complement: the next frontier in immunology? cedric ... · complement: the next frontier in...
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Complement: the next frontier in immunology?Cedric Francois, MD, PhDCorfu, May 2017
CONFIDENTIAL AND PROPRIETARY – for discussion purposes only
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CONFIDENTIAL AND PROPRIETARY – for discussion purposes only
Similarities between starfish and humans?
2
COMPLEMENT
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CONFIDENTIAL AND PROPRIETARY – for discussion purposes only
The Complement System
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CONFIDENTIAL AND PROPRIETARY – for discussion purposes only
The Complement System
4
Activation)Pathways
Classical)pathwayActivated)by)antibody.antigen)complex
Lectin)pathwayActivated)by)lectin)and)mannose)complex
Alternative)pathwaySpontaneous)C3)
convertase)activation
C5
C5bC5a MACInflammation
Inflammation Cell)removal
Cell)destruction
Eculizumab
C3
C3bC3a
Inflammation Cell destruction
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CONFIDENTIAL AND PROPRIETARY – for discussion purposes only
Complement central to innate immunity
5
Innate“Shock and Awe”
Adaptive“Self vs Non-Self”
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CONFIDENTIAL AND PROPRIETARY – for discussion purposes only
Rise of Adaptive Immunity
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RAG genesActivation)Pathways
Classical)pathwayActivated)by)antibody.antigen)complex
Lectin)pathwayActivated)by)lectin)and)mannose)complex
Alternative)pathwaySpontaneous)C3)
convertase)activation
C5
C5bC5a MACInflammation
Inflammation Cell)removal
Cell)destruction
Eculizumab
C3
C3bC3a
Inflammation Cell destruction
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CONFIDENTIAL AND PROPRIETARY – for discussion purposes only
Roles of Complement
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Activation)Pathways
Classical)pathwayActivated)by)antibody.antigen)complex
Lectin)pathwayActivated)by)lectin)and)mannose)complex
Alternative)pathwaySpontaneous)C3)
convertase)activation
C5
C5bC5a MACInflammation
Inflammation Cell)removal
Cell)destruction
Eculizumab
C3
C3bC3a
Approved Complement Inhibitors
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CONFIDENTIAL AND PROPRIETARY – for discussion purposes only
Complement Immunotherapy?in Refractory Myasthenia Gravis
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CONFIDENTIAL AND PROPRIETARY – for discussion purposes only
Complement Immunotherapy?in Neuromyelitis Optica
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CONFIDENTIAL AND PROPRIETARY – for discussion purposes only
Temporary courses of complement inhibition to correct auto-immunity in diseases like PNH and AMD
11
Science: Complement Immunotherapy
Complement Activation Phagocyte Activation
(e.g. M1/ M2) Oxidation of proteins /
phospholipids Adduct formation
Cell Death
Tissue specific Dendritic Cells
T Cells
B Cells Low affinity
Polyclonal Antibodies
Th17 Polarization
Th17 Signaling
Fluid Phase Activation
Oxidative Damage, Allergens Infections?
Break Self-Tolerance
Classical
Alternative (MDA ! CFH402)
LYSIS IMMUNE
STOP
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APL$1APL$2
Activation.Pathways
Classical.pathwayActivated)by)antibody.antigen)complex
Lectin.pathwayActivated)by)lectin)and)mannose)complex
Alternative.pathwaySpontaneous)C3)
convertase)activation
C3
C3bC3a
C5
C5bC5a MACInflammation
Inflammation Cell.removal
Cell.destruction
Lead candidates target C3 central in the complement cascade
Broad inhibition of complement
cascade
12
APL-2
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APL-2 is a potent and selective C3 inhibitor
*Janssen,J.Biol.Chem.,282(40),29241-29247,2007
� APL-2§ Long-acting version of APL-1§ Subcutaneous for PNH§ Intravitreal for GA
APL-1Ac-IC*V(Me)WQDWGAHRC*T-NH2
13
Peptides of the APL-1 / APL-2 family bind to a pocket of C3 and inhibit activation*
APL-2
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CONFIDENTIAL AND PROPRIETARY – for discussion purposes only
Complement inParoxysmal Nocturnal Hemoglobinuria
14
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CONFIDENTIAL AND PROPRIETARY – for discussion purposes only
Meaningful unmet need in PNH
DISEASE
� ~4,700 patients in the US� Severe anemia and thrombotic risk� ~35% 5-year mortality if left untreated (main cause:
thrombosis)
STANDARD OF CARE
� Soliris® only approved therapy§ ~$583,000 / year / adult patient
UNMET NEED SOLIRIS
� Average Hb ~10 g/dL� Continued Transfusion dependency 35% - 40%
*Hillmen,P.etal.Br.J.Haematology,2013,162(1):62–73(Dr.Hillmen isanadvisortoApellis)
15
35-40% of Soliristransfusion dependent*
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Intravascular vs extravascular hemolysis
Rother R,RollinsSA,Mojcik C,BrodskyRAandBellL. Discoveryanddevelopmentofthecomplementinhibitoreculizumab forthetreatmentofparoxysmalnocturnalhemoglobinuria.NatureBiotechnology.2007.25(11):1256-1264.
No#Complement+mediated#
hemolysisC5/MAC+mediated
Intravascular#hemolysisC3b+mediated
Extravascular#hemolysis
HEALTHY PNH)PatientsC3b#on#RBC
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Activation)Pathways
Classical)pathwayActivated)by)antibody.antigen)complex
Lectin)pathwayActivated)by)lectin)and)mannose)complex
Alternative)pathwaySpontaneous)C3)
convertase)activation
C5
C5bC5a MACInflammation
Inflammation Cell)removal
Cell)destruction
Eculizumab
C3
C3bC3a
Soliris does not block extravascular hemolysis
C3b$on$RBC
INTRAVASCULAR
EXTRAVASCULAR
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CONFIDENTIAL AND PROPRIETARY – for discussion purposes only
Activation)Pathways
Classical)pathwayActivated)by)antibody.antigen)complex
Lectin)pathwayActivated)by)lectin)and)mannose)complex
Alternative)pathwaySpontaneous)C3)
convertase)activation
C5
C5bC5a MACInflammation
Inflammation Cell)removal
Cell)destruction
Eculizumab
C3
C3bC3a
Can APL-2 block extravascular hemolysis?
C3b$on$RBC
INTRAVASCULAR
EXTRAVASCULAR
18
Potential Benefit APL-2 • Reduced anemia and transfusion dependency
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0
50
100
150
200
250
300
350
400
450
500
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
103 /u
L
Weeks
ReticulocyteCount
0
2
4
6
8
10
12
14
16
-28 -26 -24 -22 -20 -18 -16 -14 -12 -10 -8 -6 -4 -2 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
g/dL
Weeks
Hemoglobin
APL-2 improves Hb and normalizes reticulocytes
19
Soliris®APL-2
Normal
Normal
Hemoglobin
Reticulocyte Count Weeks
Weeks0Five of six subjects receiving 900mg / week
or 1,200mg / 2 weeks
7 6 5 4 3 2 1 0 1 2 3 4 5 6 7 Months Dosing (n=6)
Transfusions
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CONFIDENTIAL AND PROPRIETARY – for discussion purposes only20
Phase 3 Superiority APL-2 vs Soliris2018 20192017
APL-2 Twice per Week
NDA
APL-2
Expected Hb
Expected Hb
6-month efficacy Enrollment
n=TBD
n=TBD
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Complement inAge-related Macular Degeneration
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CONFIDENTIAL AND PROPRIETARY – for discussion purposes only
Meaningful unmet need in age-related macular degeneration
DISEASE
� Intermediate AMD: drusen but no serious vision loss � Wet AMD: blood leakage in retina� GA: slow progressive retinal death à starts in periphery /
blind when central � ~15M patients with AMD, ~1M with GA in US*
STANDARD OF CARE
� Wet AMD: anti-VEGF (Lucentis, Avastin, Eylea)� iAMD and GA: supportive care
UNMET NEED
� Intermediate AMD: no approved therapies � GA: no approved therapies
*http://www.asrs.org/patients/retinal-diseases/2/agerelated-macular-degeneration
Intermediate AMD
Wet AMD
GA
22
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GA Market Opportunity
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CONFIDENTIAL AND PROPRIETARY – for discussion purposes only24
(SEOM)N=40
ShamEvery Other
Month
APL-2 15 mgEvery Other Month
(AEOM)N=79
Sham Monthly
(SM)N=41
APL-2 15 mgMonthly
(AM)N=86
Safety, Tolerability and Evidence of Activity N=246
Randomized 2:1:2:1
Phase 2 GA – Filly design
Treatment Period Follow up
AM=2 D0
AEOM=2
SM=1
SEOM=1
M1 M2 M3 M4 M5 M6 M7 M8 M9 M10 M11 M12
D0 M1 M2 M3 M4 M5 M6 M7 M8 M9 M10 M11 M12
D0 M2 M4 M6 M8 M10 M12
D0 M2 M4 M6 M8 M10 M12
Randomization
M15 M18
M15 M18
M15 M18
M15 M18
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CONFIDENTIAL AND PROPRIETARY – for discussion purposes only25
Phase 2 GA – Filly design
Safety, Tolerability and Evidence of Activity N=246 subjects randomized 2:2:1:1
APL-2 15 mgEOM
N=79
APL-2 15 mgMonthly
N=86
APL-2 EOMN=78*
APL-2 MonthlyN=84*
N=40
Sham EOM
Sham Monthly
N=41
Sham PooledN=81*
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CONFIDENTIAL AND PROPRIETARY – for discussion purposes only
Primary Efficacy Endpoint� The primary endpoint is the change in square root geographic
atrophy (GA) lesion size from baseline at month 12 as measured by FAF.
Primary Safety Endpoint� Number and severity of local and systemic treatment emergent
adverse events (TEAE).
Phase 2 GA – Filly Endpoints
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� DSMB allowed study to continue based on stable VA � Updated Investigator Brochure and Informed Consent� Last patient last treatment: July 2017
Wet AMD conversions in
#
%
Yes No Yes No Yes No
# 0/29 1/52 4/24 2/55 10/35 4/51
% 0% 2% 17% 4% 29% 8%
SHAM(n=81)
1/81 4/79
EOM(n=79) EM(n=86)
14/86
ContralateralNeovascularAMD
1% 5% 16%
6/79
8%
Contralateral Wet AMD
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CONFIDENTIAL AND PROPRIETARY – for discussion purposes only
Advancement of Disease PRE-2005
HEALTHY
GA
WET AMD
BLIND
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HEALTHY
GA
WET AMD
Advancement of Disease 2005 - 2017
BLIND
~20% require onlyfew injections
~80% requirechronic anti-VEGF
~98% develop GAafter 7 years of anti-VEGF
BLIND
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Flow Superimposed on StructureEn face flow and intensity image En face intensity image
12x12 angio
CNV
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CONFIDENTIAL AND PROPRIETARY – for discussion purposes only
HEALTHY
GA
WET AMD
Advancement of Disease POST-2017?
BLIND
C3 Inh.C3 Inh.
C3 Inh.
~20% require onlyfew injections
~80% requirechronic anti-VEGF
~98% after 7 years chronic anti-VEGF
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Therapeutic Potential
ComplementImmunotherapy
AMDDry EyeUveitis
rMGNMOMSGuillain BarreAlzheimer’s
COPDFibrosis
C3GIgA NephropathyLupus NephritisTransplantation
PNHaHUS
AIH
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Fun Facts about Complement 💜🎈💊🌋🍀🍾
� C3 is required to mount a Th1 response
� Local organ synthesis of C3 is required to reject organs
� There is a fully functional complement system INSIDE intracellular vesicles that plays a key autocrine and regulatory role in immune cell biology
� Modulating complement in synaptic pruning and microglial regulation might have disease modifying potential in neurodegenerative diseases
� Complement regulation in immuno-oncology virtually unexploited
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Complement in Reproduction
BIO Derby 2017
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Thank you Dad
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Thank you Mom