PowerPoint Presentation · Rodrigo T Calado University of São Paulo São Paulo, Brazil 2 PNH...

3/22/2016

1

Confidential – For Internal Use Only 1

Perspectives on Complement

Inhibition in PNH

Rodrigo T Calado

University of São Paulo

São Paulo, Brazil

2

PNH management in 2012

PNH

Eculizumab

Hemolytic PNH AA / PNH

Severe AANo Hemolysis

IST

Moderate AAHemolysis

Moderate AANo Hemolysis

SCT

THROMBOSIS

3


PNH

Eculizumab



IST



SCT

THROMBOSIS

4

Supportive Treatments In PNH Do Not Address

Chronic Uncontrolled Complement Activity

Transfusions

– Transient treatment of anaemia1-3

– Continued hemolysis, TE, CKD, abdominal pain

Anticoagulants

– Risk of hemorrhage

– Ineffective in many PNH patients1,2

Red cell supplements

– ESAs may expand clones and elevate hemolysis

– Folic acid, iron1-3

Steroids/androgen hormones1-3

– Variable results, may address acute not chronic hemolysis

– No controlled clinical trials

1. Hillmen, et al. N Engl J Med. 1995;333:1253-1258. 2. Parker, et al. Blood. 2005;106:3699-3709. 3. Saso, et al. Brit J Haem. 1999; 104: 392-396.

5

Intermediate

(n=93)

Classic

(n=113)

Hb <12g/dl and/or thrombosis

0.6

1

0.8

0.2

0.4

10 20

0

0

Intermediate PNHAA-PNH

Classic PNH

Surv

ie

30

Temps (années)

AA – PNH syndrome

(n=224)

2 or 3 lineages**Hb10g/dl, Platelets 80 g/L, Neutrophiles 1 g/L

Best Supportive Care In Hemolytic PNH Patients

Peffault de Latour, RP et al. Blood. 2008;112(8):3099-3106. 6

Eculizumab Humanized

First in Class Anti - C5 Antibody

Rother R et al. Nat Biotech. 2007;25:1256.

Hinge

CH

3C

H2

Human IgG4 Heavy Chain

Constant Regions 2 and 3

(Eliminates complement activation)

Complementarity Determining Regions

(murine origin)

Human Framework Regions

No mutations

Germline

Human IgG2 Heavy Chain

Constant Region 1 and Hinge

(Eliminates Fc receptor binding)

3/22/2016

2

7

Eculizumab Blocks Terminal Complement1,2

C5

Pro

xim

al

Te

rmin

al

1. Soliris® (eculizumab) [package insert; 2011. 2. Rother RP et al. Nature Biotech. 2007;25(11):1256-1264.

3. Walport MJ. N Engl J Med. 2001;344(14):1058-1066. 4. Figueroa JE, Densen P. Clin Microbiol Rev. 1991;4(3):359-395.

C5a

Eculizumab

Proximal functions of

complement remain intact1,2

• Weak anaphylatoxin2,4

• Immune complex clearance2

• Microbial opsonization2

Terminal complement - C5a

and C5b-9 activity blocked1,2

Eculizumab binds with high

affinity to C51,2

Complement Cascade2,3

C5b-9C5b

C3 C3a

C3b

8

Safety: Warnings and Precautions (cont.)

SOLIRIS blocks terminal complement activation; therefore,

patients may have increased susceptibility to infections,

especially with encapsulated bacteria

Children treated with SOLIRIS may be at increased risk of

developing serious infections due to Streptococcus

pneumoniae and Haemophilus influenza Type b (Hib)

– Administer vaccinations for prevention of S. pneumonaie

and Hib according to ACIP guidelines

Use caution when administering SOLIRIS to patients with

any systemic infection

Please see full prescribing information for SOLIRIS® (eculizumab).

SOLIRIS® (eculizumab) [package insert]. Alexion Pharmaceuticals; 2011.

9

Patient Counseling

Prior to treatment, patients should fully understand:

The risks and benefits of SOLIRIS in particular the risk of

meningococcal infection; Ensure that patients receive the Medication

Guide

Patients should be educated about any of the signs and symptoms of

meningococcal infection

Patients are required to receive a meningococcal vaccination at least

2 weeks prior to receiving the first dose of SOLIRIS, if they have not

previously been vaccinated

– Vaccination may not prevent meningococcal infection

Patients should be informed that there may be an increased risk of

other infections

Please see full prescribing information for SOLIRIS® (eculizumab).

SOLIRIS® (eculizumab) [package insert]. Alexion Pharmaceuticals; 2011.

See FDA-Approved Patient Labeling (Medication Guide)

10

Inhibition of Chronic Complement Activity

As Measured by LDH

Time, Weeks

La

cta

te D

eh

yd

rog

en

as

e (

U/L

)

0

500

1000

1500

2000

2500

0 4 8 12 16 20 24 28 32 36 40 44 48 52

100% of Patients Responded to Soliris After First Dose

*TRIUMPH placebo patients switched to Eculizumab after Week 26.

All TRIUMPH patients entered the long-term extension study.

P<0.001 at all measured time points.1. Hillmen P et al. Blood. 2007;110(12):4123-4128. 2. Kanakura Y et al. Int J Hematol. 2011;93:36-46.

*TRIUMPH – Placebo / Extension1

TRIUMPH – Ecu/ Extension1

SHEPHERD – Ecu1

AEGIS2

Upper limit of the normal

range (103-223 U/L)

13

Time (years)

Improved Overall Survival in Patients

Treated With Eculizumab

Cu

mu

lati

ve S

urv

ivin

g (

%)

Eculizumab n = 79

Untreated n = 30

1 2 3 4 5 6 7 8 9

20

40

60

80

100

0

Kelly RJ et al. Blood. 2011;117:6786-6792.

14


PNH

Eculizumab



IST



SCT

THROMBOSIS

3/22/2016

3

15


PNH

Eculizumab



IST



SCT

THROMBOSIS

16


PNH

Eculizumab



IST



SCT

THROMBOSIS

17

Severe (SAA)

Hypocellularity (<30%) &

At least 2/3 critèria:

PNN <0.5x109/L

Platelets <20x109/L

Reticulocytes <20x109/L

Very severe (vSAA)

PNN <0.2x109/L

ModerateNot all criteria for SAA

PNN >0.5x109/L

Transfusions?

Yes No

Treatment Follow-up

Camitta et al. Blood 1976

AA and treatment

18


PNH

Eculizumab



IST



SCT

THROMBOSIS

19

Saint Louis experienced Haematologica 2012;97:710-6

AA and sibling donor

HSCT for SAA; young patients and HLA-identical sibling Donor

Marrow

Cy- ATG

CsA + MTX

Long-term outcomes! Median follow-up 73 Mo

Patient characteristics

Characteristics 61 patients

Age at transplant, median (range) ys 21 (4 to 43)

Etiology, n (%)

Idiopathic 49 (80)

Viral hepatitis 7 (11)

PNH 5 (8)

Previously treated, n (%)

No 38 (62)

Yes 23 (38)

20

HSCT for SAA; young patients and HLA-identical sibling Donor

Event No of Events 6yr-CI (%)

Secondary Cancer 1 2 (0-9)

Osteonecrosis 10 21 (10-36)

Cardiovascular complications

1 2 (0-9)

Endocrine dysfunctions

7 19 (9-31)

Saint Louis experienced Haematologica 2012;97:710-6

87,5 % (IC 95%, 78-97)

AA and sibling donor

3/22/2016

4

21

Not upfront! Results with IST

Years after Start of Treatment

15129630

Cum

ula

tive P

roport

ion S

urv

ivin

g

1,0

,8

,6

,4

,2

0,0

ATG

ATG + CsA

Haematologica 2007;92(1):11-8.

Blood 2003; 101: 1236

AA and no sibling donor

22


PNH

Eculizumab



IST



SCT

THROMBOSIS

Sib.No

Sib.

23


PNH

Eculizumab



IST



SCT

THROMBOSIS

Sib.No

Sib.

24

Two Diseases: PNH and AA

Two distinct diseases with significant morbidity and mortality:

PNH – Hemolysis → Thrombosis, End-organ damage

AA/MDS – Aplasia/dysplasia → Anemia, cytopenias

Progress independently

Treat hemolysis in PNH with Eculizumab

Treat aplasia/dysplasia in AA/MDS with immune-

modulating or hypomethylating agents, and/or supportive

care

26

All PNH patients (9/9) experienced an exacerbation of hemolysis during

ATG treatment. ATG was associated with diminished platelet counts in

non-responding patients. (Paquette et al 1997)

ATG lead a 1.6 g / dL decline in Hgb and an increase in LDH from 284

to 1127 U per L.

– Acute renal failure (Scr from 0.9 to 4.2 mg per dL) and the

appearance of dark-colored urine.

– Pre- and post-ATG direct antiglobulin tests were negative. Tran et

al. 2006;

ATG treatment resulted in profound systemic complement activation .

Cell bound TCC increased 2.37 fold and 1.3 fold by day 10 and 30

respectively over baseline (Ebenbichler et al. 1996)

Risk associated with IST can accelerate the

proliferation of both normal and PNH clones

27

Eculizumab Reduces Hemolysis and Improves

Fatigue in IST-Treated Patients

* P<0.01 when prior and post months compared. . P<0.05 when prior and post months compared.

• IST: Severe hemolysis

• Ecu: Significant and sustained

reduction in hemolysis

• IST: Severe fatigue

• Ecu: Significant and sustained

reduction in fatigue

• Demonstrates effectiveness of

treatment with Eculizumab to

reduce hemolysis and fatigue

in AA patients despite

concomitant IST treatment

IST

200

450

700

950

1,200

1,450

-12 -9 -6 -3 0 3 6 9 12

Months of Eculizumab

LDH* * *

N=12

Me

an

LD

H (

U/IL

)


20

25

30

35

40

-12 -9 -6 -3 0 3 6 9 12

¥ ¥¥

N=10

FACIT-Fatigue

Me

an

FA

CIT

Fa

tig

ue


Schrezenmieier et al Blood 2009

3/22/2016

5

28

IST

* P<0.05 when prior and post months compared.

• IST-treated patients had

significant transfusion

requirement

• Soliris significantly reduced

transfusion requirements

• Transfusion reduction

apparent after 6 months of

treatment with continued

improvement

• Hemoglobin remains stable

and in the setting of reduced

transfusions

7

8

9

10

-12 -9 -6 -3 0 3 6 9 12

Months on Eculizumab

Hgb

N=12


Me

an

Hb

(g

/dL

)

Transfusion

Me

an

Tra

ns

fus

ion

Un

its

/Ye

ar


**N=12

Soliris Reduces Transfusion Requirements in

IST-Treated Patients

Transfusions

Schrezenmieier et al Blood 2009 29


PNH

Eculizumab



IST



SCT

THROMBOSIS

Sib.No

Sib.

30


PNH

Eculizumab



IST



SCT

THROMBOSIS

Sib.No

Sib.

31

Is the leading cause of death2

– Accounts for 40-67% of deaths1

– First thrombotic event can be fatal1,3

– First TE increases risk for death 5 to 10-fold1

Up to 44% of patients experience clinical thrombotic events1

Occurs in typical and atypical sites4

Is not adequately managed with anticoagulation1

All patients with PNH are at risk for thrombosis1

Thrombosis in PNH1

1. Hillmen et al. Blood. 2007;110:4123-4128. 2. International PNH Group et al. Blood. 2005;106(12):3699-3709. 3. Audebert HJ et al. J Neurol. 2005;252:1379-

1386. 4. Lee JW et al. Hematologica 2010;95(s2): Abstract #506.

33

94% Reduction of Thrombotic Events on

Long Term EculizumabTherapy1

Sustained benefit out to 8 years

in reducing the rate of TE events

with Eculizumab treatment

From 34 pre-treatment events

(21/79 patients) to 2 events

during Eculizumab therapy

– 7 patients had TEs within

12 months prior to starting

Eculizumab and had no

further thromboses on therapy

Kelly RJ et al. Blood. 2011;117:6786-6792.

34

Eculizumab and anticoagulation in patients

with a history of thrombosis

23 patients with Classic PNH (10 french centers)(15 patients without anticoagulant therapy)

600 mg/7 days 900 mg/15 days

eculizumab

Week 0 Week 5 Week 11

(W0) (W5) (W11)

Helley et al, Haematologica 2010

3/22/2016

6

35



D-D

imère

s (n

g/m

L)

J0 S5 S11

0

0,5

1,0

1,5

2,0

2,5

3,0

3,5

u

p = 0,010

J0 S5 S11 J0 S5 S11

u

Without WithanticoagulationHelley et al, Haematologica 2010

36



D-D

imère

s (n

g/m

L)

J0 S5 S11

0

0,5

1,0

1,5

2,0

2,5

3,0

3,5

u

p = 0,010

J0 S5 S11 J0 S5 S11

u

Without WithanticoagulationHelley et al, Haematologica 2010

37

SCT and Thrombosis

Socié et al, Lancet 1996; Peffault de Latour et al, Blood 2008; Peffault de Latour et al, Haematologica 2012

Patients (n=211) Indications for SCT

AA (n=118);

Thrombosis (n=47);

Recurrent severe hemolytic crisis (n=64)

SCT characteristics HLA-identical siblings (n=136, 65%)

Source of stem cells

BM, n=135 (64%); PBSC, n=71 (34%) and CB, n=4 (2%)

GvHD prophylaxis CSA±MTX (n=154, 73%)

Results

Engraftment, n=188 (n=202)

Acute GvHD grade II-IV, n=52 (29%)

Extensive Chronic GvHD, n=26 (26%)

38

SCT and Thrombosis

Socié et al, Lancet 1996; Peffault de Latour et al, Blood 2008; Peffault de Latour et al, Haematologica 2012

SFH EBMT

122 47

Non grafted SCT

Not confirmed1

121

Severity ?

27

2

Date ?2 2

F-up<6mo post Thr

MDS before 1

4292

2424 Matched pairs

2520151050

80

60

20

Time since thrombosis (year)

40

100

SCT

Non Grafted

p Log Rank = .01

p Cox stratified on pairs = .007

HR SCT/non grafted = 10.0(1.3-78.1)

Overall Survival (OS)

39


PNH

Eculizumab



IST



SCT

THROMBOSIS

Sib.No

Sib.

40

Take home messages

PNH

Eculizumab



IST



SCT

THROMBOSIS

Sib.No

Sib.

Thank you!

3/22/2016

7

COMPSTATINA Peptide Drug to Block Complement at the C3 Level

Qu et al., 2012, Immunobiology

4V9H3,000 nM

4(1MeW)10 nM

Cp400.5 nM

1996 2006 2012

AMD [Phase II]POT-4 [Potentia/Alcon]

AMD, PNH, Sepsis,Hemodialysis, …

C3b

C5

C5aMAC

C4

C2

FD

FB

C3a C3b C3d

C1 MBL Fic P

Compsta n

iC3b

C3

P1:1 (molar) binding

Effect of compstatin analogs on hemolysis of PNH RBCsDose-dependent inhibition

PNH RBC hemolysis:Cp40 (AMY-101) and PEG-Cp40 (AMY-105)

0

10

20

30

40

50

60

70

80

90

100

0,1 1 10 100

Concentration (uM)

% o

f ly

sis

ob

serv

ed

in

aN

HS

CP30

AMY-101

AMY-105

Risitano et al, Blood 2014

C3-FITC

Erythrocytes in

acidified serum

+ Cp40 10 uM

CD

59

-PE

CD

59

-PE

Erythrocytes in

acidified serum

+ PEG-Cp40 10 uM

Both Cp40 and its PEGylated derivative completely

abolish hemolysis of PNH erythrocytes in vitro

Cp40 and PEG-Cp40 completely prevent C3 fragment

deposition on PNH RBCs incubated in aNHS

Non-PEGylated Cp40 in monkeysAn alternative strategy for clinical utilization

High bioavailability after s.c. injection,

but short half-life (12-15h)

Repetitive s.c. injections every 12 hours

(1 mg/kg) resulted in sustained

pharmacological levels

Twice daily s.c. administration of Cp40

(1 mg/kg) seems the optimal schedule for

initial clinical investigation in humans

pro: C3 activity can be regained

rapidly in case of adverse eventRisitano et al, Blood 2014

Application for

marketing authorization?

2 weeks (multiple injections)

PK/PD data in

human

volunteers

2016 2018

Apr Jul Oct Jan Apr Jul Oct Jan

AMY-101 clinical development plan

Phase Ia: First-in-human PK/PD study

in human volunteers

1 day (single injection)

2 weeks (multiple injections)

Phase II/III: efficacy studies

in different PNH populations

Jan

Phase Ib/II: First-in-PNH pilot study

in 10 untreated PNH patients

Proof of

concept in

PNH

2017

Phase I in healthy volunteer (HV) ongoing (EU funding FP7 program)

Phase I in PNH: planned for mid 2016

Academic collaboration between Naples (Risitano), Sao Paulo (Calado

and Scheinberg) and Philadelphia (Lambris)

A first-in-PNH trial on 10 untreated PNH patients

Two-week exposure; SC injection (dose and scheduled confirmed

after PK/PD data in HV)

Supported by the AAMDS Foundation, the AIEPN and Amyndas (sponsor

of the study)

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