leading the next evolution of immunotherapies

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Leading the Next Evolution of Immunotherapies

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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 timingthereof, expectations regarding the sufficiency of cash to fund operations through 2023, expectations regarding the plans of itscollaborators, 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 inapproved 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 Evolution of Immunotherapies

With a Highly Productive Directed Evolution Platform

Dual Costimulation Antagonist

Systemic Lupus Erythematosus

Partnered with

Phase 2

Conditional CD28 Costimulator and Dual Checkpoint Inhibitor

Immuno-oncology

Phase 1- Monotherapy- Combination with

KEYTRUDA®

Dual B Cell Cytokine Antagonist

B Cell-Mediated Inflammatory Diseases

Phase 1 Start Targeted 2021

ALPN-101ALPN-202

ALPN-303

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ALPN-101Autoimmune/Inflammatory Diseases:Dual CD28/ICOS Antagonist

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ALPN-101 inhibits T cell and T-Dependent B cell activation

ALPN-101ALPN-101

ICOSLCD80/86(B7)

CD80/86(B7)

ICOSL

ICOSCD28

CTLA4-lg*

T-cellactivation

T cell T cell

CD28ICOS

APC/B cell

Current therapeutics block only the CD28 pathway ALPN-101 (ICOSL vlgD-Fc) blocks both CD28 and ICOS pathways

APC/B cell

ALPN-101: A First-In-Class Dual CD28/ICOS Antagonist For Multiple Inflammatory Disease Indications

________________* Orencia 2019 Sales were $3B (Source: BMS)

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ALPN-101: Dual-Targeted for Naïve and Activated Pathogenic Cells

CD28ICOS

Naïve T cells • Express CD28

Activated/Effector/Memory• Upregulate the highly related

costimulatory receptor ICOS

• Often downregulate CD28

ICOS is particularly important in:• Follicular helper T cells (TFH) and

germinal center reactions

• T-dept B cell activity – e.g., antibody

• T cell memory

NEED TO BLOCK BOTH:• CD28: new / naïve cells

• ICOS: activated cells

ALPN-101

CD28+

CD28+/-ICOS+

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DISEASE MODEL REFERENCE

Sjögren’s Syndrome NOD sialoadenitis

Arthritis CIA

Lupus bm12

GVHD Multiple

Multiple Sclerosis EAE

Inflammatory Bowel CD45hi colitis

Uveitis EAU

ALPN-101 Shows Differentiated Activity in Multiple Preclinical Models

Fc C

ontro

l

ALPN

-101

Abat

acep

t

WT

ICO

SL-F

c

Aba

+ W

T IC

OSL

Nai

ve

0

1

2

3

His

tolo

gy S

core

(0-3

)

***** **

** p < 0.05** p < 0.01**** p < 0.0001

% incidence: 70% 15% 65% 55% 47% 66%(N) (20) (20) (20) (20) (19) (3)

Sialoadenitis (Sjögren’s Syndrome)

ALPN

-101

Anti-PD-L1-accelerated NOD

Improved Histopathology

Fc Control ALPN-101 Naive0

1000

2000

3000

4000

5000

IgG

ant

i-dsD

NA (n

g/m

L)

Reduced anti-dsDNA

B6.H-2bm12B6 Murine Lupus

Systemic Lupus Erythematosus

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Pathway (Treatment) Cytokine

GM-CSFIL-13

IL-17AIL-2

IL-21IFNγ

IL-12 p70IL-17FIL-6

TNFαGM-CSF

IL-13IL-17A

IL-2IL-21IFNγ

IL-12 p70IL-17FIL-6

TNFαGM-CSF

IL-13IL-17A

IL-2IL-21IFNγ

IL-12 p70IL-17FIL-6

TNFαGM-CSF

IL-13IL-17A

IL-2IL-21IFNγ

IL-12 p70IL-17FIL-6

TNFα

ICOS Only (Prezalumab)

CD28 Only (Abatacept)

CD28 + ICOS (Abatacept + Prezalumab)

CD28 / ICOS (ALPN-101)

Rheumatoid Arthritis Systemic Lupus Erythematosus Sjögren's Syndrome Multiple Sclerosis Interstitial Lung

DiseasePsoriatic Arthritis

ALPN-101: A Uniquely Potent Immunomodulator of Diseased Cells % Inhibition

>0 50 100

CD28 / ICOS(ALPN-101)

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ALPN-101 Exhibits Dose-Dependent PK/PD and is Well-Tolerated in HumansPhase 1 Healthy Volunteer Single and Multiple Ascending Doses

Dose-proportional PK/PD• T1/2 ~4.3-8.6 days• Bioavailability ~61% at 3 mg/kg• Modest accumulation (≤1.66X)

Well-Tolerated• No cytokine storm or release, or

clinically-significant infusion-related, hypersensitivity, or allergic reactions

• No grade ≥ 3 adverse events• AEs in > 5% of ALPN-101: headache,

upper respiratory tract infection, aphthous ulcer, administration site recall reaction (KLH injection), and back pain

0 7 14 21 28 35 42 490.1

1

10

Time (day)

[ALP

N-10

1] (µ

g/m

L)

0.3 mg/kg, Q1W (n=6)1 mg/kg, Q1W (n=6)1 mg/kg, Q2W (n=5)

Multiple Ascending Dose

0 7 14 21 280.1

1

10

100

Time (day)

[ALP

N-10

1] (µ

g/m

L)

3 mg/kg, SC (n=4)1 mg/kg, SC (n=3)

10 mg/kg (n=4)3 mg/kg (n=4)1 mg/kg (n=4)0.3 mg/kg (n=4)0.1 mg/kg (n=4)0.03 mg/kg (n=3)0.012 mg/kg (n=2)

Single Ascending Dose

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• Randomized, Double Blind, Placebo controlled, International• N = 130 (65/arm)• NCT04835441

Synergy: ALPN-101 in Systemic Lupus Erythematosus Phase 2PHASE 2

ALPN-101

Placebo

Week 1 Week 24

Primary• Safety

Secondary• Efficacy (Disease Activity)• Pharmacokinetics• Immunogenicity (ADA)• Pharmacodynamics

• Adults with active systemic lupus erythematosus ≥ 6 months

• Positive ANA, anti-dsDNA, and/or anti-Smith

• Stable standard-of-care background therapy

Study Population

Key Objectives

________________ADA: Anti-Drug AntibodiesANA: Antinuclear Antibodiesanti-dsDNA: Anti-double stranded DNA

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Alpine and AbbVie Strategic Partnership for ALPN-101$60M upfront payment and up to $805M for option exercise and success-based milestones

Exclusive option and licensing agreement for development and commercialization of ALPN-101

Validates Alpine’s Directed Evolution Platform

Provides funding to accelerate development of Alpine’s pipeline in oncology and autoimmune and inflammatory disease

Transformative Strategic Partnership

$60M upfront payment

$75M in pre-option development milestones

$75M option exercise fee

$205M in development and commercial milestones

$450M certain sales-based cash milestone payments

Royalties of high-single digit % to a low double-digit % of net sales

Key Financial Terms

Alpine responsible for development efforts to complete a Phase II study of ALPN-101 for treatment of systematic lupus erythematosus

Upon option exercise, AbbVie responsible for all development and commercialization

Partnership Structure

________________Source: Alpine Immune Sciences Form 8-K current report filed with SEC June 18, 2020.

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ALPN-202Oncology: Conditional CD28 Costimulator and Dual Checkpoint Inhibitor

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PD-1/PD-L1 inhibitors fail to elicit anti-tumor activation without adequate T cell activation

CD80/86(B7)

Tumor cell

ALPN-202 (CD80 vlgD-Fc*) mediates PD-L1-dependentCD28 costimulation along with PD-L1 and CTLA-4 inhibition

Tumor cell

ALPN-202

PD-L1

ALPN-202CD28PD-1

CTLA-4

CTLA-4CD28

PD-L1

Anti-PD-1

CTLA-4

CD80/86(B7)

PD-1

IncreasedT cell

activation

PotentialT cell

inhibition

PotentialT cell

activationT cell T cell

Approximately ~70% of Patients Receiving PD-1/L1 Therapy Do Not Respond

ALPN-202: A Conditional CD28 Costimulator and Dual Checkpoint Inhibitor

________________* Effectorless IgG1 Fc

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ALPN-202 Exhibits Potent Monotherapy Efficacy in vivo,Superior to PD-L1 Inhibition

ALPN-202-pretreated

Naive

PD-L1 Inhibitor-Superior, Efficacy as Monotherapy

0 10 20 30 400

500

1000

1500

2000

Day

Med

ian

Tum

or V

olum

e (m

m3 )

Fc ControlALPN-202durvalumab (anti PD-L1)

p < 0.0001 ALPN-202 vs durvalumab

Mice dosed

0/11 mice tumor free



…with Evidence of Anti-Tumor Immunity

Superior Intra-Tumoral Inflammatory Signatures

50 60 700

100

200

300

400

500

Day

Med

ian

Tum

or V

olum

e (m

m3 )

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NEON-1: A First-In-Human Dose Escalation and Expansion Study of ALPN-202 in Advanced Malignancies

Characteristic Total (N=32)Age (mean yr ± SD) 63 ± 12

Female 13 (41%)

Caucasian 25 (78%)

Dose regimen: Weekly 20 (63%)

Prior lines of therapy (mean ± SD) 3.9 ± 2.3

Received ≥ 1 prior I/O therapy 9 (28%)

Tumor Type:- Pancreatic- Colorectal- Mesothelioma- Cholangiocarcinoma- Head & Neck- Uterine- Other (1 each of esophageal, melanoma,

ovarian/fallopian, porocarcinoma, prostate, renal, thymoma, uveal melanoma)

8 (25%)7 (22%)3 (9%)2 (6%)2 (6%)2 (6%)

8 (25%)

0.1 mg/kg

0.3 mg/kg

1 mg/kg

3 mg/kg

10 mg/kg

0.001 mg/kg

0.01 mg/kg

20 mg/kg0.3

mg/kg

1 mg/kg

3 mg/kg

10 mg/kg

20 mg/kg

Q1W Schedule:

Q3W Schedule:

• N = 28-78 (1-6/arm)• Advanced solid tumors or lymphoma, s/p checkpoints if appropriate• Open-label ALPN-202 IV Q1W or Q3W

3+3 CohortsSingle Subject Cohorts

NCT04186637Dose Escalation (Part A)

Expansion Cohorts (Part B): TBD ________________Data as of April 22, 2021

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ALPN-202 Appears Well-Tolerated to Date

Adverse Event of InterestSubjects (N=32)

Infusion Related Reaction 6 (19%)Skin & Subcutaneous Disorders• Rash(1)

• Pruritis• Rosacea

9 (28%)9 (28%)1 (3%)1 (3%)

Hyper- or hypothyroidism 3 (9%)Acute Kidney Injury (SAE) 1 (3%)Testicular Pain (SAE) 1 (3%)

CategorySubjects (N=32)

Any Related Adverse Event (AE) 21 (66%)Any Related AE Gr ≥ 3 1 (3%)Any Serious AE (SAE) 9 (28%)Any Related SAE 1 (3%)AE of Interest (AEI)• Infusion-Related Reaction• Immune-Related AE• Tumor Lysis Syndrome

16 (50%)6 (19%)12 (38%)

0AEI Gr ≥ 3 1 (3%)Dose-limiting toxicity 0Cytokine release syndrome 0

________________Data as of April 22, 2021(1) Rash macular, rash maculo-papular or rash papular

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ALPN-202 Shows Early Potential for Clinical Benefit

Best Response Evaluable (N=23)Partial Response 1 (4.3%)Stable Disease 13 (57%)Progressive Disease 9 (39%)

________________Data as of April 22, 2021

Best Change in Target Lesion Size

Cha

nge

from

Bas

elin

e in

su

m o

f lon

gest

dia

met

ers

(%)

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ALPN-202 Exhibits Dose-Dependent PK/PD

Days Post-C1D1 (Nominal) Days Post-C1D1 (Nominal)0 7 14 21

1

10

100

1000

10000

100000

[ALP

N-2

02] (

ng/m

L)

0 7 14 21

0

20

40

60

80

Targ

et S

atur

atio

n (%

)

Pharmacokinetics Target Saturation (Peripheral T cells)

0.001 mg/kg Q1W0.01 mg/kg Q1W

1 mg/kg Q1W

0.1 mg/kg Q1W0.3 mg/kg Q1W

________________Data as of April 22, 2021

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0 7 14 21

50

100

150

Days Post-C1D1

% o

f Bas

elin

e

ALPN-202 Promotes T Cell Activation

0 7 14 210

10

20

30

40

Days Post-C1D1

% o

f CD4

+

0.001 mg/kg Q1W0.01 mg/kg Q1W0.1 mg/kg Q1W

0.3 mg/kg Q1W1 mg/kg Q3W

CD4+CD25hiCD127loFoxp3+

Activation (ICOS+) Regulatory T cells (Treg)

________________Data as of April 22, 2021

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NEON-2: Dose Escalation and Expansion Study of ALPN-202 + Pembrolizumab Combination in Advanced Malignancies

1mg/kg

3 mg/kg

10 mg/kg

0.3mg/kg

• N = up to 60 (3-6/arm) – Q1-3W IV by 3+3• Advanced solid tumors or lymphoma

• No available therapies, or• Eligible to receive PD-1i

• All subjects receive pembrolizumab Q6W• Open-label ALPN-202 IV Q1W or Q3W

• Safety: Adverse events, immunogenicity, cytokines• Efficacy: ORR, DOR, DFS/PFS, OS• PK/PD: esp target saturation and costimulatory capacity• Baseline tumor expression of PD-L1, CD28, CD80, CD86

0.1 mg/kg

1mg/kg

3 mg/kg

10 mg/kg

0.3mg/kg

0.1 mg/kg

Dose Escalation

Key Assessments

Expansion Cohorts (TBD)

Q1W Schedule:

Q3W Schedule:

________________NEON-2 began dosing study participants in June 2021

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ALPN-202 Clinical Development Plan in Advanced Malignancies

NONCLINICAL

1-month GLP toxicology completed

CMC“mAb-like” manufacturing process

Current GMP DS expected to supply to phase 2

Pembrolizumab supply agreement with Merck

CLINICAL

Dose-dependent PK/PD; well tolerated to ≥ 3 mg/kg

Manageable, anticipated immune-related toxicities to date

Early evidence of clinical benefit in immune-resistant cancers

Immuno-phenotyping consistent with advantages of CD28 agonism

NEON-1: Monotherapy

2021 2022 2023

NEON-2: KEYTRUDA® (pembrolizumab) Combination

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ALPN-303Dual B Cell Cytokine Antagonist

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ALPN-303: Engineered Inhibitor of BAFF (BLyS) and APRIL Clinically-Validated B cell Modulatory Pathways

Immature B cell survival

and maturation

Plasma cell survival

T-cell-independent antibody responses

B cell regulationClass-switch recombination

ALPN-303

ALPN-303

APRIL Membrane BAFF Soluble BAFF

TACI BCMA BAFFR

________________Source: Nat Rev Rheumatol 10: 365, 2014; Nat Rev Rheumatol 9:705, 2013

2424

Res

pond

ers

(%)

ALPN-303:Potential Best-in-Class BAFF/APRIL InhibitorOptimized Design and Dual Inhibition

Phase 2b (NCT02885610)

Enhanced Dual Target BindingBest-In-Class Potential

Variant TNF domain (vTD)

Modest Efficacy in SLE

SRI4

Res

pons

e (%

)

Encouraging SLE Efficacy

Belimumab (Benlysta®)Anti-BAFF mAb

Telitacicept (RC18)TACI (WT) Fc FusionBAFF + APRIL Antagonist

ALPN-303Next-Gen TACI Fc FusionSuperior BAFF + APRIL Antagonist

________________Source: Lancet 377:721 (2011); Arthritis Rheumatol 2019; 71 (suppl 10), L18.

Fast Track

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1 10 100 1000 10000 1000000

2500

5000

7500

10000

APRIL Pathway

[ pM ]

1 10 100 1000 10000 1000000

2500

5000

7500

10000

BAFF Pathway

[ pM ]

RLU

(±SD

)

ALPN-303TelitaciceptBelimumab

ALPN-303 Appears Superior to Existing BAFF/APRIL Inhibitors in vitro

BAFF Pathway APRIL Pathway

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0 5×106 1×107 1.5×107 2×107 2.5×107

Naive

ALPN-303

Telitacicept

Atacicept

Fc Control

# Cells Per Spleen (Mean + SD)

# Transitional-1# Transitional-2# Follicular# Marginal Zone# Germinal Centre# Plasma Cells

ALPN-303: A More Potent B Cell Modulator in vivoKLH Immunization Mouse Model

Clearer Developmental B Cell Blockade Greater Reductions in IgG Anti-KLH 2⁰ Responses

Transitional-1Transitional-2FollicularMarginal ZoneGerminal CenterPlasma Cells

ALPN-303

Fc Contro

l

Atacice

pt

Telitac

icept

ALPN-303

0.0

1.0

2.0

3.0

4.0

OD

450 a

t 1:1

00,0

00O

D45

0at

1:1

00,0

00

Fc Control TelitaciceptAtacicept ALPN-303

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ALPN-303 Exhibits Encouraging Efficacy in Murine Connective Tissue Disease Autoantibodies, as well as Renal Disease (Lupus) and Sialoadenitis (Sjögren’s-like)

Fc Control

ALPN-303

NZB/NZW F1

Histopathology Immune Deposits

Proteinuria Anti-dsDNA

SialoadenitisNephritis

Renal DiseaseFc controlALPN-303

Fc controlALPN-303

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ALPN-303 Development Plan

Phase 2 Systemic Lupus Erythematosus

Ph 1 (HV)

GLP-Tox

1 modata

Clinically validated pathway for lupus and potentially other autoimmune diseases

Potential best-in-class engineering suggested by early preclinical data

Fast-to-market and broad lifecycle development strategy

TBD Other Indications

CMC

Pharmacology

2020 2021 2022 2023 2024

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ALPN Directed Evolution Platform

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ALPN Directed Evolution PlatformTurning a Diversity of Immune Proteins Into Novel Therapeutics

Native Immune Domain Variant DomainNovel Therapeutic Candidate

ALPN-101(ICOSL vIgD-Fc)

ALPN-202(CD80 vIgD-Fc)

SELECT(SCREENING)AMPLIFY

(PRODUCTION)

DIVERSIFY(MUTAGENESIS)

Fc

Fc

Directed Evolution

ICOSL

SELECT(SCREENING)

AMPLIFY (PRODUCTION)

DIVERSIFY(MUTAGENESIS)

ICOSLvlgD ICOS

CD80CD80vlgD

________________vIgD: variant Ig domain.

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Modular Nature of vIgDs and vTDs Facilitates Multiple Therapeutic FormatsAbbVie and Adaptimmune Partnerships Validate Platform Potential

vIgDs / vTDs

~70-110 aa / ~40-140 aa

Multi-specific Fc Fusion

Cell Therapy Enhancement

mAbmAb-vIgD Fusion (V-mAb)

Fc

Fc

ALPN-101 -ALPN-202ALPN-303

TCR/CAR

PLATFORM TECHNOLOGYPowerful platform technology to be leveraged for strategic partnerships and licensing opportunities

________________vIgD: variant Ig domain.vTD: variant TNF domain.

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Corporate Update

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JULY 2020 Raised $60 million in private placement led by Omega Funds

Strong Financial Position Following AbbVie Partnership and Private Placement led by Omega Funds

~23.9 million shares outstanding as of May 6, 2021

$115.4 millionCash & Investments as of last reported dateMarch 31, 2021

JUNE 2020Received $60 million upfront cash payment from AbbVie

SUFFICIENT CASH RUNWAY TO FUND OPERATIONS THROUGH 2023(1)

______________________________________________________________________________________(1) Includes potential pre-option milestones from AbbVie

Q3 2021 To receive $45 million in milestones under AbbVie Collaboration

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PROGRAM PRECLINICAL PHASE 1 PHASE 2 PHASE 3COMMERCIAL

RIGHTS TARGET MILESTONES

INFLAMMATORY DISEASES

ALPN-101 Dual CD28/ICOS Antagonist

Phase 2 initiation (mid-21)

ALPN-303 Dual B Cell Cytokine Antagonist

Phase 1 initiation (4Q21)

IMMUNO-ONCOLOGY

ALPN-202Conditional CD28 Costimulator and Dual Checkpoint Inhibitor

Monotherapy (NEON-1) Data Update (mid-21)

PD-1 combo (NEON-2) Initiation (2H21)

ENGINEERED CELLULAR THERAPIES

Secreted and Transmembrane Immunomodulatory Proteins (SIPs & TIPs)

ALPN Pipeline

Undisclosed

B cell-mediated diseases

Lupus

MonotherapyAdvanced Malignancies

KEYTRUDA® Combination Advanced Malignancies

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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

Strong Leadership Team Deep Clinical, Regulatory, and Commercial Expertise

LEA

DE

RS

HIP

TE

AM

Paul RickeyChief Financial Officer

Jan L. Hillson, M.D.Senior VP of Clinical Development

Stanford Peng, M.D., Ph.D. President & Head of R&D

Wayne Gombotz, Ph.D.Chief Technical Officer

Remy Durand, Ph.D.Chief Business Officer

DIR

EC

TOR

S

Mitchell H. Gold, M.D. Executive Chairman & CEO

Pamela Holland, Ph.D.Senior VP of Research

Zelanna Goldberg, M.D., M.A.S.Chief Medical Officer

leading the next evolution of immunotherapies

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