Nivalis Therapeutics: Introduction To Alpine Immune Sciences April 28, 2017

The following excerpt is from the company's SEC filing.

Company Overview Company developing novel potential therapies focused on targeting IgSF proteins in the immune synapse Seed financing from Alpine BioVentures and a $48 million Series A from OrbiMed, Frazier Healthcare, and Alpine BioVentures Collaboration with Kite Pharma for use of two TIPs™ with Kite’s CAR-T and TCR platforms Headcount currently ~35 employees Expect vIgD™ molecule in clinic in 2H-2018 for autoimmune/inflammation

Snapshot of Alpine Immune Sciences Our novel variant Immunoglobulin Domain (vIgD™) platform is based on directed evolution of an IgSF structure to multiple bindi ng partners in the immune synapse First-in-class, multi-valent molecules with dual functionality and potential significant activity Dual ICOS/CD28 agonists/antagonists (first in class) Multiple additional discovery stage and pre-clinical programs underway (single checkpoint antagonists, multi-checkpoint antagonists, and costimulatory agonists/antagonists) vIgD™ platform also potentially capable of TREG depletion, TREG activation and T cell inhibitory receptor antagonists vIgD™ program in inflammatory disease demonstrated in vivo proof of concept

APC/T cell immune synapse (yellow) Image: Brian Cobb, Case Western Immune system activation involves multiple interactions of cell surface molecules in the immune synapse Three-dimensional structure of the synapse is critical to the final outcome of immune cell effector functions vIgD™ molecules are evolved to efficiently mediate complex multi-protein interactions Alpine Immune Sciences’ vIgDs™ are Functional Constituents of the Immune Synapse

Basic Premise: Engineer IgSF Proteins for Potentially Powerful Therapeutic Outcomes IgSF proteins are already evolved for immunologic function IgSF proteins are the core structures & building blocks of the immune system Image: Joan Weddell, 2006

Alpine Immune Sciences’ Variant Immunoglobulin Domain (vIgD™) Platform vIgDs are engineered, non-antibody IgSF domains derived from the extracellular portions of immune system proteins vIgDs are engineered via directed evolution to bind one or more cognate ligands to optimize immune system activation or inhibition vIgDs have demonstrated greater in vitro functional activity than the wild-type IgSF molecule Nature 2001 410: 608-611 The IgSF fold is a biologically important domain type found in over 400 human proteins, most of which are known to function on immune or neurological cells

Alpine’s Approach to Directed Evolution IgSF Protein Limited counterstructure(s) Low/modest affinity vIgD™ Multiple, engineered, and tailored counterstructure(s) Improved/high affinity Desired specificity IgV/IgC Yeast Display Flow Cytometric Selection Fc Fusion Protein Generation Counterstructure Binding Functional Assays

New Biology: Affinity Maturation of ICOSL Towards Both ICOS and CD28 First described finding of a dual ICOS/CD28 binder Novel product profile indicative of platform potential 0 200 400 600 800 1000 1200 1400 10 100 1000 10000 100000 MFI ICOS Fc [pM] ICOSL : ICOS Fc ICOSL WT ICOS F1 ICOS F2 0 100 200 300 400 500 600 700 0 1 5 25 125 MFI CD28 Fc [nM] ICOSL : CD28 Fc ICOSL WT CD28 F1 CD28 F2

Dual ICOS/CD28 Antagonist vIgDs™ Reduce T Cell Activation to Undetectable Levels in Human MLR WT ICOSL 1st Gen ICOSL vIgDs 2nd/3rd Gen ICOSL vIgDs Belatacept PD-L2-Fc Human IgG

vIgDs™ Can Be Formatted Specifically for Various Therapeutic Applications Oncology CAR-T (TIP™) mAb Costimulatory Agonist Costimulatory V-mAb Fc Target 1 Target 2 vIgD™ Multi-Checkpoint Antagonist Costimulatory Agonist Fc Localizer Localized vIgD™ ICOSL ECD Fc vIgD™ ICOSL Autoimmune

Alpine Immune Sciences’ Path to Three INDs Program Discovery In vitro PoC In vivo PoC Clinical Candidate Selected Therapeutic Area TIP™/SIP Undisclosed targets SIP: Undisclosed Soluble vIgD™ ALPN-101 (Fc-ICOS/CD28) Multi-Target CPI Localized vIgD™ V-mAb-ICOSL Other targets Oncology Inflammation Oncology Oncology Oncology Oncology IND 2H-2018

Belatacept and Abatacept are Proof-of-Concept For IgSF-Fc Fusion Therapeutics Two IgSF-Fc molecules on market today (~$2.5 billion annual sales) show IgSF proteins are therapeutically active, manufacturable, and capable of obtaining FDA approval. Belatacept: Small AA changes resulted in 10-fold improvement with belatacept in T cell inhibition vs. WT rCTLA-4.Fc No reported issues of immunogenicity after five years on the market Alpine’s lead vIgD™ program is differentiated by blocking both ICOS & CD28

ALPN-101 Program: An ICOS/CD28 Dual Antagonist vIgD™ for Autoimmune/Inflammatory Disease Indications APC T cell Fc vIgD™ ICOSL CD80/CD86 CD28 ICOS ICOSL CD80/CD86 CD28 ICOS ICOSL Activating Blocking ICOSL

First Generation ICOS/CD28 Dual Antagonist vIgD™ Suppresses GvHD in Immunocompromised Mice Day -1: Female NSG mice (10/group) irradiated (100 rad) & administered 10mg gamma globulin SC Day 0: Mice received 10 million human PBMC, IV Day 0: IP dosing began and continued 3x weekly (M, W, F): 100ug WT-Fc, 1st Gen ICOSL vIgDs. Belatacept (hCTLA-4-Ig) dosed at 75ug. Day 15: All mice bled and engrafted human CD45+ cells were phenotyped by flow cytometry Day 35: Study terminated. Endpoints included survival, body weight loss, and disease activity index. GVHD study protocol -1 2 7 12 14 19 23 28 33 -40 -30 -20 -10 0 GvHD Study #1: % Body Weight Loss Study Days M e a n % B o d y W e i g h t L o s s + / - S E M Saline WT ICOSL-Fc 1st Gen ICOSL vIgD Belatacept 0 10 20 30 40 0 1 2 3 4 5 6 7 Disease Activity Index (DAI) Study Days G r a d e Saline WT ICOSL-Fc 1st Gen ICOSL vIgD Belatacept

ICOS/CD28 Dual Antagonist vIgDs™ Suppress Inflammation in DTH Model All groups of mice treated with Alpine ICOSL vIgDs showed significantly less ova-induced ear swelling as compared to control (p < 0.0001) PBS (Control) Abatacept 1st Gen ICOSL vIgD 2nd Gen ICOSL vIgDs

First Generation Dual ICOS/CD28 Antagonist Appears to Show Reduced Paw Swelling in Pilot Collagen-Induced Arthritis Model Abatacept 1st Gen ICOSL vIgD™ PBS (Control) 0 5 10 15 20 25 30 0 1 2 3 4 Mean CIA 1701 clinical scores Day post-boost a v g p a w s c o r e PBS Orencia AIS83

First Generation Dual ICOS/CD28 Antagonist Appears to Show Reduced Paw Swelling in Pilot Collagen-Induced Arthritis Model Maximum paw score Abatacept 1st Gen ICOSL vIgD™ PBS (Control) Maximum paw thickness Abatacept 1st Gen ICOSL vIgD™ PBS (Control) 1st Gen ICOSL vIgD™ Abatacept PBS (control) 1st Gen ICOSL vIgD™ Abatacept PBS (control)

Dual ICOS/CD28 Antagonist Appears to Reduce Symptoms of Disease in Pilot Collagen-Induced Arthritis Study Images representative of arthritis severity Pilot study protocol: Healthy mice were primed with chick collagen in complete Freund’s adjuvant via intradermal injection in the base of the tail at week -3. On day 0, mice received a similar chick collagen boost. The same day, test ICOSL vIgDs were administered intraperitoneally and were continued 3x/week for 3 weeks. The study measures inflammation caused by the chick collagen injection and resulting immune response, and is a model of inflammation/swelling similar to human arthritis. PBS-treated control mouse Mouse treated with 1st Gen ICOSL vIgD™

Summary of Dual ICOS/CD28 Antagonist vIgD™ Program Individual ICOSL domains identified with increased affinity for ICOS & CD28 Minimal mutations (2-4) confer large increases in functional activity A single affinity maturation program results in lead candidates for multiple applications (oncology & autoimmune/inflammation) In vivo proof of concept data in GVHD, DTH, and CIA models Alpine plans to file IND 2H-2018 for autoimmune/inflammation

TIP™ Applications in Engineered Cellular Therapies (ECTs) Engineered T cell Tumor cell T cell CAR CD19 TIP Costim Receptor 1 TCR MHC Costim Receptor 2

Kite Pharma Collaboration Summary Kite Pharma licensed two TIPs™ for use in CAR-T, TCR, and TIL therapies $5.5 million up front cash plus research support Up to $530 million in additional research, clinical, and regulatory milestones Low single-digit royalties on sales Alpine retains rights to all vIgDs™ and vIgD applications to specified targets as well as all non-Kite targets for TIP™ programs Alpine to complete in vitro work with agreed-upon endpoints Kite to perform in vivo studies and is responsible for manufacturing and clinical trials

Alpine Multi-Checkpoint Antagonist vIgD™ T cell Suppression T cell Activation MHC Inhibitory Receptor 1 Inhibitory Ligand 1 TCR Inhibitory Ligand 2 Inhibitory Ligand 1 Fc vIgD Multi-Checkpoint Antagonist Inhibitory Receptor 2 or 3 MHC Inhibitory Receptor 1 TCR Tumor cell T cell Inhibitory Ligand 2 Inhibitory Receptor 2 Inhibitory Receptor 3 Inhibitory Receptor 1 Inhibitory Ligand 2 (Dual Binder)

V-mAb: Localized Costimulatory Signal with Antibody of Choice Anti-tumor mAb Tumor Suppression V-mAb Dependent Tumor Immunity Costimulatory Agonist Costimulatory V-mAb Tumor cell T cell TCR MHC Activating Receptor 1 Tumor Antigen TCR MHC Tumor Antigen TCR signal only, no costimulation, no effector function Activating Receptor 2 Activating Receptor 1 Activating Receptor 2 Tumor Antigen Tumor Antigen

Summary of Alpine Immune Sciences Alpine Immune Sciences vIgD™ platform focused on affinity-enhanced IgSF immune targets Initial preclinical validation in immuno-oncology and inflammation Novel platform potentially capable of TREG depletion, TREG activation, and T cell inhibitory receptor agonists Broad range of targets creates potential partnering opportunities Kite Pharma collaboration supports TIP™ platform, with potential additional research, clinical, and regulatory milestone payments. Expect to have ~$90 million in cash & cash equivalents at closing of merger Balance sheet supports bringing three products into the clinic, with the first IND filing expected 2H-2018 with our dual ICOS/CD28 antagonist


The above information was disclosed in a filing to the SEC. To see the filing, click here.

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