INVESTOR PRESENTATION JANUARY 2019
Forward Looking Statements This presentation contains forward-looking statements as that term is defined in Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. Statements in this press release that are not purely historical are forward- looking statements. Such forward-looking statements include, among other things, references to novel technologies and methods and our business and product development plans, including the advancement of our proprietary and co-development programs into and through the clinic. Actual results could differ from those projected in any forward-looking statements due to numerous factors. Such factors include, among others, our ability to raise the additional funding we will need to continue to pursue our business and product development plans; the inherent uncertainties associated with developing new products or technologies and operating as a development stage company; our ability to develop, complete clinical trials for, obtain approvals for and commercialize any of our product candidates, including our ability to recruit and enroll patients in our studies; our ability to address the requests of the FDA; competition in the industry in which we operate and market conditions. These forward-looking statements are made as of the date of this press release, and we assume no obligation to update the forward-looking statements, or to update the reasons why actual results could differ from those projected in the forward-looking statements, except as required by law. Investors should consult all of the information set forth herein and should also refer to the risk factor disclosure set forth in the reports and other documents we file with the SEC available at www.sec.gov, including without limitation the Company's Annual Report on Form 10-K for the fiscal year ended December 31, 2017 and the Company's Quarterly Reports on Form 10-Q. 2
Proprietary Anticalin® Protein Drug Class Pipeline Highlights Anchor Partnerships Projected Inflection Points • PRS-060: Inhaled IL4-Rα antagonist • Validation through three anchor • Respiratory: Co-developed for moderate-to-severe asthma partnerships (AstraZeneca) inhaled IL4-Rα (partnered with AstraZeneca) • $120+M in upfront payments and antagonist (PRS-060) MAD Phase I • Next-generation respiratory: Includes 3 milestones since January 2017 data, including FeNO reduction vs. placebo discovery-stage inhaled therapeutics • Each partnership includes options for programs (2 proprietary, 1 partnered co-development & US-focused • IO: Wholly-owned bispecific 4-1BB with AstraZeneca) commercialization rights agonist (PRS-343) Phase I data in • PRS-343: 4-1BB/HER2 bispecific for 2019 solid tumors • Additional IO IND in 2019 • PRS-344: 4-1BB/PD-L1 bispecific (partnered with Servier) 3
Pipeline RESPIRATORY CANDIDATE TARGETS PARTNER COMMERCIAL RIGHTS DISCOVERY PRECLINICAL PHASE I PHASE II PRS-060 IL4-Rα Pieris Worldwide Profit-Share Option Proprietary Programs n.d. n/a Pieris Worldwide AstraZeneca Program #2 n.d. AstraZeneca *3 additional respiratory programs in collaboration with AstraZeneca IMMUNO-ONCOLOGY CANDIDATE TARGETS PARTNER COMMERCIAL RIGHTS DISCOVERY PRECLINICAL PHASE I PHASE II HER2/4-1BB n/a Pieris Worldwide PRS-343 + Anti-PD-L1 n/a Pieris Worldwide PRS-344 PD-L1/4-1BB Pieris U.S. Option PRS-300 Series n.d. n/a Pieris Worldwide *3 additional IO bispecific programs in collaboration with Servier, with Pieris retaining US rights for 2 of 5 programs *3 bispecific programs in collaboration with Seattle Genetics, with Pieris retaining US rights for 1 program OTHER DISEASE AREAS CANDIDATE TARGETS PARTNER COMMERCIAL RIGHTS DISCOVERY PRECLINICAL PHASE I PHASE II PRS-080 Hepcidin Major Markets Ex-ASKA Territories 4
What are Anticalin proteins? A Novel Therapeutic Class with Underpinned by a Powerful Favorable Drug-Like Properties Target Drug Discovery Platform • Derived from lipocalins (human • Highly diverse libraries (>1011) of extracellular binding proteins) potential drug candidates… • TLC and NGAL lipocalins used as • Automated high-throughput drug “templates” for drug development screening technology (phage • Engineerable binding pocket for display)… robust target engagement • Extensive protein engineering • Monomeric, monovalent, small size know-how… (~18 kDa vs 150kDa mAbs) • …resulting in high hit rates, • Can be formulated for inhalable quick-to-development candidates delivery • Can be formatted into novel bi/multispecific constructs Anticalin • Broad IP position Protein 5
Anticalin Protein-Based Drug Candidates can be Tailored to Multiple Formats Building Blocks Pure Anticalin Anticalin Multispecific Proteins Protein Fc-Anticalin Proteins Antibody PRS-060 Fc Multispecific Antibody-Anticalin PRS-343 Proteins PRS-344 Potent Multi-Target Engagement • Novel Inhaled and Multispecific MoA • Favorable Drug-like Properties 6
Partnerships • PRS-060 + 4 additional novel inhaled • 3-program partnership based on tumor- • PRS-344: PD-L1/4-1BB antibody/Anticalin Anticalin protein programs localized costimulatory bispecific fusion bispecific proteins • Retained co-development and co- • 5-program deal (all bispecific fusion commercialization (US) options on PRS- • Pieris retains opt-in rights for 50/50 global proteins) 060 and up to 2 additional programs profit split and U.S. commercialization rights on one of the programs • Pieris retains option for full U.S. rights for 3 • $57.5M upfront & 2017 milestone out of 5 programs • $30M upfront payment, $1.2B milestone • ~$2.1B in milestone potential, plus double- potential • $31M upfront payment, $1.8B milestone digit royalties potential • Up to double-digit royalties on non-co- • AZ funds all PRS-060 development costs developed products • Up to low double-digit royalties on non-co- through post-Ph 2a co-development opt-in developed products decision • Access to complementary formulation and device know-how for inhaled delivery Strong Partners • Significant Cash Flow • Retained Commercial Rights 7
Anticalin Technology Advantages: Differentiated Respiratory Platform Tear lipocalin (TLC) is abundant in human lung and permeates lung epithelium Very low predicted immunogenicity Stable, monovalent molecules with high melting temperatures and insensitivity to mechanical stress Inhalation pharmacokinetics suitable for once or twice daily administration and compatible with flexible treatment regimes 8
PRS-060: IL-4Rα Antagonist Candidate PRS-060 Function/MoA Inhibiting IL4-Rα (disrupts IL‐4 & IL‐13 signaling) Indications Moderate-to-severe asthma Development Phase I multiple-ascending dose trial PRS-060 Co-development and U.S. co-commercialization Commercial Rights rights, including gross margin share 9
PRS-060 is an Inhaled Drug Candidate for Uncontrolled Asthma Why did we design this? What We Know Regeneron/Sanofi’s dupilumab (systemically administered anti-IL-4Ra antibody) has demonstrated the following: Reduction in biomarker (FeNO*) Improved lung function Exacerbation Reduction & Steroid Sparing 67% 80% reduction in avg. reduction high-eosinophil in corticosteroid patients use *Fractional exhaled nitric oxide What We Are Testing • Is this a local phenomenon? • First-in-man study underway via inhaled delivery 10
Preclinical In Vivo PoC Supports Clinical Development • First inhaled Anticalin protein to potently engage the highly-validated asthma target, IL-4Ra • Localized target engagement in lung tissue supports a rationale for a potential convenient, low-dose, low- cost alternative to systemically-administered antibodies • Preclinical in vivo PoC for pulmonary delivery at doses supportive of daily administration Total and differential cell counts in OVA Lung model Histopathology hIL-13-induced increases in eotaxin Control 48-hr gene expression Percentage inhibition of lung inflammatory cells 06 6 10 48hr after OVA challenge 78% 71% 79% 66% 5 10 06 4 10 06 3 10 06 2 10 06 expression Cell differential Cell ** ** PRS-060 48-hr 06 1 10 in eotaxin Change Fold ** 0 * Total Macrophages Eosinophils Lymphocytes 48hr timepoint Anticaln control *p<0.05, **p<0.001 compared with control TLPC134, (TLPC134) unpaired two-tailed t test (n=9-10); data are Mean SEM PRS-060 Inhibits the influx of key inflammatory cells 24-hr duration of action at doses both in lavage fluid and lung tissue feasible for inhalation 11
PRS-060 Phase I Trial Single Ascending Multiple Ascending Dose Dose Dosing patients with mild asthma, Healthy volunteers elevated FeNO at baseline Initiated in December 2017 Initiated in July 2018 Evaluating safety, tolerability, PK, Study completed PD and will also evaluate FeNO reduction vs. placebo Safe and well tolerated in single Pieris is sponsoring the trial, dose administration ranging from AstraZeneca is reimbursing Pieris 0.25-400mg for all associated costs 12
Moderate-to-Severe Asthma Market Opportunity U.S. EU asthma patients over 12 asthma patients over 12 19.0M years of age in the U.S 19.0M47.8M years of age in the EU with moderate-to- 21.5M with moderate-to- 7.8M7.8M severe asthma (41%) severe asthma (45%) 3.1M3.1M uncontrolled (40%) 8.6M uncontrolled (40%) 1.9M high EOs (60%) 1.2M low EOs (40%) 5.2M high EOs (60%) 3.4M low EOs (40%) All numbers reflect 2016 estimates. Source: Artisan Healthcare Consulting analysis, including the following: CDC, Eurostat, Rabe (2004), Cazzoletti (2007), Colice (2012), Hekking (2015). 13
Anticalin Technology Advantages: Well-Equipped for Targeted IO Agonism A Varied Immune ...Does Not Materially Impact Target Engagement... ...But Impacts Efficacy Synapse... The Natural Immune Synapse ~15nm TNFRSL (e.g. 4-1BB Ligand) C-terminal Heavy chain fusion 13.4 nm TNFRS ~8nm (e.g. 4-1BB) C-terminal Light chain fusion \ Efficacy Experimental Design IFN-g IL-2 ~5nm Activation TCell 4-1BB/HER-2 bispecific N-terminal Heavy chain fusion Signal 1 Signal 2 4-1BB HER-2 ~5nm a-CD3 a-CD3 Antibodyantibody Culture Dish N-terminal Light chain HER-2+ fusion Tumor Cell Stand-alone Bispecific-based 14 building block affinity building block affinity
PRS-343: 4-1BB/HER2 Bispecific HER2-Targeting Candidate PRS-343 Antibody Tumor-targeted 4-1BB agonism, HER2 Function/MoA antagonism Indications HER2+ solid tumors Development Phase I Commercial Rights Fully proprietary 4-1BB-Targeting Anticalin Proteins 15
4-1BB (CD137): Validated Target in Need of Appropriate Drug • Marker for tumor-specific T cells in TME • Drives anti-tumor cytolytic activity • Ameliorates T-cell exhaustion & critical for T-cell expansion • Drives central memory T-cell phenotype Systemically agonizing 4-1BB mAb (urelumab) has shown clinical activity yet caused significant toxicity HER2-Targeting Antibody HER2+ Tumor Cell PRS-343 Tumor-Specific 4-1BB-Targeting T Cell Anticalin Proteins PRS-343 was designed for TME-specific 4-1BB activation* *4-1BB trimerization required for activation 16
PRS-343 Shows Localized Activity in Humanized Mouse Model CD8+ Proliferation in TME Peripheral CD8+ Proliferation Systemic Toxicity PRS-343 Yes No No 4-1BB mAb No Yes Yes Isotype Control No No No CD8+ Proliferation in TMEPeripheral CD8+ Proliferation Systemic Toxicity hCD3 hCD4 hCD8 Plot 100μg PRS-343 100 CD3 CD4 CD8 100μg anti-4-1BB 100µg 30 CD45 20 PRS-343 + mAb 10 % CD8 Frequency [%] Frequency 0 of 100μ IgG4 isotype CD45+ 30 CD3 CD4 CD8 ctrl 100µg CD45 50 20 Isotype Ctrl 10 Frequency [%] Frequency 0 Percent Survival Percent 30 CD3 CD4 CD8 CD45 100µg 20 Anti-4-1BB 10 Frequency[%] 0 0 10 20 30 40 Experimental Design: • SKOV-3 tumor cells grafted onto immune-deficient mice and grown to predetermined volume • Human PBLs + control or PBLs + PRS-343 administered 17
PRS-343 Phase I Escalation and Expansion Trials First patient dosed September 2017 Bladder Enrolling patients with HER2+ solid tumors Dose-escalation trial ongoing; expansion initiation pending positive escalation data Gastric Full PK, safety, tolerability and biomarker data in 2019 Other(s) First patient dosed in combination with atezolizumab (Tecentriq®) in August 2018 (drug supply agreement with Roche) ESCALATION MD Anderson Cancer Center 18
PRS-344: 4-1BB/PD-L1 Bispecific PD-L1-Targeting Candidate PRS-344 Antibody Function/MoA Localized 4-1BB agonism with PD-L1 antagonism Indications N.d. Development Preclinical Opt-in for co-development with full U.S. Commercial Rights commercial rights; royalty on ex-U.S. sales 4-1BB-Targeting Anticalin Proteins 19
PRS-344: Addressing Synergistic IO Biology • Combining the benefits of tumor-localized 4-1BB agonism with PD-L1 blockade • Pan-tumor opportunity • Publications support preclinical rationale of the combination, as evidenced below: Synergistic Response of PD-1+4-1BB Combination Demonstrated In Preclinical Models PD-L1 Targeting Antibody PD-1+4-1BB combo demonstrates robust preclinical anti-tumor activity 4-1BB agonism enhances mitochondrial function in T 4-1BB-Targeting cells Anticalin Proteins Adapted Menk et al. JEM (2018) Adapted Menk et al. JEM (2018) 20
Financial Overview (As of 9/30/18) $137.3 M $0.0 $35.7 M 54.1 M Cash & Cash Debt YTD OPEX CSO Equivalents $120+ M non-dilutive capital since January 2017 21
Scientific and Clinical Advisory Boards SCIENTIFIC ADVISORY BOARD: SCIENTIFIC ADVISORY BOARD: CLINICAL ADVISORY BOARD: ONCOLOGY RESPIRATORY ONCOLOGY • E. John Werry, PhD • Gary Anderson, PhD • Sandra Swain, MD University of Pennsylvania University of Melbourne Georgetown University Cancer Center • Vijay Kuchroo DVM, PhD • Peter Barnes, FRS • Noah Hahnm, MD Harvard Medical School Imperial College Johns Hopkins University School of • Michael Curran, PhD • Bruce Levy, MD Medicine MD Anderson Cancer Center Harvard University, Brigham and • David Ilson, MD, PhD • Dario Vignali, PhD Women’s Hospital Memorial Sloan-Kettering Cancer University of Pittsburgh • Fan Chung, MD, DSc Center, Weill Cornell Medical College • Padmanee Sharma, PhD Imperial College • Funda Eric-Bernstam, MD, PhD MD Anderson Cancer Center • Ian Adcock, PhD Institute for Personalized Cancer Imperial College Therapy, MD Anderson Cancer Center • Oliver Eickelberg, MD University of Denver • Mario Sznol, MD Yale University • Sally Wenzel, MD University of Pittsburgh Medical Center 22
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Pieris Pharmaceuticals 255 State Street Lise-Meitner-str. 30 Boston, MA 02109 85254 Freising USA Germany IR: kelman@pieris.com BD: niemeier@pieris.com NASDAQ: PIRS www.pieris.com