creating new immunotherapies to fight disease
TRANSCRIPT
1
Creating New
Immunotherapies
to Fight Disease
Non-Confidential
January 2019
2
Forward Looking Statements
This presentation contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933,
Section 21E of the Securities Exchange Act of 1934 and the Private Securities Litigation Reform Act of 1995. These forward-
looking statements are not based on historical fact and include statements regarding Alpine’s platform technology, potential
therapies, potential milestone and royalty payments, future development plans, clinical and regulatory objectives and the timing
thereof, expectations regarding the sufficiency of cash to fund operations into 2020, expectations regarding the plans of its
collaborator, expectations of future collaborations, and expectations regarding the potential efficacy and commercial potential of
Alpine’s and its collaborator’s product candidates. Forward-looking statements generally include statements that are predictive in
nature and depend upon or refer to future events or conditions, and include words such as “may”, “will”, “should”, “would”,
“expect”, “plan”, “intend”, and other similar expressions among others. These forward-looking statements are based on current
assumptions involving risks, uncertainties, and other factors that may cause actual results, events, or developments to be
materially different from those expressed or implied by such forward-looking statements. These risks and uncertainties, many of
which are beyond our control, include, but are not limited to: Alpine’s discovery-stage and pre-clinical programs may not
advance into the clinic or result in approved products on a timely or cost-effective basis or at all; Alpine may not achieve
additional milestone payments pursuant to its collaborations; the impact of competition; adverse conditions in the general
domestic and global economic markets; as well as the other risks identified in our filings with the Securities and Exchange
Commission. These forward-looking statements speak only as of the date hereof, Alpine undertakes no obligation to update
forward-looking statements, and readers are cautioned not to place undue reliance on such forward-looking statements.
“Variant Immunoglobulin Domain”, “vIgD”, “Transmembrane Immunomodulatory Protein”, “TIP”, “Secreted Immunomodulatory
Protein”, and “SIP” are registered trademarks or trademarks of Alpine Immune Sciences, Inc. in various jurisdictions.
All rights reserved.
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Leading the Next Generation of Immunotherapies
Platform Technology
Powerful platform technology
to be leveraged for strategic
partnerships and licensing
opportunities
Alpine’s lead programs in inflammation and oncology targeted to enter the clinic in 2019
Management Team
Proven development,
regulatory, and commercial
success in both autoimmune
diseases and oncology
Investors
Premier Life Sciences
investors
ALPN-101
Dual ICOS/CD28 antagonist
for inflammatory diseases
targeted to begin clinical
studies Q1-2019
ALPN-202
Dual PD-L1/CTLA-4 antagonist,
and CD28 agonist for oncology
indications targeted to enter the
clinic Q4-2019
Cell Therapy Enhancement
Engineered expression of
costimulatory ligands or
selective checkpoint
antagonists
Using Directed Evolution to Create Powerful Multifunctional Immunotherapies
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POWERFUL
SCIENTIFIC PLATFORM
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Turning Immunoglobulin Superfamily (IgSF) Proteins Into Novel Therapeutics
• IgSF is the largest human protein superfamily, with
765 members identified1
• Named for the Ig domain (70-110 amino acids)
found in antibodies
• Includes many targets which have evolved as
critical regulators of immunity, e.g.
1Nature 409:860 (2001)
Group Examples
Checkpoint PD-1, PD-L1, CTLA-4, TIGIT, Lag-3,
VISTA, CD47
Costimulatory CD28, ICOS, CD80, CD86, CD2
Antigen Receptor-
Related
CD3, TCR, BCR, MHC, CD19, CD4, CD8
Cytokine Receptors IL-1R, IL-6R, CSF1RNat Rev Immunol 2:116 (2002)
The CD28 Protein FamilyA Critical IgSF Subfamily
X
6
Variant Ig Domains (vIgDs) are IgSFs Engineered via Directed Evolution to
Acquire Target Specificity and Optimize Immune Modulation
Bead and/or flow cytometric
selection
vIgD
Fc-fusion protein
generation
Counter-structure binding
assays
Functional assays
IgSF ECD Yeast Display
LibrariesIgSF Protein
Optimized vIgD
Limited counter-structureswith low/moderate affinity
Random and/or targeted mutagenesis
Assess in vivo andin vitro pharmacology
Analyze yeast outputs for desired binding
Sequence yeast outputs to identify unique variant hits
Mammalian cell line production
A tailored non-
antibody domain
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vIgDs Facilitate Multiple Potential Therapeutic Formats
Formats: vIgD Fc Fusion V-mAb Cell Therapy
Enhancement
Structure 70-110 aa vIgD-Ig Fc Multi-vIgD-Fc vIgD-mAb fusion vIgD ± TM
Example
Schematic
Purpose(s) Base domain Single domain
therapeutic
•Multi-functional, multi-domain therapeutic
•Target- (e.g., tumor-) specific immune activity
Potentiation of
engineered
immunotherapy
Examples • ICOSL vIgD
•CD80 vIgD
•ALPN-101
•ALPN-202
•NKp30-ICOSL-Fc
(B7-H6-specific)
•PDL1-CD155-Fc
•Trastuzumab-ICOSL
(anti-HER2)
•CD86 vIgD TIP
•PD-1-CD28
“Switch” TIP
TCR/
CARFc mAbFc
TIP Transmembrane Immunomodulatory Protein
Lead Programs
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TWO LEAD PROGRAMS
ALPN-101 & ALPN 202
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ALPN-101
Autoimmune/Inflammatory Diseases
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ALPN-101: a First-In-Class Dual CD28/ICOS Antagonist for Multiple
Inflammatory Disease Indications
CD28 and ICOS:
Key T cell Costimulatory
Pathways
ICOSCD28
ICOSLCD80
CD86
T cell
APC
Currently Available
Therapeutics Block
Only the CD28 Pathway
ICOSCD28
ICOSLCD80
CD86
CTLA4-Ig
ICOSCD28
ICOSLCD80
CD86
ALPN-101
ICOSL vIgD-Fc*
ALPN-101 (ICOSL vIgD-Fc)
Blocks Both CD28 & ICOS
Pathways
*Effectorless IgG1 Fc†Orencia 2017 sales = $2.5B (Source: BMS)
†
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Inhibition of Both CD28 and ICOS Pathways
Likely Required to Treat Many Serious Inflammatory Diseases
Naïve T cell
CD28+ ICOS-
CD28+ ICOS+
T cell activation:
ICOS
CD28 (some cells) CD28- ICOS+CD28lo ICOS+
Activated / Effector / Memory / TFH cellsVarious populations
CD28
ICOS
During activation, T cells lose CD28 dependence but
upregulate ICOS – the most closely related IgSF member
Activation / Time
CD28 ICOS
Rela
tive O
vera
ll C
ostim
ula
tory
Dependence / E
xpre
ssio
n
Relative Redundancy of CD28 and ICOS
- Lupus (Arthritis Rheum 62:3077, 2010)
- Sjögren’s (Mod Rheumatol 26:891, 2016)
- Myositis (Ann Rheum Dis 77:55, 2018)
- GvHD (Transpl Immunol 43-44:54, 2017)
- IBD (Gastroenterology 143:62, 2012)
- Multiple Sclerosis (Mult Scler 23:686, 2017)
CD28 blockade (abatacept) has been
only modestly or not effective in:
- Lupus (Arthritis Rheumatol 70:1071, 2018)
ICOS blockade (prezalumab) has
been only modestly effective in:
- GvHD (JCI Insight 1:e86660, 2016)
- Arthritis (Nature 542:110, 2017)
- Sjögren’s (Arthritis Rheumatol 70:774, 2018)
- Myositis (Brain 127:1182, 2004)
- IBD (Gastroenterology 126:829, 2004)
- Multiple Sclerosis (PLoS One 8:e57820, 2013)
ICOS+ / TFH cells have been
implicated in:
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ALPN-101 Harbors Broad Potential in Multiple Therapeutic AreasSuperior Efficacy in Diverse Disease Models vs. Active Comparators
GI: Inflammatory Bowel Disease
Heme/Onc: Acute Graft-Versus-Host Disease Rheumatology: Rheumatoid, Psoriatic, Juvenile Idiopathic Arthritis
Preventative Dosing Therapeutic Dosing
Neurology: Multiple Sclerosis
MOG Adoptive Transfer Experimental
Autoimmune Encephalomyelitis
Company data
Human Xenogenic NSG
CD45RBhi Colitis
Collagen-
Induced
Arthritis
ICOSL vIgD-Fc
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Initial Indications for ALPN-101 are Psoriatic Arthritis and Acute GvHD
PsA offers a considerable
commercial opportunity
• ~250-300K patients per year affected with
moderate to severe psoriatic arthritis
• TNFs, IL-17s, and IL-12/23s expected to dominate
market. Competitive pipeline offering few novel
MOAs
• Orencia’s revenues are projected at $250M+ U.S. in
2025 despite modest effects
• ALPN-101 has shown ability to differentiate from
Orencia in multiple preclinical models
GvHD has significant unmet needs.
The opportunity is relatively small
but rapidly evolving
• ~4K Acute GvHD patients per year
• Predominately a T Cell mediated disease
• 30-50% do not respond to available therapies
• Preclinical data strongly support activity of
ALPN-101 in this disease population
• Single dose of ALPN-101 has been shown to be
effective in aggressive preclinical model
Psoriatic Arthritis (PsA) Acute GvHD
New therapeutic options needed for a host of other potentially ICOS/CD28 mediated diseases:
Lupus, Sjogren’s syndrome, Inflammatory Bowel disease (IBD), Ophthalmology (Uveitis/Dry Eye),
and Pulmonary Fibrosis
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Initial Clinical Strategy for Lead Program ALPN-101
Phase 1 Healthy
Volunteer
Phase 1b Psoriatic Arthritis
Phase 1b Acute Graft-versus-Host Disease
✓ Preclinical development
✓ GMP manufacturing with sufficient drug substance to complete initial Phase 1 Studies
Phase 2 / Pivotal Trials
Expansion into other indications
Key Biomarker and
Safety Data (PK/PD)
Preliminary Data
Readout to support Ph2
2019 2020 2021 2022 2023
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ALPN-101 Development and Lifecycle Vision
Heme/OncAcute GvHD
TransplantationAllograft Rejection
Rejection Prophylaxis
Heme/OncChronic GvHD
GvHD Prophylaxis
RheumatologyPsoriatic Arthritis
RheumatologySjögren’s Syndrome
Systemic Lupus Erythematosus RheumatologySystemic Sclerosis
Inflammatory Myositis
Vasculitis
RheumatologyJuvenile Idiopathic Arthritis
Rheumatoid Arthritis
GastroenterologyCrohn’s Disease
Ulcerative Colitis
NeuroscienceMultiple Sclerosis
OphthalmologyUveitis
PulmonologyInterstitial Lung Disease
• Broad, diverse market potential
• Initial core investments in
rheumatology and heme/onc will
enable most efficient proof-of-concept
• Compatible with self-sustained or
partnered development
16
ALPN-202
Oncology
17
ALPN-202 is a Dual PD-L1/CTLA-4 Antagonist with PD-L1 Dependent
T-Cell Activation (e.g., Costimulation)
Greater than 70% of Patients
Receiving PD-1/L1 Therapy
Do Not Respond,
Likely Due to Insufficient T
Cell Activation, e.g.
Costimulation
ALPN-202 is a first-in-class molecule with the
potential to improve response rates through
necessary costimulation
ALPN-202 Driven Immune Response
ALPN-202(CD80 vIgD-Fc)
Fc
CD80 vIgDs
PD-1 CD28
PD-L1
TCR/CD3
Complex
MHC
Tumor cell
T cell
ALPN-202
TCR/CD3
Complex
MHC B7
CTLA-4
Tumor cell
T cell
CD28
ALPN-202
181 10 100 1000 10000 1000001000000
0
20000
40000
60000
[pM]
MF
I
Fc Control
ALPN-202
Ipilimumab(anti-CTLA-4)
1 100 10000 10000000
5000
10000
15000
20000
25000
IL-2
(p
g/m
L)
ALPN-202
WT CD80-Fc
Durvalumab (anti-PD-L1)
Nivolumab (anti-PD-1)
Fc Control
No PD-L1
1 100 10000 10000000
5000
10000
15000
20000
25000
[pM]
IL-2
(p
g/m
L)
With PD-L1
1 10 100 1000 10000 10000010000000
1000
2000
3000
[pM]
MF
I
Fc Control
ALPN-202
Atezolizumab(anti-PD-L1)
Three Primary Mechanisms of Action of ALPN-202
1. PD-L1 Antagonism
2. CTLA-4 Antagonism
3. PD-L1-Dependent Costimulation
(CD28 Agonism)
Primary T cells + K562 ± hPD-L1
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ALPN-202 Exhibits Potent Efficacy in vivoAnti PD-L1 Superiority as Judged by Tumor Responses and Gene Signatures
ALPN-202-pretreated
Naive
PD-L1 inhibitor-superior, Efficacy as Monotherapy …with Evidence of Anti-Tumor Immunity
Superior Intra-Tumoral Inflammatory Signatures
0 10 20 30 400
500
1000
1500
2000
Day
Me
dia
n T
um
or
Vo
lum
e (
mm3
)
Fc Control
ALPN-202
durvalumab (anti PD-L1)
p < 0.0001
ALPN-202 vs
durvalumab
Mice dosed
0/11 mice tumor free
2/11 mice tumor free
8/11 mice tumor free
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ALPN-202 Phase 1 Strategy
Demonstrate Early Monotherapy Activity and Enable Combo Development
• Population: advanced malignancies (all-comer)
- May enrich for any translationally justified tumors
- Consider 1st line PD-(L)1 on-label tumors in combo
• Design
- “Subtherapeutic”: Single patient cohorts
- “Active” doses: 3+3 dose escalation,
• Assessments
- ORR, DOR, PFS, OS
- Retrospective biomarker analysis
Monotherapy Dose
EscalationMonotherapy Dose Expansion
PD-1 Combo Dose
EscalationPD-1 Combo Dose Expansion
Combo within or as separate protocol
Single arm
PD-1 resistant
tumors/patients
3-way combo
PD-1 labeled
indication(s)
Monotherapy
Efficacy
Observed
Combo
Appropriate
2121
FOCUS ON
DELIVERING VALUE
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Enhancement of
Cell-Based
Immunotherapies
TIP/SIP Program
Improved Cell
Proliferation &
Persistence
Enhanced
T Cell Killing
Engagement of
Bystander T cellsIncreased Tumor
Immunogenicity
23
TIP/SIP: vIgD-Based Enhancement of Engineered Cell-Based Therapies
24
vIgD TIPs Potently Augment Engineered T Cell ActivityExample: CD86 vIgD TIPs with HPV E6 TCR
vIgD TIPs exhibit superior proliferation, cytokine production, and cytotoxicity over TCR as well
as TCR + wild-type IgSF TIPs. Reproduced across multiple targets and CAR/TCR systems.
Improved Cytotoxicity
Increased T cell Cytokine Production
Enhanced T cell Proliferation
25
Switch vIgD TIPs Improve T Cell Activity, Proliferation, and Cytotoxicity
0 10000 20000 30000 40000 500000
1000
2000
3000
4000
CD4+ T Cells Proliferation
Target Cell #
Cell c
ou
nt
0 10000 20000 30000 40000 500000
5000
10000
15000
20000
CD8+ T Cell Proliferation
Target Cell #
Cell c
ou
nt
Enhanced T cell Proliferation Improved Cytotoxicity
Increased T Cell Cytokine Production
0 10000 20000 30000 40000 500000
1000
2000
3000
4000
5000
IFN Release 24 Hours
Target Cell #
pg
/ml
2:1 1:1 1:20
20
40
60
Killing of Caski Cells at 24 Hours
E:T Ratio
% K
illin
g o
f T
arg
et
Cells TCR only
H1646 PD1-CD28
H1646 PD1-CD28.4-1BB
H1646 PD1-CD28.ICOS
H1646 PD1-CD28.ICOS.4-1BB
H1646 PD1-No ICD
Intracellular CD28, ICOS, and 4-1BB ICDs alone or in combination
PD-1 vIgD ECD TMD CD28/ICOS/4-1BB ICD
26
ALPN-101 & ALPN-202 Recent Scientific Presentations
December 1, 2018
Therapeutic Candidate ALPN-101, a
Dual ICOS/CD28 Antagonist, Potently
Suppresses Human/NSG Mouse
Xenograft Graft Vs. Host Disease
(GvHD) in a Dose Ranging Study and
Reduces Disease Activity in a Mouse
Model of Hemophagocytic
Lymphohistiocytosis (HLH)
October 21, 2018
ALPN-101, a Dual ICOS/CD28
Antagonist, Potently Suppresses
Disease in Multiple Mouse Models of
Autoimmunity
October 21, 2018
Therapeutic Candidate ALPN-101, a
Dual ICOS/CD28 Antagonist,
Demonstrates In Vivo Efficacy in an
Experimental Autoimmune
Encephalomyelitis (EAE) Model
November 9, 2018
ALPN-202, a combined PD-L1/CTLA-4
antagonist and PD-L1-dependent
CD28 T cell costimulator, elicits potent
intratumoral T cell immunity superior to
and differentiated from PD-L1 inhibitor
monotherapy
December 2, 2018
Oral Presentation from Indiana Univ.
Collaborators
ICOSL+ Plasmacytoid Dendritic Cells
As Biomarker and Inducer of
Graft-Versus-Host Disease
December 1, 2018
“Switch” Transmembrane
Immunomodulatory Proteins (TIPs)
Consisting of High-Affinity PD-1
Extracellular Domains (PD-1 vIgDs)
and Costimulatory Intracellular
Domains Potently Enhance the Activity
of TCR-Engineered T Cells
27
Pipeline of Potential Novel Therapies
PROGRAM DISCOVERY IND-ENABLING PHASE 1 COLLABORATOR
Autoimmune/Inflammatory Diseases
ALPN-101 (Dual ICOS/CD28 antagonist)
Undisclosed Programs
Immuno-Oncology
ALPN-202 (PD-L1/CTLA-4 Antagonist & CD28 Agonist)
Undisclosed Programs
Cellular Therapy Enhancement (Undisclosed Targets)
PsA
GvHD
28
Strong Financial Position
$62 millioncash equivalents as of
September 30, 2018
$25 millionraised January 2019
Sufficient
cash runway to fund operations
into 2021
~13.9 million shares outstanding as
of August 2018
Analyst Coverage
29
Strong Leadership Team with Deep Clinical, Regulatory, and
Commercial Expertise
LEADERSHIP TEAM PRINCIPAL INVESTORS
Stanford Peng, M.D., Ph.D. EVP of R&D, Chief Medical Officer
Ryan Swanson VP of Immunology & Co-Founder
Paul RickeyChief Financial Officer
Mark Litton, Ph.D.President & Chief Operating Officer
Kristine Swiderek, Ph.D.Senior VP of Research
Mitchell H. Gold, M.D. Executive Chairman & CEO
30
Leading the Next Generation of Immunotherapies
Platform Technology
Powerful platform technology
to be leveraged for strategic
partnerships and licensing
opportunities
Alpine’s lead programs in inflammation and oncology targeted to enter the clinic in 2019
Management Team
Proven development,
regulatory, and commercial
success in both autoimmune
diseases and oncology
Investors
Premier Life Sciences
investors
ALPN-101
Dual ICOS/CD28 antagonist
for inflammatory diseases
targeted to begin clinical
studies Q1-2019
ALPN-202
Dual PD-L1/CTLA-4 antagonist,
and CD28 agonist for oncology
indications targeted to enter the
clinic Q4-2019
Cell Therapy Enhancement
Engineered expression of
costimulatory ligands or
selective checkpoint
antagonists
Using Directed Evolution to Create Powerful Multifunctional Immunotherapies
31
Thank You
COPYRIGHT © 2019 ALPINE IMMUNE SCIENCES, INC. ALL RIGHTS RESERVED.