XmAb™5871 anti-CD19

Antibodies by Design:
XmAb® Antibody Therapeutics
December 2014
Antibodies by Design
Forward-Looking Statements
Statements contained herein regarding matters that are not historical facts are "forward -looking statements" within the meaning of
the Private Securities Litigation Reform Act of 1995, including statements associated with Xencor’s expectations regarding future
therapeutic and commercial potential of Xencor’s business plans, technologies, programs, drug candidates and intellectual property
related to Xencor’s XmAb technology being discovered and developed by Xencor or its partners. Because such statements are
subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward -looking
statements. Words such as "believes," "anticipates," "plans," "expects," "intends," "will," "goal," "potential" and similar e xpressions
are intended to identify forward-looking statements. These forward-looking statements are based upon Xencor’s current expectations
and involve assumptions that may never materialize or may prove to be incorrect. Actual results and the timing of events cou ld differ
materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties, which include,
without limitation, risks associated with the process of discovering, developing and commercializing drugs that are safe and effective
for use as human therapeutics, and in the endeavor of building a business around such drugs. These and other risks concerning
Xencor’s programs and technology are described in additional detail in Xencor’s SEC filings. All forward-looking statements speak
only as of the date on which they were made. Xencor undertakes no obligation to update such statements to reflect events that occur
or circumstances that exist after the date on which they were made.
2
Xencor Mission: Engineering Antibody Immune
Functions To Make Better Drugs
 XmAb platform uses key mAb structure, the Fc domain
– Augments native immune properties of mAb
– Native half-life, production and stability
Antibody Structure
Fv
– Platform generated all clinical and pre-clinical programs
– Continually expanding platform functionality
– 85 issued and 122 pending patents worldwide
 Developing therapeutics to treat autoimmune
diseases, asthma and allergic diseases and cancer
– Eight mAb clinical programs ongoing internally and with
partners
 Six collaborations
3
XmAb® Fc Domains
Value Drivers
Antibodies by Design
 Development inflection points expected in near term
–
XmAb5871 Phase 1b/2a rheumatoid arthritis (RA) topline data expected
YE2014
–
XmAb7195 Phase 1a IgE reduction data expected Jan 2015
–
XmAb5574/MOR208 Phase 2 data expected YE2014
(MorphoSys at ASH 2014)
–
Bispecific programs primate data presented at YE2014
(ASH 2014)
Antibody Structure
Fv
 XmAb® platform is basis for value creation
–
Continual stream of mAb drugs with novel immune modulation for
treating disease
–
Preserves key structure and function of mAbs, the Fc domain
 Augments native immune properties of mAb
 Native half-life, production and stability
4
XmAb® Fc Domains
XmAb® Fc Domains Shift Focus of Antibody Drug
Discovery by Creating New Axis for Differentiation
Standard Antibodies
Fv
focus
Same Fc
Rituxan
Herceptin
Xolair
Humira
Fv bispecifics
XmAb5871
XmAb7195
Xtend-TNF
XmAb bispecific
XmAb Antibodies
Xencor Fc
Domains
XmAb5574
5
XmAb® Fc Domains Augment
Natural Antibody Functions
Natural Fc
Function
Fc Receptor
Immune regulation
Antigen clearance
Cytotoxicity
(immune cell)
Circulating halflife
Stable
homodimer
structure
FcgRIIb
FcgRIIa, FcgRIIIa
FcRn
N/A
FcgR
Fc domain redesigns
XmAb
Enhanced
Function
Immune
Inhibitor
Domain
Cytotoxic
Domain
Xtend
Domain
Bispecific
Domain
Immune inhibition
Rapid clearance
Enhanced
cytotoxicity
(immune cell)
Prolonged halflife
Stable
heterodimer
structure
Additional Fc domains: stability, complement activation
99.5% identical to natural antibody
Plug-and-play substitution into any antibody
6
Fc Domain
XmAb® Technology has Created Numerous Differentiated
Antibodies and Technology Licenses
Leads
PROGRAM
Fc DOMAIN
PRIMARY
INDICATION
XmAb5871
Immune Inhibitor
Autoimmune
XmAb7195
Immune Inhibitor
Asthma/allergy
XmAb5574/MOR208
Cytotoxic
Oncology
CLL/NHL/ALL
DISCOVERY
LEAD
PRECLIN
PHASE 1
PHASE 2
COMMERCIAL
RIGHTS
*
7
XmAb Technology
Licensees
Internal
Preclinical
* Currently in Phase 2a portion of Phase 1b/2a clinical trial
CD123 x CD3
Heterodimer
Oncology
CD38 x CD3
Heterodimer
Oncology
CD20 x CD3
Heterodimer
Oncology
Xtend-TNF
Xtend
Autoimmune
Anti-X/CD32b
Immune Inhibitor
TBD
Undisclosed
Cytotoxic
Oncology
Undisclosed
Cytotoxic
Oncology
Undisclosed
Cytotoxic
Oncology
Undisclosed
Stability
Autoimmune
Undisclosed
Xtend
Undisclosed
Undisclosed
Xtend
Hematology
Undisclosed
Xtend
Autoimmune
XmAb5871 Target Product Profile:
Inhibit Multiple Pathways of B cells without Killing B cells
Fv binds CD19
B-cell impact
Rituxan
Growth inhibition
Immune Inhibitor Fc Domain
FcgRIIb binding up by ~400x.
Benlysta
XmAb5871


T-cell stimulation inhibition

*
Antibody production
inhibition


Depletion

ACR20 in RA
51%
Black box warnings
4
#
25-35%
0
# Fatal infusion reactions, severe mucocutaneous reactions, Hepatitis B virus reactivation, progressive
multifocal leukoencephalopathy
* Reduced CD86 expression
Rituxan product label. Benlysta product label. Benlysta RA data, Stohl, J Rheumatol, 2013.
8
XmAb®5871: Enhance natural regulatory role of FcgRIIb
with XmAb Fc Domain
Natural:
Ag + Ag Immune Complex
Ag
XmAb5871:
anti-CD19 with
Immune Inhibitor Fc domain
Ag
XmAb5871
BCR
FcgRIIb
FcgRIIb
CD19
BCR
complex
B cell
B cell
 FcgRIIb inhibitory activity requires bridging to specific co-targets
 Inhibits many activation pathways in both healthy and diseased B cells
 Potent suppression of B-cell responses without destroying B cells
9
Chu, Mol Immunol, 2008
XmAb®5871: Preliminary Clinical Data Supports
Potent B-cell Inhibition without B-cell Depletion
Phase 1a: Inhibition of Antigen Challenge

Currently in Phase 2a in RA

Development planned in IgG4-Related Disease
Day 21 measurement
–

Potent, yet reversible, B-cell inhibition data in Phase 1
–
–
.03
Plan trial start 2015
Observed effective suppression of B-cell responses to
antigen without destroying B cell
Target best-in-class efficacy with better tolerability
0.1 0.2 0.6 2.0 5.0 10
Dose level (mg/kg)
Phase 1a: Reversible Biomarker Suppression
Stimulated
% B a s eCD86
lin e SExpression
t im u la t e d C D 8 6 e x p r e s s i o n
Ex vivo: Survival prolonged in
SLE PBMC-engrafted huSCID mice
p=0.0027
100
X m A b 5 8 7 1 ( 2 m g /k g )
P e rc e n t
150
P la c e b o
75
XENP5871
100
50
50
25
0
0
0
10
PBS
20
40
60
D ays
80
100
0
10
20
30
40
50
Horton, J Immunol, 2011
XmAb®5871 Phase 1b/2a trial: Ongoing Study in
Patients with Active RA

Phase 1b/2a trial: ongoing study in patients with active rheumatoid arthritis on
stable non-biologic disease modifying anti-rheumatic drug (DMARD) therapy
–
Multi-center, randomized, placebo controlled, double-blinded
–
Phase 1b Multiple Ascending Dose portion of trial – Enrollment completed August 2013 (29 patients)
 Six bi-weekly IV infusions, 0.3, 1.0, 3.0 and 10.0 mg/kg
 Primary objectives: safety, tolerability, PK and immunogenicity
–
Phase 2a portion of trial – First patient enrolled September 2013
 Six bi-weekly IV infusions, 10 mg/kg
 Up to 30 patients total, 2:1 randomization
 Evaluate RA disease response by Disease Activity Score 28 using C-reactive Protein (DAS28
CRP) at Week 13
Phase 2a RA topline data expected YE2014
11
XmAb®5871 B-cell Inhibition Potential in Numerous
Indications Considered for Possible Development
Large Indications









Ankylosing spondylitis (AS)
Scleroderma
Moderate-severe systemic lupus erythematosus (SLE)
Sjogren’s syndrome
Lupus nephritis
Relapsing-remitting multiple sclerosis (RRMS)
Rheumatoid arthritis
Crohn’s disease
IBD
Small Indications













Autoimmune hemolytic anemia
Acquired Factor VIII inhibition
Pemphigus
Discoid lupus erythematosus (DLE)
Waldenstrom’s macroglobulinemia (WM)
Desensitization for renal transplantation
IgG4-related disease
Idiopathic thrombocytopenic purpura (ITP)
Chronic GVHD
Antiphospholipid syndrome
Refractory Myasthenia gravis
Chronic inflammatory demyelinating polyneuropathy
Steroid-refractory Uveitis
Key criteria: Competitive landscape, unmet need,
cost/speed of development
12
Planned Clinical Development of XmAb®5871 in
IgG4-Related Disease in 2015

Multiorgan disease
–
–
Pancreas, biliary ducts, salivary glands
common
Majority have multiple organs involved
A
A) Characteristic histology including
obliterative phlebitis (arrow) in
pancreatitis
B) Lung disease, thickening of
bronchovascular bundle

Common histopathology is observed
across all organs and is the established
diagnostic criteria
–
–
–

Histopathologic criteria for diagnosis
reduces risk of heterogeneous disease
seen in other autoimmune indications

Prevalence
–
13
Dense lymphocytic infiltrate
 IgG4+ plasma cells
Storiform fibrosis
Obliterative phlebitis
C) Submandibular gland
enlargement
B
C
~ 10-20,000 patients in US
Stone J et al 2012 NEJM 366:539.
Deshpande V et al 2012 Mod Path 25:1181.
Kamisawa et al 2014 Lancet doi:10.1016/S0140-6736(08)61345-8
(figures)
XmAb®7195 Targets IgE, the Key Activating Mediator of
Allergic Diseases
IgE
allergen
IgM, IgG
IgE
Th2 stimuli
B cell
IgE B cell
Plasma
Cell
Airflow obstruction
allergen
IgE
Skin inflammation
Nasal inflammation
FceR1
Histamine
Prostaglandins
Leukotrienes
Mast Cell
IgE reduction is very well validated for severe asthma.
Xolair 2012 sales est. > $1.2B.
14
Unmet Need in Severe Asthma:
Xolair’s Modest Potency Due to Limited IgE Reduction

Xolair dose set by patient IgE level and
body weight
–
–

Product label defines eligible IgE load
Allergic asthma poorly controlled on combination
inhaler therapy, often oral corticosteroids
Xolair IgE reduction is modest, thereby
contra-indicated for hardest-to-treat >20%
of patients (highest IgE and body mass)
–
Xolair package insert and Sorkness, JACI, 2013
Deemed target IgE level

Refractory severe asthmatics respond to
Xolair only if their IgE is controlled

Of treated patients, about 50% fail to
achieve deemed target IgE reduction after
treatment with Xolair, thereby limiting
efficacy
–
15
Lowe, Br J Clin Pharmacol, 2009 (Novartis)
XmAb®7195 Reduces IgE in vivo Below Detection Limits
via Natural FcgRIIb Pathways
Xolair: 1 mechanism of action, binds IgE
IgE
allergen
IgE
Plasma
Cell
IgE B cell
Incomplete blockade of IgE
XmAb7195: 3 mechanisms of action
XmAb7195
FcγRIIb
1
2
Binds IgE
3
Sends IgE to liver sinusoidal
endothelial cells for destruction
Reduces IgE production
IgE
IgE B cell
Plasma
Cell
FcγRIIb
16
XmAb®7195 Localizes IgE to the Liver
89Zr-IgE Distribution by PET Imaging
No Ab
XmAb7195
anti-IgE (IgG1 Fc)
1 hour post injection
17
XmAb®7195 Single Dose in Chimpanzees Reduces Total
IgE Consistent with Clearance Mechanism
total IgE (ug/ml)
IgE (ug/ml)
10
Xolair: 3-5x increased
1
XmAb7195: drops below 0.2 ug/ml LLOQ
Xolair
XmAb7195
0.1
0.01
0.001
0
10
20
30
40
50
Days
Xolair: Total IgE increases 3-5x
IgE
XmAb7195: Total IgE dramatically
reduced by Fc-mediated clearance
FcγRIIb
18
Liver sinusoidal
endothelial cells
XmAb®7195 Single Dose in Chimpanzees
Superior Reduction of High Free IgE Levels
Xolair data
IgE vs. asthma symptoms
Xolair
~ 50 ng/ml
XmAb7195
< 4 ng/ml
Lowe, BJCP, 2009
Limit of quantification
Free IgE (ng/ml)
XmAb7195
< 4 ng/ml

Chimps have naturally high IgE levels:
–



Lowe, Br J Clin Pharmacol, 2009 (Novartis)
Five of six chimps on study off the Xolair dosing table
Single 5 mg/kg dose approximates Xolair top dose of 375 mg
XmAb7195 clearance of free IgE is very rapid
XmAb7195 has potential to address full spectrum of severe asthmatics, including
the hardest-to-treat asthma patient population with high IgE levels
–
19
Xolair
~ 50 ng/ml
Ineligible for current therapies
On-going and planned Phase 1 Studies
To Target Safety and IgE Reduction

Phase 1 trials
–
–
–

Phase 2 proof-of-concept preliminary scheme
–
–
–

20
Readily monitor IgE reduction throughout trials
Phase 1a Single Ascending Dose
 Will include cohorts of allergic subjects with high IgE levels required (> 300 IU/ml)
Phase 1b Multiple Ascending Dose (following successful Phase 1a trial safety
assessment)
 Will include cohorts of mild to moderate asthma patients
Intermediate term treatment (6 months) of poorly controlled asthmatics
Expected to include high IgE/Body mass patients
Dosing guided by Phase 1 IgE reduction data
Phase 1a initial IgE reduction data by January 2015
XmAb®5574/MOR208 Depletes B-cell Tumors in
Hematologic Oncology
Fv binds CD19

Most advanced of 4 XmAb® Cytotoxic
programs in clinic
–
–
–

Clinical Stage Cytotoxics
Partner
21
2
Boehringer Ingelheim
1
Boehringer Ingelheim
1
CSL
1
CLL, acute lymphoblastic leukemia (ALL), nonHodgkin lymphoma (NHL)

MorphoSys licensed in June 2010

Multiple phase 2 starts by MorphoSys in BALL, NHL and CLL

Phase 2 data in NHL from MorphoSys
expected YE2014 (ASH 2014)
Phase
MorphoSys
CD19 expression profile on broader range of
B-cell tumors than CD20
–
Cytotoxic Fc Domain enhances binding
to FcgRIIIa ~40x and FcgRIIa ~5x.
Phase 1/2a chronic lymphocytic leukemia (CLL)
monotherapy trial completed
30% objective response rate (Dr. John Byrd, PI,
Ohio State)
Well tolerated, no MTD reached
–
Diffuse large B-cell lymphoma (DLBCL) fast track
designation from FDA
XmAb® Technology Continues to Broaden
R&D Pipeline at Xencor
Natural Fc
Function
Fc Receptor
Immune regulation
Antigen clearance
Cytotoxicity
(immune cell)
Circulating halflife
FcgRIIb
FcgRIIa, FcgRIIIa
FcRn
Stable
homodimer
structure
FcgR
Fc domain redesigns
XmAb
Enhanced
Function
Immune
Inhibitor
Domain
Cytotoxic
Domain
Xtend
Domain
Bispecific
Domain
Immune inhibition
Rapid clearance
Enhanced
cytotoxicity
(immune cell)
Prolonged halflife
Stable
heterodimer
structure
Additional Fc domains: stability, complement activation
99.5% identical to natural antibody
Plug-and-play substitution into any antibody
22
Fc Domain
XmAb® Bispecific Fc Domains
Retain Beneficial Natural Antibody Properties

Overcomes numerous problems of first-generation bispecific formats
–
–
–

Antibody-like half-life in vivo
Readily produced and purified
Stable dimeric structure to build numerous formats
Enhanced separation
Heterodimer favored
High stability
Robust heterodimer Fc scaffold enables rapid
candidate generation and format flexibility
Stable cell line expression of XmAb14045
Heterodimer Fc domain thermal stability
T m = 7 2 .1 
C p ( k c a l/m o l/ C )
30
T m = 7 7 .5 
20
10
0
30
23
40
50
60
70
T e m p e ra tu re ( C )
80
90
Xencor Lead Bispecific Programs: T-Cell Engagement
with Tuned Potency and mAb-like PK
CD123 x CD3 (XmAb14045)
Anti-tumor
e.g. CD123
Basophils in periphery (top) and bone marrow (bottom)
Cynomolgus monkey, single IV bolus
Profound, sustained depletion
3000
Number of Events
XP14045
XP14045
2000
1000
0
0
200
400
Hours
24

CD123 x CD3 (XmAb14045) for AML selected for
IND-enabling studies

CD20 x CD3 for B-cell malignancy

CD38 x CD3 for myeloma

GMP process development underway

Primate data YE2014 (ASH 2014)
600
Patent Coverage of XmAb® Platform and Lead Programs
is Multi-layered

XmAb platform
–
–
–

Total patent estate
–
–
25
22 issued and 56 pending US patents
63 issued and 66 pending foreign patents
Issued US and foreign patents for each key XmAb Fc
domain
Fv domains
Humanized and affinity
optimized
50 issued and 83 pending US patents
126 issued and 113 pending foreign patents

XmAb7195 patent expiry 2030

XmAb5871 patent expiry 2028

XmAb5574 patent expiry 2029
XmAb®
Fc domains with patented
mutations
Milestones and goals 2013-2014

2013
 XmAb5871 Phase 1b start and Phase 2a start in RA
 Three XmAb technology licenses: Alexion, CSL, Merck
 Partner milestones
 MorphoSys Phase 2 XmAb5574/MOR208
 Janssen technology option exercise
 Completed IPO, net $72.4 million

2014 expected

–
–

XmAb7195 Phase 1a start HV/High IgE
XmAb7195 Phase 1a IgE reduction data
XmAb5871 Phase 1b/2a topline data in RA
Bispecific program initiation
 XmAb14045, anti-CD123 x CD3 (IND-enabling studies)
– Additional technology licensing deals
 Additional partner milestones
 Merck Phase 1 start
 Alexion Phase 1 start Xtend™ technology

26
Cash expected at 12/31/2014 $54 million, runway expected through 2016
Antibodies by Design:
XmAb® Antibody Therapeutics
December 2014
Antibodies by Design

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