Leading the Next Evolution of Immunotherapies Jefferies 2019 Healthcare Conference June 2019 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 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. 2 Leading the Next Evolution of Immunotherapies Seeking True Remissions in Inflammatory Diseases and Oncology ALPN-101 ALPN-202 Platform Technology First-in-class dual Dual PD-L1/CTLA-4 CD28/ICOS inhibitor for antagonist and CD28 agonist Strategic Partnerships inflammatory diseases for oncology Licensing Opportunities Enrolling Phase 1 IND-Enabling (Healthy Volunteers) (Submission Target 4Q19) 3 ALPN Pipeline 2Q19 PROGRAM DISCOVERY IND-ENABLING PHASE 1 COLLABORATOR Inflammatory Diseases ALPN-101 Dual CD28/ICOS Antagonist Healthy Volunteer Study Acute Graft-Versus-Host Disease Psoriatic Arthritis Immuno-Oncology ALPN-202 PD-L1/CTLA-4 Antagonist & CD28 Agonist Advanced Malignancies Engineered Cellular Therapies Secreted and Transmembrane Immunomodulatory Undisclosed Proteins (SIPs & TIPs) (Targets Undisclosed) 4 ALPN-101 Autoimmune/Inflammatory Diseases: Dual ICOS/CD28 Antagonist 5 Current Therapies Do Not Inhibition of Both CD28 and ICOS Induce Remission in Patients Pathways May be Required to Impact Targeting CD28 Alone is Insufficient… Many Serious Inflammatory Diseases CD28 blockade (abatacept) has been only modestly or not effective in: - Lupus (Arthritis Rheum 62:3077, 2010) During activation, many effector T cells lose CD28 dependence - Sjögren’s (Mod Rheumatol 26:891, 2016) - Myositis (Ann Rheum Dis 77:55, 2018) but upregulate ICOS – the most closely related IgSF member - GvHD (Transpl Immunol 43-44:54, 2017) - IBD (Gastroenterology 143:62, 2012) - Multiple Sclerosis (Mult Scler 23:686, 2017) T cell activation: ICOS blockade (prezalumab) has ICOS ↑ been only modestly effective in: Naïve T cell CD28 ↓ (some cells) CD28+ ICOS+ CD28lo ICOS+ CD28- ICOS+ CD28+ ICOS- - Lupus (Arthritis Rheumatol 70:1071, 2018) CD28 Activated / Effector / Memory / T cells ICOS FH Various populations ICOS+ / TFH cells have been implicated in: - GvHD (JCI Insight 1:e86660, 2016) - Arthritis (Nature 542:110, 2017) - Sjögren’s (Arthritis Rheumatol 70:774, 2018) - Myositis (Brain 127:1182, 2004) (Gastroenterology 126:829, 2004) - IBD 6 - Multiple Sclerosis (PLoS One 8:e57820, 2013) ALPN-101: a First-In-Class Dual CD28/ICOS Antagonist For Multiple Inflammatory Disease Indications CD28 and ICOS: Currently Available ALPN-101 (ICOSL vIgD-Fc) Key T cell Costimulatory Therapeutics Block Blocks Both CD28 & ICOS Pathways Only the CD28 Pathway Pathways APC APC APC CD80 CD80 CD86 CD80 CD86 ICOSL ICOSL CD86 ICOSL CTLA4-Ig ALPN-101 † ICOSL vIgD-Fc* CD28 ICOS CD28 ICOS CD28 ICOS T cell T cell T cell †Orencia 2018 sales = $2.7B (Source: BMS) *Effectorless IgG1 Fc 7 Two Mechanisms of Action for ALPN-101: Dual CD28/ICOS Antagonist ICD28/CD86 Inhibition ICOS/ICOSL Inhibition Stimulation of Jurkat Transfectants with Stimulation of Jurkat Transfectants with K562-OKT3 and plate-bound WT CD86-Fc K562-OKT3 and Plate-Bound WT ICOSL-Fc 100 ALPN-101 ALPN-101 Belatacept 60 Anti-ICOSL mAb 80 Abatacept Abatacept 40 60 40 20 %Inhibition ofluciferase signal 20 0 %Inhibition of luciferase signal -2 0 2 4 0 -4 -2 0 2 4 Log Transform of Test Article Log Transform of Test Article -20 Concentration (nM) Concentration (nM) 8 Superior and Single-Dose Preclinical Activity in Multiple Diseases Humanized Graft-Versus-Host Disease (GVHD)1 Collagen-Induced Arthritis2 Additional Data Supports Other Therapeutic Areas: 3 1 Dillon et al TCT #426, 2019 • Multiple Sclerosis (Experimental Autoimmune Encephalomyelitis) 2 Dillon et al. ACR # 71873, 2018 3 Dillon et al. ANA #S254, 2018 4 4. ALPN, unpublished • Inflammatory Bowel Disease, Sjögren’s Syndrome 9 Initial Dual Orphan and Non-Orphan Clinical Development Plans 2019 2020 2021 2022 2023 Phase 1 Healthy Volunteer Early PK/PD Phase 1(b) Acute Graft-Versus-Host Disease Safety, PK Phase 2a Psoriatic Arthritis KLH immune responses Ex vivo SEB cytokines Phase 2b / Pivotal Trials Alternative Indications Current non-clinical coverage: 3 months Current GMP supply sufficient through phase 2a / 2021 10 ALPN-101 Development and Lifecycle Vision Drives Potential Value Ophthalmology • Broad, diverse market potential Uveitis • Initial trials in rheumatology and heme/onc will enable most efficient development Neuroscience Pulmonology Multiple Sclerosis Interstitial Lung Disease • Larger Indications approachable with partners Gastroenterology Crohn’s Disease Ulcerative Colitis Rheumatology Rheumatology Sjögren’s Syndrome Juvenile Idiopathic Arthritis Rheumatoid Arthritis Systemic Lupus Erythematosus Rheumatology Rheumatology Systemic Sclerosis Inflammatory Myositis Psoriatic Arthritis Vasculitis Heme/Onc Heme/Onc Transplantation Acute GvHD Chronic GvHD Allograft Rejection GvHD Prophylaxis Rejection Prophylaxis 11 ALPN-202 Oncology: Conditional T-cell Agonist 12 ALPN-202: A First-in-Class Tri-Functional Immuno-Oncology Biologic Dual PD-L1/CTLA-4 Antagonist and PD-L1-Dependent CD28 Agonist Without Adequate T Cell Activation, ALPN-202 Mediates PD-L1-Dependent PD-L1/PD-1 Inhibits T Cell PD-(L)1 Inhibitors Fail to Elicit (T Cell) CD28 Agonism Along with PD-L1 and Activation Anti-Tumor Responses CTLA-4 Inhibition Tumor (If present) MHC/ PD-L1 Pep PD-L1 PD-L1 CD80CD86 ALPN-202 (CD80 vIgD-Fc*) Anti-PD-1 CD28 PD-1 CTLA-4 PD-1 CD28 TCR/ CD3 +++ CD28 PD-1 TCR/ T cell Inadequate T CD3 Activation J Exp Med 1995;182:459-65 T cell Science 2017;355:1423-1427 cell activation * CD80 vIgD is an ALPN-proprietary variant CD80 IgV domain, engineered by directed evolution. The Fc is an effectorless IgG1 Fc. Approximately ~70% of Patients Receiving PD-1/L1 Therapy Do Not Respond 13 Three Primary Mechanisms of Action of ALPN-202 1. PD-L1 – PD-1 Antagonism 3. PD-L1-Dependent Costimulation 3000 (CD28 Agonism) 25000 ALPN-202 No PD-L1 2000 WT CD80-Fc 20000 Durvalumab (anti-PD-L1) MFI Nivolumab (anti-PD-1) 15000 1000 ALPN-202 Fc Control Atezolizumab (anti-PD-L1) 10000 Fc Control IL-2 (pg/mL) 0 5000 1 10 100 1000 10000 1000001000000 [pM] 0 1 100 10000 1000000 2. CTLA-4 – B7 Antagonism 25000 With PD-L1 60000 20000 15000 40000 10000 IL-2 (pg/mL) MFI ALPN-202 5000 20000 Ipilimumab (anti-CTLA-4) 0 Fc Control 1 100 10000 1000000 0 [pM] 1 10 100 1000 10000 1000001000000 Primary T cells + K562 ± hPD-L1 14 [pM] ALPN-202 Exhibits Potent Efficacy in vivo, Superior to PD-L1 Inhibition PD-L1 inhibitor-superior, Efficacy as Monotherapy …with Evidence of Anti-Tumor Immunity ) 3 2000 Fc Control 0/11 mice tumor free ALPN-202-pretreated ALPN-202 1500 durvalumab (anti PD-L1) Naive p < 0.0001 ALPN-202 vs durvalumab 1000 2/11 mice tumor free 500 8/11 mice tumor free Median Tumor Volume (mm Volume Tumor Median 0 0 10 20 30 40 Mice dosed Day Superior Intra-Tumoral Inflammatory Signatures 15 ALPN-202 Phase 1 Development Plan 2020 2021 2022 2023 Dose Escalation: Any Advanced Malignancy MTD or maximal PD Expansion Cohorts: Selected Tumor Types ± Biomarker Phase 1b Combination(s) TBD Pilot toxicology studies completed; definitive studies in progress GMP DS completed 16 vIgD Platform 17 Turning Immunoglobulin Superfamily (IgSF) Proteins Into Novel Therapeutics • IgSF is the largest human protein superfamily – 765 The CD28 Protein Family 1 genes identified