complement: the next frontier in immunology? cedric ... · complement: the next frontier in...

Complement: the next frontier in immunology?Cedric Francois, MD, PhDCorfu, May 2017

CONFIDENTIAL AND PROPRIETARY – for discussion purposes only


Similarities between starfish and humans?

2

COMPLEMENT


The Complement System

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The Complement System

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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

Inflammation Cell destruction


Complement central to innate immunity

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Innate“Shock and Awe”

Adaptive“Self vs Non-Self”


Rise of Adaptive Immunity

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RAG genesActivation)Pathways





C5



Cell)destruction

Eculizumab

C3

C3bC3a

Inflammation Cell destruction


Roles of Complement

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Activation)Pathways





C5



Cell)destruction

Eculizumab

C3

C3bC3a

Approved Complement Inhibitors

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Complement Immunotherapy?in Refractory Myasthenia Gravis

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Complement Immunotherapy?in Neuromyelitis Optica

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Temporary courses of complement inhibition to correct auto-immunity in diseases like PNH and AMD

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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


APL$1APL$2

Activation.Pathways

Classical.pathwayActivated)by)antibody.antigen)complex

Lectin.pathwayActivated)by)lectin)and)mannose)complex

Alternative.pathwaySpontaneous)C3)


C3

C3bC3a

C5


Inflammation Cell.removal

Cell.destruction

Lead candidates target C3 central in the complement cascade

Broad inhibition of complement

cascade

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APL-2


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

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Peptides of the APL-1 / APL-2 family bind to a pocket of C3 and inhibit activation*

APL-2


Complement inParoxysmal Nocturnal Hemoglobinuria

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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)

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35-40% of Soliristransfusion dependent*


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





C5



Cell)destruction

Eculizumab

C3

C3bC3a

Soliris does not block extravascular hemolysis

C3b$on$RBC

INTRAVASCULAR

EXTRAVASCULAR

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Activation)Pathways





C5



Cell)destruction

Eculizumab

C3

C3bC3a

Can APL-2 block extravascular hemolysis?

C3b$on$RBC

INTRAVASCULAR

EXTRAVASCULAR

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Potential Benefit APL-2 • Reduced anemia and transfusion dependency


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

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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

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


Complement inAge-related Macular Degeneration

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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

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GA Market Opportunity


(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


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*


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


� 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


Advancement of Disease PRE-2005

HEALTHY

GA

WET AMD

BLIND


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


Flow Superimposed on StructureEn face flow and intensity image En face intensity image

12x12 angio

CNV


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


Therapeutic Potential

ComplementImmunotherapy

AMDDry EyeUveitis

rMGNMOMSGuillain BarreAlzheimer’s

COPDFibrosis

C3GIgA NephropathyLupus NephritisTransplantation

PNHaHUS

AIH


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


Complement in Reproduction

BIO Derby 2017


Thank you Dad


Thank you Mom

complement: the next frontier in immunology? cedric ... · complement: the next frontier in...

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