Leading the Next Evolution of Immunotherapies - Q1 2021 - Alpine ...
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Leading the Next Evolution of
Immunotherapies
Q1 2021
1
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 through 2024, expectations regarding the plans of its
collaborators, 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 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.
2
Leading the Next
Evolution of ALPN-303
Immunotherapies ALPN-202 Dual B Cell
Cytokine Antagonist
ALPN-101 Conditional CD28
Costimulator and Dual B Cell-Mediated
With a Highly Productive Dual Costimulation Checkpoint Inhibitor Inflammatory
Directed Evolution Antagonist Diseases
Platform Immuno-oncology
Systemic Lupus Phase 1
Erythematosus Phase 1 Start Targeted 2021
Partnered with Advanced
Malignancies
Phase 2
In Preparation
3
ALPN-101
Autoimmune/Inflammatory Diseases:
Dual CD28/ICOS Antagonist
4
ALPN-101: A First-In-Class Dual CD28/ICOS Antagonist
For Multiple Inflammatory Disease Indications
Current therapeutics block only the CD28 pathway ALPN-101 (ICOSL vlgD-Fc) blocks both CD28 and ICOS pathways
APC/B cell APC/B cell
ALPN-101
CD80/86
CD80/86 ICOSL
CTLA4-lg* (B7) ALPN-101
(B7)
ICOSL
ICOS
CD28
CD28 ICOS
T cell T-cell ALPN-101 inhibits T cell and T cell
activation T-Dependent B cell activation
________________
5
* Orencia 2019 Sales were $3B (Source: BMS)
ALPN-101: Dual-Targeted for Naïve and Activated Pathogenic Cells
Naïve T cells
ICOS is particularly important in:
• Express CD28
• Follicular helper T cells (TFH) and
CD28+ germinal center reactions
• T-dept B cell activity – e.g., antibody
ALPN-101 Activated/Effector/Memory • T cell memory
• Upregulate the highly related
costimulatory receptor ICOS
• Often downregulate CD28 CD28
ICOS
NEED TO BLOCK BOTH:
CD28+/-
• CD28: new / naïve cells
ICOS+
• ICOS: activated cells
6ALPN-101 Shows Differentiated Activity in Multiple Preclinical Models
DISEASE MODEL REFERENCE
Sialoadenitis (Sjögren’s Syndrome)
Sjögren’s Syndrome NOD sialoadenitis
Improved Histopathology
Arthritis CIA
* * p < 0.05
****
Lupus bm12 ** ** p < 0.01
Histology Score (0-3)
* **** p < 0.0001
3
GVHD Multiple
Multiple Sclerosis EAE 2
Inflammatory Bowel CD45hi colitis 1
Uveitis EAU
0
WT ICOSL-Fc
Aba + WT ICOSL
ALPN-101
Abatacept
Naive
ALPN-101
Fc Control
Systemic Lupus Erythematosus
5000
IgG anti-dsDNA (ng/mL)
4000
3000 Reduced anti-dsDNA
2000
1000
% incidence: 70% 15% 65% 55% 47% 66%
(N) (20) (20) (20) (20) (19) (3)
0
Fc Control ALPN-101 Naive B6.H-2bm12B6 Murine Lupus Anti-PD-L1-accelerated NOD 7ALPN-101: A Uniquely Potent Immunomodulator of Diseased Cells % Inhibition
>0 50 100
Pathway Sjögren's Interstitial Lung
Cytokine Rheumatoid Arthritis Psoriatic Arthritis Systemic Lupus Erythematosus Multiple Sclerosis
(Treatment) Syndrome Disease
GM-CSF
IL-13
IL-17A
IL-2
ICOS Only IL-21
(Prezalumab) IFNγ
IL-12 p70
IL-17F
IL-6
TNFα
GM-CSF
IL-13
IL-17A
IL-2
CD28 Only IL-21
(Abatacept) IFNγ
IL-12 p70
IL-17F
IL-6
TNFα
GM-CSF
IL-13
IL-17A
IL-2
CD28 + ICOS
IL-21
(Abatacept +
IFNγ
Prezalumab)
IL-12 p70
IL-17F
IL-6
TNFα
GM-CSF
IL-13
IL-17A
IL-2
CD28
CD28 // ICOS
ICOS IL-21
(ALPN-101)
(ALPN-101) IFNγ
IL-12 p70
IL-17F
IL-6
TNFα
8ALPN-101 Exhibits Dose-Dependent PK/PD in Humans
Phase 1 Healthy Volunteer Single and Multiple Ascending Doses
Single Ascending Dose Multiple Ascending Dose
10 mg/kg (n=4)
100 3 mg/kg (n=4)
• Dose-proportional
0.3 mg/kg, Q1W (n=6)
1 mg/kg (n=4) 1 mg/kg, Q1W (n=6)
0.3 mg/kg (n=4) 1 mg/kg, Q2W (n=5)
0.1 mg/kg (n=4) 10
Cmax and AUCinf
[ALPN-101] (g/mL)
0.03 mg/kg (n=3)
[ALPN-101] (g/mL)
0.012 mg/kg (n=2)
10
3 mg/kg, SC (n=4)
1 mg/kg, SC (n=3)
• Terminal t1/2 4.3-8.6 days 1
1
• SC bioavailability
0.1 0.1
61% at 3 mg/kg 0 7 14
Time (day)
21 28 0 7 14 21 28
Time (day)
35 42 49
• Minimal-modest accumulation
with repeat dosing
(Cmax+ AUCτ ≤1.66X)
• Dose-related duration of high
target saturation (>95%) and
suppression of anti-KLH IgG
9ALPN-101 is Well-Tolerated in Humans
Phase 1 Healthy Volunteer Single and Multiple Ascending Doses
• No clinically-significant infusion-
related, hypersensitivity, or CATEGORY / SINGLE DOSE MULTIPLE DOSE
allergic reactions NUMBER OF
SUBJECTS, N
TOTAL
(N=96) PLACEBO ALPN-101 PLACEBO ALPN-101
(INCIDENCE, %) (N=24) (N=48) (N=6) (N=18)
• No cytokine storm or release
Any AE 69 (71.9%) 14 (58.3%) 34 (70.8%) 6 (100%) 15 (83.3%)
(assessed by CytokineMAP
A&B) Treatment-
27 (28.1%) 4 (16.7%) 14 (29.2%) 2 (33.3%) 7 (38.9%)
Related AE
• No grade 3+ adverse events Grade 1 AE 66 (68.8%) 14 (58.3%) 31 (64.6%) 6 (100%) 15 (83.3%)
• AEs in > 5% of ALPN-101: Grade 2 AE 21 (21.9%) 2 (8.3%) 12 (25.0%) 3 (50%) 4 (22.2%)
headache, upper respiratory
tract infection, aphthous ulcer, Grade 3-5 AE 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
administration site recall
reaction (KLH injection), and
back pain
10Alpine and AbbVie Strategic Partnership for ALPN-101
$60M upfront payment and up to $805M for option exercise and success-based milestones
Transformative Key Financial Partnership
Strategic Partnership Terms Structure
Exclusive option and licensing $60M upfront payment Alpine responsible for development
agreement for development and efforts to complete a Phase II
commercialization of ALPN-101 $75M in pre-option development study of ALPN-101 for treatment of
milestones systematic lupus erythematosus
Validates Alpine’s Directed
Evolution Platform $75M option exercise fee Upon option exercise, AbbVie
responsible for all development
Provides funding to accelerate and commercialization
development of Alpine’s pipeline $205M in development and
in oncology and autoimmune commercial milestones
and inflammatory disease
$450M certain sales-based cash
milestone payments
Royalties of high-single digit % to a
low double-digit % of net sales
11
________________
Source: Alpine Immune Sciences Form 8-K current report filed with SEC June 18, 2020.ALPN-202
Oncology: Conditional CD28
Costimulator and Dual Checkpoint
Inhibitor
12ALPN-202: A Conditional CD28 Costimulator and Dual Checkpoint Inhibitor
PD-1/PD-L1 inhibitors fail to elicit anti-tumor ALPN-202 (CD80 vlgD-Fc*) mediates PD-L1-dependent
activation without adequate T cell activation CD28 costimulation along with PD-L1 and CTLA-4 inhibition
Approximately ~70% of Patients Receiving PD-1/L1 Therapy Do Not Respond
Tumor cell
Tumor cell
CD80/86
PD-L1
(B7)
CD80/86
Anti-PD-1 (B7)
PD-L1
ALPN-202
ALPN-202
CTLA-4 PD-1 CD28
CD28
CTLA-4
PD-1
Potential Potential Increased
T cell T cell
T cell T cell T cell
________________ activation inhibition activation 13
* Effectorless IgG1 FcThree Primary Mechanisms of Action of ALPN-202:
Conditional CD28 costimulation and dual PD-L1/CTLA-4 inhibition
1. PD-L1 – PD-1 Antagonism 3. PD-L1-Dependent CD28 Costimulation
3000 60000
No PD-L1 Fc Control
50000 ALPN-202
Durvalumab (anti-PD-L1)
2000
IL-2 (pg/mL)
40000
MFI
30000
1000 ALPN-202
Atezolizumab
20000
(anti-PD-L1)
Fc Control
0 10000
1 100 10000 1000000
0
[pM] 10 100 1000 10000 100000
Conc (pM)
2. CTLA-4 – B7 Antagonism 60000 ALPN-202 + FR104 (anti-CD28)
With PD-L1 ALPN-202 + Durvalumab
60000 50000 Durvalumab (anti-PD-L1)
ALPN-202
IL-2 (pg/mL)
40000 Fc Control
40000
30000
MFI
ALPN-202 20000
20000
Ipilimumab
(anti-CTLA-4) 10000
Fc Control
0 0
1 100 10000 1000000 1 10 100 1000 10000 100000
[pM]
Conc (pM) Primary T cells + K562 ± hPD-L1 14ALPN-202 Exhibits Potent Monotherapy Efficacy in vivo,
Superior to PD-L1 Inhibition
PD-L1 Inhibitor-Superior, Efficacy as Monotherapy …with Evidence of Anti-Tumor Immunity
2000 500
Median Tumor Volume (mm3)
Median Tumor Volume (mm3)
Fc Control 0/11 mice tumor free ALPN-202-pretreated
ALPN-202
1500 durvalumab (anti PD-L1) 400 Naive
p < 0.0001 300
ALPN-202 vs durvalumab
1000 2/11 mice tumor free
200
500
100
8/11 mice tumor free
0 0
0 10 20 30 40 50 60 70
Mice dosed Day Day
Superior Intra-Tumoral Inflammatory Signatures
15ALPN-202 Phase 1 Advanced Malignancies (NEON-1): Study Schema
PHASE 1a. DOSE ESCALATION PHASE 1b. EXPANSION COHORTS
• N = 28-78 (1-6/arm) • N =30 (to be increased when specified)
• Advanced solid tumors or lymphoma, • Specific PD-1-refractory indications
s/p checkpoints if appropriate and/or populations
• Open-label ALPN-202 IV Q1-3W 20 mg/kg • Designed to be a PD-1/CTLA-4-superior
monotherapy
• Sentinel dosing for each dose level 10
3
• Retains potential for combination
20 mg/kg regimens – I/O, chemotherapy, etc.
1
10 • Tissue-based biomarker(s) based on
Q3W: 0.3 MoA of ALPN-202 to be explored
3
1
0.3 KEY ENDPOINTS
• 3+3 cohorts
Q1W: 0.1 mg/kg • IV Q1-3W • Safety: Adverse events,
immunogenicity, cytokines
10 g/kg • Single-subject cohorts • Efficacy: ORR, DOR, DFS/PFS, OS
1 g/kg • IV Q1W regimen • PK/PD: esp target saturation and
costimulatory capacity
MABEL-justified starting dose 16ALPN-202 Clinical Development Plan in Advanced Malignancies
CLINICAL
Dose Escalation: Any Advanced Malignancy
(Monotherapy)
NEON-1 MTD or
(Phase 1) maximal PD
Expansion Cohorts: Selected Tumor Types ± Biomarker
(Monotherapy)
Phase 1b Combination(s) TBD
2021 2022 2023
NONCLINICAL CMC
1-month GLP toxicology completed “mAb-like” manufacturing process
No clinically-significant cytokine release or Current GMP supply likely sufficient through phase 2
immune-related toxicities observed
17ALPN-303
Dual B Cell Cytokine Antagonist
18ALPN-303: Potential Best-in-Class BAFF/APRIL Inhibitor
Optimized Design and Dual Inhibition
Variant TNF
domain (vTD)
Fast Track
Belimumab (Benlysta®) Telitacicept (RC18) ALPN-303
Anti-BAFF mAb TACI (WT) Fc Fusion Next-Gen TACI Fc Fusion
BAFF + APRIL Antagonist Superior BAFF + APRIL
Antagonist
Modest Efficacy in SLE Encouraging SLE Efficacy
Phase 2b
SRI4 Response (%) (NCT02885610)
Responders (%)
Enhanced Dual Target Binding
Best-In-Class Potential
________________ 19
Source: Lancet 377:721 (2011); Arthritis Rheumatol 2019; 71 (suppl 10), L18.ALPN-303 Appears Superior to Existing BAFF/APRIL Inhibitors in vitro
BAFF
BAFF Pathway
Pathway APRILPathway
APRIL Pathway
10000 10000
7500 7500
RLU (SD)
5000 5000
Belimumab
2500 Telitacicept 2500
ALPN-303
0 0
1 10 100 1000 10000 100000 1 10 100 1000 10000 100000
[ pM ] [ pM ]
20ALPN-303: A More Potent B Cell Modulator in vivo
KLH Immunization Mouse Model
Clearer Developmental B Cell Blockade Greater Reductions in IgG Anti-KLH 2⁰ Responses
Fc Control
4.0
1:100,000
at 1:100,000
3.0
Atacicept
2.0
450 at
OD450
Telitacicept 1.0
OD
# #Transitional-1
Transitional-1 0.0
# #Transitional-2
Transitional-2
ALPN-303
ALPN-303
Fc Control Atacicept Telitacicept
pt
pt
ol
03
ALPN-303
# #Follicular
Follicular
tr
ce
e
-3
ic
on
# #Marginal
Marginal Zone
Zone
N
ci
ac
LP
C
ta
lit
# #Germinal
Germinal Centre
Centre
A
Fc
A
Te
Naive
# #Plasma
Plasma Cells
Cells
0 5×10 6 1×10 7 1.5×10 7 2×10 7 2.5×10 7
# Cells Per Spleen (Mean + SD)
21ALPN-303 Exhibits Encouraging Efficacy in Murine Connective Tissue Disease
Autoantibodies, as well as Renal Disease (Lupus) and Sialoadenitis (Sjögren’s-like)
Proteinuria Anti-dsDNA
Fc control Fc control
ALPN-303 ALPN-303 Renal Disease
Histopathology Immune Deposits
Fc Control
Nephritis Sialadenitis ALPN-303
NZB/NZW F1 22ALPN-303 Development Plan
CMC
Pharmacology GLP-Tox
1 mo
data
Ph 1 (HV)
Phase 2 PoC SLE or Sjögren’s
TBD Other Indications
2020 2021 2022 2023 2024
Clinically validated pathway for systemic lupus and potentially other autoimmune diseases
Potential best-in-class engineering suggested by early preclinical data
Fast-to-market and broad lifecycle development strategy
23ALPN Directed
Evolution Platform
24ALPN Directed Evolution Platform
Turning a Diversity of Immune Proteins Into Novel Therapeutics
Novel Therapeutic
Native Immune Domain Directed Evolution Variant Domain Candidate
DIVERSIFY
(MUTAGENESIS) ALPN-101
(ICOSL vIgD-Fc)
ICOSL ICOSL
ICOS Fc
vlgD
SELECT
AMPLIFY
(SCREENING)
(PRODUCTION)
DIVERSIFY
(MUTAGENESIS) ALPN-202
CD80
(CD80 vIgD-Fc)
CD80 vlgD
Fc
AMPLIFY SELECT
(PRODUCTION) (SCREENING)
________________ 25
vIgD: variant Ig domain.Modular Nature of vIgDs and vTDs Facilitates Multiple Therapeutic Formats
AbbVie and Adaptimmune Partnerships Validate Platform Potential
Fc ALPN-101 -
ALPN-202
Fc
Multi-specific ALPN-303
Fc Fusion
vIgDs / vTDs
TCR/CAR
Cell Therapy
Enhancement
~70-110 aa / ~40-140 aa
PLATFORM TECHNOLOGY mAb-vIgD Fusion mAb
Powerful platform technology (V-mAb)
to be leveraged for strategic
partnerships and licensing
opportunities
________________
vIgD: variant Ig domain. 26
vTD: variant TNF domain.Corporate
Update
27Strong Financial
Position Following
AbbVie Partnership $141.3 million ~23.8 million
Cash & Investments shares outstanding
and Private
as of as of
Placement led by September 30, 2020 November 5, 2020
Omega Funds
SUFFICIENT CASH RUNWAY TO FUND OPERATIONS THROUGH 2023*
JUNE 2020 JULY 2020
Received $60 million Raised $60 million in
upfront cash payment private placement led
from AbbVie by Omega Funds
28
*Includes potential pre-option milestones from AbbVieALPN Pipeline
COMMERCIAL TARGET
PROGRAM PRECLINICAL PHASE 1 PHASE 2 PHASE 3 RIGHTS MILESTONES
INFLAMMATORY DISEASES
ALPN-101 1H21:
Lupus
Dual CD28/ICOS Antagonist Phase 2 initiation
ALPN-303
B cell-mediated 2H21:
Dual B Cell Cytokine diseases Phase 1 initiation
Antagonist
IMMUNO-ONCOLOGY
ALPN-202
1H21:
Conditional CD28
Phase 1a data update
Costimulator Advanced Malignancies
2H21:
and Dual Checkpoint
Expansion Cohorts
Inhibitor
ENGINEERED CELLULAR THERAPIES
Secreted and
Transmembrane
Undisclosed
Immunomodulatory Proteins
(SIPs & TIPs)
29Strong Leadership Team
Deep Clinical, Regulatory, and Commercial Expertise
LEADERSHIP TEAM
Mitchell H. Gold, M.D. Stanford Peng, M.D., Ph.D. Paul Rickey
Executive Chairman & CEO President & Head of R&D Chief Financial Officer
Jan L. Hillson, M.D. Wayne Gombotz, Ph.D. Remy Durand, Ph.D. Pamela Holland, Ph.D.
Senior VP of Clinical Development Chief Technical Officer Chief Business Officer Senior VP of Research
DIRECTORS
Mitchell H. Gold, M.D. Min Cui, Ph.D. Natasha Hernday Jay Venkatesan, M.D.
Peter Thompson, M.D. James N. Topper, M.D., Ph.D. Robert Conway Chris Peetz
30Thank You COPYRIGHT © 2021 ALPINE IMMUNE SCIENCES, INC. ALL RIGHTS RESERVED. 31
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