopag Eltrom bopag Characteristic Characteristic N = 6 2 N = 6 2 N = 1 3 5 N = 1 3 5

Patient Demographic

Age Age — — yr yr Median Median 52.5 52.5 47 47 Range Range 18 18-77 77 18 18-85 85 Range Range 18 18 77 77 18 18 85 85 Sex Sex — — no. (%)

no. (%)

Female Female 43 (69) 43 (69) 93 (69) 93 (69) Race Race no (%) no (%) Race Race — no. (%)

no. (%)

White White 44 (71) 44 (71) 101 (75) 101 (75) Asian Asian 13 (21) 13 (21) 21 (16) 21 (16) Other Other 5 (8) 5 (8) 13 (10) 13 (10) Stratification variables Stratification variables — — no. (%)

no. (%)

Platelets £15,000/μL* Platelets £15,000/μL* 30 (48) 30 (48) 67 (50) 67 (50) , /μ , /μ ( ) ( ) ( ) ( ) Splenectomy Splenectomy 21 (34) 21 (34) 50 (37) 50 (37) Concomitant ITP medication Concomitant ITP medication 31 (50) 31 (50) 63 (47) 63 (47)

SLIDE 27

Bl di S t Bl di S t (%) (%) 47 (77) 47 (77) 98 (73) 98 (73) Bleeding Symptoms Bleeding Symptoms — no. (%)

no. (%)

47 (77) 47 (77) 98 (73) 98 (73) Clinically significant bleeding Clinically significant bleeding 17 (28) 17 (28) 30 (22) 30 (22) symptoms symptoms — — no. (%)†

no. (%)†

17 (28) 17 (28) 30 (22) 30 (22) Number of prior ITP therapies Number of prior ITP therapies — — no. no. (%)‡ (%)‡ (%)‡ (%)‡ ≥2 ≥2 50 (81) 50 (81) 105 (78) 105 (78) ≥3 ≥3 32 (52) 32 (52) 75 (56) 75 (56) ≥4 ≥4 20 (32) 20 (32) 51 (38) 51 (38) ≥5 ≥5 11 (18) 11 (18) 35 (26) 35 (26)

SLIDE 28

Results: Proportion of Responders

Patients in the eltrombopag group were

Results: Proportion of Responders

Patients in the eltrombopag group were

Patients in the eltrombopag group were 8 times more likely to respond with 8 times more likely to respond with platelet counts 50,000 to 400,000/ platelet counts 50,000 to 400,000/µL L p a

u

50,000 o 00,000/ p a

u

50,000 o 00,000/µ compared with those in the placebo compared with those in the placebo group group g p g p –Odds ratio [99% CI] = 8.2 [3.59 Odds ratio [99% CI] = 8.2 [3.59– 18.73]; 18.73]; P <0.001 <0.001 ]; ];

SLIDE 29

Proportion of Responders Proportion of Responders

SLIDE 30

Median Platelet Counts Over Time

Platelet counts were elevated in the

Median Platelet Counts Over Time

Platelet counts were elevated in the

Platelet counts were elevated in the eltrombopag group versus the placebo eltrombopag group versus the placebo group irrespective of splenectomy group irrespective of splenectomy group irrespective of splenectomy group irrespective of splenectomy status ( status (P = 0.562), baseline = 0.562), baseline concomitant ITP medication use ( concomitant ITP medication use (P = = ( 0.890), or baseline platelet count 0.890), or baseline platelet count ≤15,000/µL ( 15,000/µL (P = 0.804) = 0.804)

SLIDE 31

Median Platelet Counts Over Time Median Platelet Counts Over Time

SLIDE 32

Figure 2D. Median Platelet Counts b S l t St t by Splenectomy Status

120 140 160

unt

On therapy Post t

60 80 100 120

platelet cou 1,000/µL)

20 40 60

Median p (x 1

Study week

Placebo not splenectomized Placebo splenectomized

BL 1 2 3 4 5 6 10 14 18 22 26 1 2 4

Placebo, not splenectomized Placebo, splenectomized Eltrombopag, not splenectomized Eltrombopag, splenectomized

SLIDE 33

Bleeding Symptoms

Compared with placebo eltrombopag

Bleeding Symptoms

Compared with placebo, eltrombopag

Compared with placebo, eltrombopag treatment reduced the risk of any treatment reduced the risk of any bleeding by 76% (WHO grades 1 bleeding by 76% (WHO grades 1-4; 4; P bleeding by 76% (WHO grades 1 bleeding by 76% (WHO grades 1 4; 4; P <0.001) and the risk of clinically <0.001) and the risk of clinically significant bleeding by 65% (WHO significant bleeding by 65% (WHO g g y ( g g y ( grades 2 grades 2-

4;

4; P <0.001) <0.001)

SLIDE 34

Figure 3A. Incidence of Bleeding Symptoms Figure 3B. Incidence of Clinically Significant Bleeding Symptoms

SLIDE 35

Figure 3C. Reduction of C it t ITP M di ti Concomitant ITP Medication

SLIDE 36

Figure 3D. Use of Rescue Therapy Figure 3D. Use of Rescue Therapy

SLIDE 37

Figure 3E. Mean Change in SF- 36v2 and FACT-Th6 Scores

SLIDE 38

Placebo Placebo Eltrom bopag Eltrom bopag

Adverse Events Adverse Events

Adverse event Adverse event — — no. ( % )

no. ( % )

N = 6 1 * * N = 6 1 * * N = 1 3 5 N = 1 3 5 Any on Any on-

therapy adverse event

therapy adverse event ( ≥1 0 % incidence) 1 0 % incidence) 5 6 ( 9 2 ) 5 6 ( 9 2 ) 1 1 8 ( 8 7 ) 1 1 8 ( 8 7 ) ( ) Headache Headache 2 0 ( 3 3 ) 2 0 ( 3 3 ) 4 1 ( 3 0 ) 4 1 ( 3 0 ) Diarrhea Diarrhea 6 ( 1 0 ) 6 ( 1 0 ) 1 7 ( 1 3 ) 1 7 ( 1 3 ) Nausea Nausea 4 ( 7 ) 4 ( 7 ) 1 6 ( 1 2 ) 1 6 ( 1 2 ) Nasopharyngitis Nasopharyngitis 8 ( 1 3 ) 8 ( 1 3 ) 1 4 ( 1 0 ) 1 4 ( 1 0 ) Upper respiratory tract infection Upper respiratory tract infection 7 ( 1 1 ) 7 ( 1 1 ) 1 4 ( 1 0 ) 1 4 ( 1 0 ) Fatigue Fatigue 8 ( 1 3 ) 8 ( 1 3 ) 1 3 ( 1 0 ) 1 3 ( 1 0 ) i i i i i i ( ) ( ) ( ) ( ) Pain in extrem ity Pain in extrem ity 6 ( 1 0 ) 6 ( 1 0 ) 9 ( 7 ) 9 ( 7 ) Epistaxis Epistaxis 6 ( 1 0 ) 6 ( 1 0 ) 7 ( 5 ) 7 ( 5 ) Dizziness Dizziness 6 ( 1 0 ) 6 ( 1 0 ) 5 ( 4 ) 5 ( 4 ) Dizziness Dizziness 6 ( 1 0 ) 6 ( 1 0 ) 5 ( 4 ) 5 ( 4 ) Peripheral edem a* Peripheral edem a* 6 ( 1 0 ) 6 ( 1 0 ) 2 ( 1 ) 2 ( 1 )

SLIDE 39

Adverse event Adverse event — — no. ( % )

no. ( % )

Placebo Placebo N = 6 1 * * N = 6 1 * * Eltrom bopag Eltrom bopag N = 1 3 5 N = 1 3 5 Additional adverse events w ith Additional adverse events w ith ≥5 % higher incidence in either 5 % higher incidence in either eltrom bopag or placebo eltrom bopag or placebo Vom iting Vom iting 1 ( 2 ) 1 ( 2 ) 1 0 ( 7 ) 1 0 ( 7 ) Vom iting Vom iting 1 ( 2 ) 1 ( 2 ) 1 0 ( 7 ) 1 0 ( 7 ) I nsom nia* I nsom nia* 4 ( 7 ) 4 ( 7 ) 2 ( 1 ) 2 ( 1 ) Ecchym osis Ecchym osis 4 ( 7 ) 4 ( 7 ) 2 ( 1 ) 2 ( 1 ) Ecchym osis Ecchym osis 4 ( 7 ) 4 ( 7 ) 2 ( 1 ) 2 ( 1 ) Dyspepsia ( P= 0 .0 1 2 ) ,* Dyspepsia ( P= 0 .0 1 2 ) ,* 4 ( 7 ) 4 ( 7 ) 2 ( 1 ) 2 ( 1 ) Conjunctivitis Conjunctivitis 4 ( 7 ) 4 ( 7 ) 1 ( < 1 ) 1 ( < 1 ) Cellulitis. Cellulitis. 4 ( 7 ) 4 ( 7 ) Eye sw elling Eye sw elling 3 ( 5 ) 3 ( 5 ) Any serious adverse event Any serious adverse event 1 1 ( 1 8 ) 1 1 ( 1 8 ) 1 5 ( 1 1 ) 1 5 ( 1 1 )

SLIDE 40

Events of Special Interest Events of Special Interest

Events of special interest Placebo Placebo

Eltrom popag Eltrom popag

Events of special interest Placebo Placebo

Eltrom popag Eltrom popag

Bleeding adverse event On-therapy bleeding adverse event 1 9 ( 3 1 ) 2 6 ( 1 9 ) On-therapy serious bleeding adverse event† 4 ( 7 ) 1 ( <1 ) Post-therapy bleeding adverse event 6 ( 1 0 ) 6 ( 4 ) Post-therapy serious bleeding adverse event 1 ( 2 ) 2 ( 1 ) Throm boem bolic event 3 ( 2 ) Hepatobiliary laboratory abnorm ality ( on therapy) 4 ( 7 ) 1 7 ( 1 3 ) Cataract‡ 6 ( 1 0 ) 1 0 ( 7 ) ( ) ( ) Malignancy§ 1 ( 2 ) 1 ( <1 ) Bone m arrow reticulin form ation¶ Transient decrease in platelet countsǁ 4 ( 7 ) 9 ( 7 ) Death 1 ( 2 )

SLIDE 41

Hepatobiliary laboratory abnormalities

ccurred in 13% of patients receiving
ccurred in 13% of patients receiving

eltrombopag versus 7% receiving eltrombopag versus 7% receiving eltrombopag versus 7% receiving eltrombopag versus 7% receiving

placebo. There was 1 grade 4
placebo. There was 1 grade 4

hepatobiliary laboratory abnormality in hepatobiliary laboratory abnormality in f p y y y p y y y a patient on placebo, Of the 17 patients a patient on placebo, Of the 17 patients with hepatobiliary laboratory with hepatobiliary laboratory abnormalities in the eltrombopag group, abnormalities in the eltrombopag group, abnormalities in the eltrombopag group, abnormalities in the eltrombopag group, 11 had aminotransferase elevations (all 11 had aminotransferase elevations (all

f which returned to normal during
f which returned to normal during

treatment [9 patients] or within 36 treatment [9 patients] or within 36 50 50 treatment [9 patients] or within 36 treatment [9 patients] or within 36-50 50 days following discontinuation [2 days following discontinuation [2 patients]); no clinical sequelae were patients]); no clinical sequelae were d reported. reported.

SLIDE 42

Incident or worsening cataracts were

Incident or worsening cataracts were reported by 7% of patients receiving reported by 7% of patients receiving eltrombopag and 10% receiving eltrombopag and 10% receiving eltrombopag and 10% receiving eltrombopag and 10% receiving placebo placebo

SLIDE 43

Bleeding Events Bleeding Events Bleeding Events Bleeding Events

On

On-therapy bleeding adverse events therapy bleeding adverse events

On

On therapy bleeding adverse events therapy bleeding adverse events were experienced by 19% of patients were experienced by 19% of patients receiving eltrombopag versus 31% receiving eltrombopag versus 31% receiving eltrombopag versus 31% receiving eltrombopag versus 31% receiving placebo (Table 2). In the receiving placebo (Table 2). In the eltrombopag group, 3 of these bleeding eltrombopag group, 3 of these bleeding p g g p, g p g g p, g events were ≥Grade 3 compared with events were ≥Grade 3 compared with 11 events in the placebo group. 11 events in the placebo group.

SLIDE 44

Three patients in the eltrombopag

Three patients in the eltrombopag group reported on group reported on-

therapy

therapy thromboembolic events of grade 4. One thromboembolic events of grade 4. One i h d l b li i h d l b li patient had pulmonary embolism patient had pulmonary embolism (platelets 55,000 per microliter; risk (platelets 55,000 per microliter; risk factors: smoking and lupus factors: smoking and lupus factors: smoking and lupus factors: smoking and lupus anticoagulant). Another had grade 3 anticoagulant). Another had grade 3 deep vein thrombosis (platelets 49,000 deep vein thrombosis (platelets 49,000 p (p , p (p , per microliter 5 days prior; risk factors: per microliter 5 days prior; risk factors: smoking and use of oral contraceptives); smoking and use of oral contraceptives);

SLIDE 45

A third patient with rectosigmoid cancer

A third patient with rectosigmoid cancer reported a postoperative grade 4 reported a postoperative grade 4 pulmonary embolism 4 days after pulmonary embolism 4 days after di i i l b id d di i i l b id d discontinuing eltrombopag, considered discontinuing eltrombopag, considered unrelated to study medication (platelets unrelated to study medication (platelets 2 000 per microliter 11 days prior) The 2 000 per microliter 11 days prior) The 2,000 per microliter 11 days prior). The 2,000 per microliter 11 days prior). The risk factors were pre risk factors were pre-

operative
perative

intravenous immunoglobulins, intravenous immunoglobulins, g , g , hospitalization without prophylactic hospitalization without prophylactic anticoagulation, intra anticoagulation, intra-

abdominal

abdominal d d surgery, and cancer. surgery, and cancer.

SLIDE 46

The patient who experienced the on

The patient who experienced the on-

The patient who experienced the on

The patient who experienced the on therapy grade 4 pulmonary embolism therapy grade 4 pulmonary embolism also experienced 2 distinct subsequent also experienced 2 distinct subsequent also experienced 2 distinct subsequent also experienced 2 distinct subsequent events (both grade 2 deep vein events (both grade 2 deep vein thrombophlebitis) more than 200 days thrombophlebitis) more than 200 days p ) y p ) y after discontinuation of study after discontinuation of study medication. medication.

SLIDE 47

AMG 531 AMG 531 -

Romiplostim

Romiplostim

A l th b i i A l th b i i ti l ti ti l ti

A novel thrombopoiesis

A novel thrombopoiesis-

stimulating

stimulating peptibody peptibody

Structurally unrelated to thrombopoietin

Dipeptide linked to the Fc fragment of IgG

Targets thrombopoietin

Increases platelet production

Primes, but does not activate, platelets

SLIDE 48

Romiplostim Increased Platelet Counts in a Dose Dependent Manner Counts in a Dose Dependent Manner in Two Phase 1 Studies with ITP

By weight-based dosing (µg/kg)1 By unit dosing (µg)2

10,000 10,000 1000 450 nts (x 109/L) nts (x 109/L) 1000 450 100 50 10 Platelet Coun Platelet Coun 100 50 10 1 10 9 8 7 6 2 3 4 5 Dose (µg/kg) 1 Peak P 50100 200 300 400 500 Peak P D ( ) 1 Dose (µg/kg) n=24 Dose (µg) n=16

1. Bussel et al. N Engl J Med 2006;355:1672–1681
2. Newland et al. Br J Haematol 2006;135:547–553

SLIDE 49

AMG 531: Phase II AMG 531: Phase II – –Platelet Platelet Response Response

AMG 531 ( AMG 531 (µg/kg) g/kg) Placebo Placebo (N=4) (N=4) 1.0 1.0 (N=8) (N=8) 3.0 3.0 (N=8) (N=8) All All Doses Doses (N=16) (N=16) Plts double AND Plts double AND 50 50 450 450×10 109/L /L n n Plts double AND Plts double AND 50 50–450 450×10 109/L /L - n n (%) (%) 1 (25) 1 (25) 7 (88) 7 (88) 3 (38) 3 (38) 10 (63) 10 (63) Plts double AND Plts double AND ≥50 ≥50×10 109/L /L -

n (%)

n (%) 1 (25) 1 (25) 7 (88) 7 (88) 5 (63) 5 (63) 12 (75) 12 (75) Plts double Plts double -

n (%)

n (%) 1 (25) 1 (25) 8 (100) 8 (100) 7 (88) 7 (88) 15 (94) 15 (94) Plts >450 Plts >450× ×10 109/L /L -

n (%)

n (%) 0 (0) 0 (0) 0 (0) 0 (0) 2 (25) 2 (25) 2 (13) 2 (13) Peak platelet count ( Peak platelet count (×10 109/L) /L) 81 81 +/ +/-

96

96 135 135 +/ +/-

90

90 240 240 +/ +/-

288

288 188 188 +/ +/-

213

213 288 288 Bussel JB et al. N Engl J Med. 2006;355:1672.

SLIDE 50

Phase III Study of AMG 531 in ITP

Kuter et al Lancet 2008

SLIDE 51

Phase III trial of AMG 531 in Phase III trial of AMG 531 in i i h ITP i i h ITP patients with ITP patients with ITP Efficacy: Efficacy: Efficacy: Efficacy:

Platelet response: 83%

Median time to first response: 3.1 w

Median dose of AMG 531 at first

Median dose of AMG 531 at first response: 3.4 response: 3.4 µg/kg g/kg

Durable platelet response: 50%

SLIDE 52

Phase III Studies of AMG 531 in ITP

Kuter et al Lancet 2008

SLIDE 53

EXTENT EXTENT

Eltrombopag dosing period Dose modulated to platelet count Start 50 mg End St 3 Elt b tit ti (≥50 Gi/L) Stage 1: Eltrombopag dosing (≥100 Gi/L) Stage 2: Concomitant medication taper (≥50 Gi/L) Dose modulated to platelet count Screening Stage 3: Eltrombopag titration (≥50 Gi/L) Stage 4: Eltrombopag long-term safety + efficacy

SLIDE 54

Safety and Efficacy of Safety and Efficacy of long long-

term treatment with

term treatment with Romiplostin in ITP Romiplostin in ITP Romiplostin in ITP Romiplostin in ITP

Blood 2009; 113 (10) 2161 Blood 2009; 113 (10) 2161 ( ) ( )

SLIDE 55

Long term follow up efficacy data Long term follow up efficacy data Long term follow up efficacy data Long term follow up efficacy data

Eltrombopag

Romiplostin

Romiplostin p g p g

p

Number of Subjects

299 143 Follow up

Overall response

862 days (120) 1113 (483) 78.4 % 87% Durable response 56.9% N/A Reduction of ITP med 43% 50% 12% 36% Uses of rescue medication Hepatobilary abnormalities 12% 36% 7.6% 6.9%

SLIDE 56

Summary of TPOr agonist Summary of TPOr agonist Summary of TPOr agonist Summary of TPOr agonist

Eltrombopag

Romiplostin

Romiplostin p g p g

p

Structure

Non-peptide peptide body Route of Administration

Onset of action

Oral daily sc weekly 1 week 2 weeks Peak 2 weeks peak 3 to 4 weeks Efficacy 60-80% 60-80% Peak 2 weeks peak 3 to 4 weeks Reduction of Concomitant ITP medication 40-60% 40-60% 65 65% 60 80% Reduction of bleeding Improve HR o Q L 65-65% 60-80% Yes n/a

SLIDE 57

Role of TPOr agonist Role of TPOr agonist Role of TPOr agonist Role of TPOr agonist

The most obvious patients would be

The most obvious patients would be those who are refractory, defined as those who are refractory, defined as failing splenectomy, exhibiting severe failing splenectomy, exhibiting severe failing splenectomy, exhibiting severe failing splenectomy, exhibiting severe ITP and having only temporary ITP and having only temporary responses to corticosteroids and IVIg responses to corticosteroids and IVIg p g p g

SLIDE 58

Prior to Splenectomy Prior to Splenectomy Prior to Splenectomy Prior to Splenectomy

Raising the platelet counts to an

Raising the platelet counts to an adequate level before surgery adequate level before surgery

Advantages over IVIG?

SLIDE 59

Patients Who Refuse Splenectomy Patients Who Refuse Splenectomy Patients Who Refuse Splenectomy Patients Who Refuse Splenectomy

Vs Rituximab?

Vs cyclosporinA?

SLIDE 60

ITP

LESS 30 x 109/lts

Dexamethasone

Fail Danazol Splenectomy Fail Refused Contraindicated

TPOr Agonist

SLIDE 61

Less than 50 x 109/lts

ITP ITP

P S Pre-Surgery.

Include Splenectomy

TPOr AGONIST TPOr AGONIST

SLIDE 62

Potential Adverse events with Potential Adverse events with Thrombopoietin Thrombopoietin-

like agents

like agents

Th b i Th b i

Thrombocytosis

Thrombosis

Reduced threshold for platelet

Reduced threshold for platelet activation activation

Autoantibody formation

Increased bone marrow fibrosis

Increased bone marrow fibrosis (reticulin/collagen) (reticulin/collagen)

Rebound thrombocytopenia

Rebound thrombocytopenia y p y p

SLIDE 63

A Steriods A Steriods

A. Steriods
A. Steriods
B. IVIG
B. IVIG

C D l C D l

C. Danazol
C. Danazol

D.

D. TPOr Agonist

TPOr Agonist

E. No Treatment
E. No Treatment

SLIDE 64

Unsatisfactory Response Unsatisfactory Response Unsatisfactory Response Unsatisfactory Response

A St i d A St i d

A. Steriods
A. Steriods
B. IVIG
B. IVIG
C. Rituximab
C. Rituximab

D.

D. TPOr Agonist

TPOr Agonist D.

D. TPOr Agonist

TPOr Agonist

E. Splenectomy
E. Splenectomy

F C l i A F C l i A

F. CyclosporinA
F. CyclosporinA
G. Cytotoxic Drugs
G. Cytotoxic Drugs

H.

H. Danazol