Selective Modulation of Fc Receptors for Improved Therapy of Orphan Autoimmune Diseases: Lessons from IVIg
Anthony M. Manning, PhD
VP Research
May 5, 2015
Presentation Outline
• Unmet Needs in Autoimmune Disease
• Key Role for FcgR System in Pathogenesis & Learnings from IVIg
• Rational Design of SIFs
• Pre-clinical Profile of SIF3
• Next Steps in Development
2
Over 80 distinct diseases, 50 million Americans affected, $100B+ annual economic burden
NIH Autoimmune Diseases Coordinating Committee 2013; AARDA Report 2011
Rh
eum
ato
id A
rth
riti
s
Psoriasis Asthma IBD Multiple Sclerosis
Ankylosing Spondylitis Dermatomyositis Mysthemia GravisLupus APS
6.5 million
PATIENTS
2million
PATIENTS
13million
PATIENTS
1million
PATIENTS
370thousandPATIENTS
600thousandPATIENTS
150thousandPATIENTS
130thousandPATIENTS
70thousandPATIENTS
40thousandPATIENTS
Psoriasis Rheumatoid Arthritis Asthma IBD Multiple Sclerosis
There is an Immunologic Basis for Many Diseases
3
NMO: Neuromyelitis optica; CIDP: Chronic inflammatory demyelinating polyneuropathy; ANCA: ANCA associated vasculitis; MG: Myasthenia gravis; APS: Antiphospholipid syndrome; GBS: Guillain-Barre Syndrome; ITP: Idiopathic thrombocytopenic purpura; Sources: Orphanet, Medscape, Triangle Insights’ analysis, Health Advances’ analysis
500,0001,500,0002,500,0003,500,0004,500,0005,500,0006,500,0007,500,000 Psoriasis
Rheumatoid arthritis
Psoriatic arthritisUlcerative colitis
Crohn’sAnkylosing spondylitis
U.S. diagnosed prevalence of 16 autoimmune indications
0
20,000
40,000
60,000
80,000
100,000
120,000
140,000
160,000Systemic lupus erythematosus
APS
MGANCA
CIDP
NMO
U.S
. dia
gno
sed
pre
vale
nce
GBS
ITP
Pemphigus/pemphigoid
Dermatomyositis/polymyositis
Autoimmune Indications … A Tale of Two Cities
4
• Recent innovation driving improved patient care and significant market value
• Robust pipelines but mostly incremental advances
• Unmet need exists but biological basis unclear
NMO: Neuromyelitis optica; CIDP: Chronic inflammatory demyelinating polyneuropathy; ANCA: ANCA associated vasculitis; MG: Myasthenia gravis; APS: Antiphospholipid syndrome; GBS: Guillain-Barre Syndrome; ITP: Idiopathic thrombocytopenic purpura; Sources: Orphanet, Medscape, Triangle Insights’ analysis, Health Advances’ analysis
500,0001,500,0002,500,0003,500,0004,500,0005,500,0006,500,0007,500,000 Psoriasis
Rheumatoid arthritis
Psoriatic arthritisUlcerative colitis
Crohn’sAnkylosing spondylitis
US diagnosed prevalence of 16 autoimmune indications
0
20,000
40,000
60,000
80,000
100,000
120,000
140,000
160,000Systemic lupus erythematosus
APS
MGANCA
CIDP
NMO
US
dia
gno
sed
pre
vale
nce
GBS
ITP
Pemphigus/pemphigoid
Dermatomyositis/polymyositis
Autoimmune Indications … A Tale of Two Cities
5
• More than 70 distinct diseases
• Lack of recent innovation to satisfy high unmet medical needs
• Few agents in development
• Recent innovation driving improved patient care and significant market value
• Robust pipelines but mostly incremental advances
• Unmet need exists but biological basis unclear
NMO: Neuromyelitis optica; CIDP: Chronic inflammatory demyelinating polyneuropathy; ANCA: ANCA associated vasculitis; MG: Myasthenia gravis; APS: Antiphospholipid syndrome; GBS: Guillain-Barre Syndrome; ITP: Idiopathic thrombocytopenic purpura; Sources: Orphanet, Medscape, Triangle Insights’ analysis, Health Advances’ analysis
500,0001,500,0002,500,0003,500,0004,500,0005,500,0006,500,0007,500,000 Psoriasis
Rheumatoid arthritis
Psoriatic arthritisUlcerative colitis
Crohn’sAnkylosing spondylitis
US diagnosed prevalence of 16 autoimmune indications
0
20,000
40,000
60,000
80,000
100,000
120,000
140,000
160,000Systemic lupus erythematosus
APS
MGANCA
CIDP
NMO
US
dia
gno
sed
pre
vale
nce
GBS
ITP
Pemphigus/pemphigoid
Dermatomyositis/polymyositis
Autoimmune Indications … A Tale of Two Cities
6
IVIg BenlystaNplate & Promacta
$0
$100
$200
$300
$400
$500
$600
$700
$800
$900
$1,000
$1,100
2011
2012
2013
2014
2015
2016
2017
2018
2019
2020
WW
re
ven
ue
($
M)
Anti-BAFF antibody
Chronic maintenance of SLE
Approved 2011
Incremental improvement
2013 WW sales $228M
$0
$100
$200
$300
$400
$500
$600
$700
$800
$900
$1,000
$1,100
2008
2009
2010
2011
2012
2013
2014
2015
2016
2017
2018
2019
2020
WW
re
ven
ue
($
M)
Nplate Promacta
TPO agonists
Third-line agents in ITP
Not disease-modifying
Approved 2008
Combined 2013 WW sales $718M
IgG fraction from pooled plasma of ~10K donors
Approved therapy for PID and 5 inflammatory diseases
Used in >50 other indications
2013 WW sales $6.2Bn
$0.0
$2.0
$4.0
$6.0
$8.0
$10.0
2009
2010
2011
2012
2013
2014
2015
2016
2017
2018
WW
sal
es
($B
n)
Innovation in a Low-prevalence Autoimmune Disease Creates Substantial Value
7
Auto-antibodies Mediate Disease and Are Not Targeted by Current Therapeutics
8
Auto-antibodies and immune complexes mediate tissue damage and dysfunction in
autoimmune and inflammatory disease
Therapeutic strategies that indirectly target auto-antibody production have
been only partially successful
Strategies that directly target auto-antibodies and immune complexes have
proven valuable in challenging clinical settings, but have limited utility in chronic
or maintenance settings
Anti-DNA ANCA Anti-Rho
Central Role for Fcg Receptors in Autoantibody-mediated Diseases
9
IVIG Activity is Replicated by the Fc Domain Alone
10
A c u te IT P S tu d ie s
L o g D o s e [µ m o le s /k g ]
% P
late
let
Re
co
ve
ry
-0 .5 0 .0 0 .5 1 .0
0
2 0
4 0
6 0
8 0
1 0 0
IV Ig
F c
HillSlope
EC50
IVIg
0.6449
1.091
Fc
0.5144
0.8932
• Fc domain provides equivalent efficacy to IVIG in the mouse ITP model • Fc materials derived from IVIg or recombinant Fc are comparable
Murine anti-CD41-induced Acute Thrombocytopenia Model
Fc Fragment is Efficacious in Humans
11
Fc fragment efficacy is comparable to IVIG or corticosteroids in ITP patients*
0 1 2 3 4 5 6
Day
400
300
200
100
0Pla
tele
t co
un
t x 1
09/L
Platelet recovery after IVIG Fc Fragment
• 0.75g/kg Fc
Platelet recovery after IVIG or methylprednisolone (MP)
Pediatric ITP patients Balkan et al 20092g/kg IVIG
30 mg/kg MP
But Fc fragment halflife is short
Fc Fragments (43 hrs)
IVIG (19 days)
Pediatric ITP patients Debre et al 1993
Adult patients or volunteersJaneway et al 1968
Efficacy was also shown with the Fc fragment in Kawasaki disease Hsu et al 1993
*
25-50 kDa Fc fragments are rapidly eliminated via renal excretion
Proprietary IPDA algorithms
Momenta bio-characterization toolkit
Application of Momenta Patient Bio-characterization Toolkit
Kawasaki’s disease study FcR biology index
Subj 1
Subj 2
Subj 3
Subj 4
Subj 5
Subj 6
-1 0 2 3 51 4
Normal range
= Pre-IVIg = Post-IVIg
IVIg Treatment Suppresses FcR biology
12
IgG Receptors Play a Key Role in Disease and Therapy
A family of receptors binding the Fc portion of IgGs
Key mediators of auto-antibody and immune complex functions
Genetic variants associated with autoimmune diseases
IgG Receptors
FcγRI FcγRIIA FcγRIIB FcγRIIC FcγRIIIA FcγRIIIB FcRn
α
β2mα-GPI
α2γαα
ITIMαα2γ
Activation Activation Activation ActivationInhibition ActivationRecycling TransportAg uptake…
13
FcgR Modulation Profiles that Might Offer Benefit in Autoimmune Disease
14
Broad FcgRModulation
Specific FcgRModulation
Spectra of Fcg-Receptor Family Modulation
IVIg
FcgR Ratio Modulation
Specific Abs
IVIg-like (Broad Modulation)
Target FcgR Ratio Specific FcgR
Supported primarily by mouse data & human cell assays & emerging
competitor agents
Supported primarily by IVIg MOA Theoretical based on a compilation of mouse data & human
expression data
SIF3: Powerful Anti-inflammatory Agent Fully Harnessing IVIg Mechanism of Action
FcgR binding
> 100x increased affinity than IVIg
mM
nM
IVIg
SIF
15
• Homogeneous recombinant Fc-derived product
• IVIg-like specificity for FcgRs
• Unique molecular design enhances avidity and potency to modulate FcgRbiology
• Potent antagonist of autoantibody-mediated diseases
FcM=
µg/ml µg/ml
RF
U
(Ma
x-M
in)
Co
ntr
ol
FcM IC
IVIg
0
2 0
4 0
6 0
8 0
1 0 0
Establishing the SAR for Polymeric IgG Fc’sLarge Polymers of Fc Activate FcgR’s
Calcium Release in Monocytes
FcgR Signaling in MonocytesFc Multimer
p /t S y k
Fo
ld C
ha
ng
e
FcM
FcM
-LM
W
FcM
-F1
FcM
-F2
FcM
-F3
FcM
-F4
0
2 0
4 0
6 0
F c M
F c M -L M W
F c M -F 1
F c M -F 2
F c M -F 3
F c M -F 4
SDS-PAGE of Fc Multimer Fractions Monocyte Activation by Fc Multimer Fractions
Polymeric IgG Fc Results in Cellular ActivationSize Matters
A Library of Multimeric-Fc Structures
18
Diversity of Molecular Structures…. …..Assessed for Fc Receptor Modulation
Including unique mutations that regulate ordered subunit association
Structure-Activity Relationship of Polymeric Fc’s Size Matters
F c g R IIIa V 1 5 8
IC5
0 (m
M)
CH
mo
no
mer
no
rmal tr
imer ,
CK
H
inver t
ed
tr i
mer
pen
tam
er
X
pen
tam
er
Y
0 .0 0 0 1
0 .0 0 1
0 .0 1
0 .1
1
FcgRIIIA Receptor Binding Affinity
Increased apparent affinity driven by increased avidity
p /t S y k
m g /m l
Fo
ld C
ha
ng
e
0.0
0.0
05
0.0
2
0.0
5
0.1
4
0.4
1
1.2
3
3.7
0
11.1
33.3
100
0
1 0
2 0
3 0
4 0
5 0
Ig G 1
IV Ig
F c 1
F c 2
F c 3 Y
F c 3 L
F c 5 X
F c 5 Y
Structure-Activity Relationship of Polymeric Fc’s Size Matters
Ca Release in Primary Human Monocytes
FcgR Signaling in Primary Human Monocytes
Multimers Display Enhanced Avidity to FcgReceptors
Multimerization increased low affinity FcgR binding through avidity
21
F c g R IIb
IC5
0 (
mg
/mL
)
Fc1
Fc2
Fc3
1 .01 0 -3
1 .01 0 -2
1 .01 0 -1
1 .01 0 0
F c g R I
IC5
0 (
mg
/mL
)F
c1
Fc2
Fc3
0
5 .01 0 -6
1 .01 0 -5
1 .51 0 -5
F c g R IIIa
IC5
0 (
mg
/mL
)
Fc1
Fc2
Fc3
1 .01 0 -5
1 .01 0 -4
1 .01 0 -3
1 .01 0 -2
1 .01 0 -1
1 .01 0 0
F c g R IIa
IC5
0 (
mg
/mL
)
Fc1
Fc2
Fc3
1 .01 0 -6
1 .01 0 -5
1 .01 0 -4
1 .01 0 -3
1 .01 0 -2
1 .01 0 -1
1 .01 0 0
Notes: Logarithmic y-axis for FcγRIIIa, IIa, and IIb. Lower IC50 = Higher relative affinity.
170x650x
80x
1980x
10x
210x
1x
0.5x
Minimal changes for FcgRI
P re -T re a tm e n t C o n d it io n
RF
U
(Ma
x-M
in)
Med
ium
100u
g/m
L S
IF 3
Med
ium
100u
g/m
L S
IF 3
Med
ium
100u
g/m
L S
IF 3
0
5
1 0
1 5
2 0
2 5
4 4 0 mg /m L IC
4 4 mg /m L IC
V e h ic le
SIF3 is a Potent Antagonist of Immune-Complex-mediated FcgR Activation
Ca Release in Primary Human Monocytes
FcgR Signaling in Primary Human Monocytes
Phagocytosis in Monocytes
IL -8
u g /m l
pg
/ml
0 .0 0 0 1 0 .0 1 0 .1 1 1 0 1 0 0
0
1 0 0 0 0
2 0 0 0 0
3 0 0 0 0
IV Ig
S IF 3
p b Ig G 1
IgG
1 a
lon
e
In h ib it io n o f P h a g o c y to s is in P r im a r y M o n o c y te s
n g /m l
% i
nh
ibit
ion
1 0 -2 1 0 0 1 0 2 1 0 4 1 0 6
0
2 0
4 0
6 0
8 0
1 0 0
1 2 0
IV Ig
S IF 3
F c -B lo c k
SIF3 Inhibits Multiple Cellular Functions of FcgReceptors
Cytokine Production in Monocytes
Ca Release in Neutrophils Cytokine Production in PBMCs
• Fc-trimer displayed 100-fold higher potency than IVIg
24
A c u te IT P a C D 4 1 -0 0 7
IV Ig v s . F c 2 v s . F c 3
lo g IV Ig /F c D o s e [g /k g ]
Pla
tele
t P
ro
tec
tio
n [
%]
-3 -2 -1 0
0
2 0
4 0
6 0
8 0
1 0 0
1 2 0
a C D 4 1 (3 .5 u g ) + IV Ig
a C D 4 1 (3 .5 u g ) + F c 2
a C D 4 1 (3 .5 u g ) + F c 3
Murine anti-CD41-induced Acute Thrombocytopenia Model
A c u te IT P a C D 4 1 -0 0 7
IV Ig v s . F c 2 v s . F c 3
lo g IV Ig /F c D o s e [g /k g ]
Pla
tele
t P
ro
tec
tio
n [
%]
-3 -2 -1 0
0
2 0
4 0
6 0
8 0
1 0 0
1 2 0
a C D 4 1 (3 .5 u g ) + IV Ig
a C D 4 1 (3 .5 u g ) + F c 2
a C D 4 1 (3 .5 u g ) + F c 3
IC50 IVIg = 338 mg/kgIC50 rFc dimer = 93 mg/kgIC50 rF trimer = 30 mg/kg
SIF3 Displays Enhanced Potency in an Acute ITP Mouse Model When Compared to IVIg
P l a t e l e t L e v e l s D a y 5
I so
t yp
e (
1. 5
ug
) +
Sa
l in
e
CD
41
( 1. 5
ug
) +
Sa
l in
e
CD
41
( 1. 5
ug
) +
IV
I g a
t 1
g/ K
g
CD
41
( 1. 5
ug
) +
M- 1
13
at
0. 0
04
g/ K
g
CD
41
( 1. 5
ug
) +
M- 1
13
at
0. 0
2 g
/ Kg
CD
41
( 1. 5
ug
) +
M- 1
13
at
0. 1
g/ K
g
0
3 0 0
6 0 0
9 0 0n o r m a l r a n g e
Pla
te
le
t 1
09
/L
IVIg Fc3Controls
Da
y 0
Da
y 1
Da
y 2
Da
y 3
Da
y 4
Da
y 5
Da
y 6
Da
y 7
Da
y 8
Da
y 9
Da
y 1
0
0
2
4
6
8
1 0
1 2
M - 1 1 3 , 0 . 1 g / k g
M - 1 1 2 , 0 . 1 g / k g
I V I g , 0 . 1 g / k g
P B S c o n t r o l
I V I g , 1 g / k g
Av
er
ag
e C
lin
ica
l S
co
re
SIF3 Displays Enhanced Efficacy and Potency in K/BxNand ITP Mouse Models When Compared to IVIg
K/BxN Serum Transfer Arthritis ModelMurine anti-CD41 Antibody-induced Chronic Thrombocytopenia Model
• Fc2 and Fc3 at 0.1 g/kg showed similar levels of protection to IVIg at 1 g/kg indicating that Fc2 and Fc3 were more potent than IVIg
• Chronic ITP model suggest ~50 times potency increase for Fc3 over IVIg
M112= Fc2M113= Fc3
Inhibition of complement deposition in the paws
SIF3, 0.05 g/kgIVIg 1 g/kgVehicle
IVIg 1 g/kg
SIF3, 0.05 g/kg
Vehicle
SIF3 Suppresses Collagen-Antibody-Induced Arthritis
Greater potency and efficacy than IVIg
27
28 Day Multi-Dose Safety Assessment in Mice
Day 0
PrebleedPK & ADA
Day -5
Day 7
Cytokines Day 3
PK, ADA & Tissue Paramters
Assessment parameters :• PK assay: day -5, 6, 13, 20 & day 27• ADA assays: day -5, 6, 13, 20 & day 27• Cytokines: day -5, 3, 10, 13, 17 & 27• Complement deposition in tissues-IHC Day 13 & 27• Complement assay with Plasma• PAF assay: day 13 & 27• Blood cell count, Vet Scan: Day 13 & 27• Toxicity/Clinical chemistry: Day 13 & 27• Tissue assessment
Day 21
Study Design
Day 14
Dosing with SIF3 @ 0.1g/kg and 0.01g/kg iv
PK & ADA Day 6
CytokinesDay 10
Collection of tissues PK & ADA
Day 13
CytokinesDay 17
PK & ADA Day 20 Day 27
Urine collection for baseline readout
Day 13
SIF3 was well-tolerated and no remarkable findings were observed
SIF3 Has Appropriate Properties for Manufacturing
• Product is homogenous >98 % trimer by CE-SDS
• Titers greater than 3 g/l in early cell line development
28
0
20
40
60
80
100
120
0 4 7 14
% b
y SE
C
Time (days)
Stability at 45C :SEC profiling of main species @ 45C
SIF3
IgG1
0
20
40
60
80
100
T=0 T=3h T=6h T=24h
Are
a-%
Stability at pH 3:SIF SEC profiling
Hexamer
Penatmer
Trimer
Dimer
Monomer
0
20
40
60
80
100
120
T= 0 T= 3h T= 6h T= 24h
Are
a-%
Stability at pH 3: IgG1 SEC profiling
Aggregate-1
Aggregate-2
Aggregate-3
IgG1
Next Steps in Development
• SIF3 is in pre-clinical development
• Anticipate initiation of clinical trials in 2H 2016
• Potential in multiple autoimmune diseases with autoantibody-mediate pathology and activated FcgR system
• Potential as a personalized therapy
29