UNITED STATES
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FORM 8-K
CURRENT REPORT
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Date of Report (Date of earliest event reported): May 25, 2021
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Item 7.01 Regulation FD Disclosure.
Attached hereto as Exhibit 99.2 and incorporated by reference herein is the May 2021 Investor Presentation of Pieris Pharmaceuticals, Inc.
The information set forth under this “Item 7.01. Regulation FD Disclosure,” including Exhibit 99.1 attached hereto, shall not be deemed “filed” for any purpose, and shall not be deemed incorporated by reference into any filing under the Securities Act of 1933, as amended, or the Securities Exchange Act of 1934, as amended, regardless of any general incorporation language in any such filing. except as shall be expressly set forth by specific reference in such filing.
Item 9.01 Financial Statements and Exhibits
(d) Exhibits.
SIGNATURE
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
| PIERIS PHARMACEUTICALS, INC. | ||||||||
| Dated: May 25, 2020 | /s/ Tom Bures | |||||||
| Tom Bures | ||||||||
| Vice President, Finance | ||||||||
PIERIS PHARMACEUTICALS SUPERIOR MEDICINES THROUGH EFFICIENT BIOLOGY CORPORATE PRESENTATION MAY 2021
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 presentation that are not purely historical are forward-looking statements. Such forward-looking statements include, among other things, whether data from patients enrolled to date will be sufficient to inform the recommended phase 2 dose for the Company’s planned proof of concept study of cinrebafusp alfa in gastric cancer; the expected timing and potential outcomes of the reporting by the Company of key clinical data from its programs, 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 and the expected timing for reporting data, making IND filings or achieving other milestones related to our programs, including PRS-060/AZD1402, cinrebafusp alfa, PRS-344, and PRS-352 and the expected timing of the initiation of the next stage of cinrebafusp alfa’s development in gastric cancer. 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; competition in the industry in which we operate; delays or disruptions due to COVID-19; and market conditions. These forward-looking statements are made as of the date of this presentation, 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, 2020 and the Company's Quarterly Reports on Form 10-Q. 2
Executive Summary 3 • Protein therapeutics that exploit biology validated by mAbs; engineered for focused activity at disease locus • Improved activity, reduced side effects, increased convenience Superior Medicines via Efficient Biology • Oral inhaled antagonists for respiratory disease • Locally activated immuno-oncology bispecifics • 2 POC readouts in ‘22; several follow-on candidates Two Focus Areas • ~$200M since 2017 in upfronts, milestones and equity investments • Several co-developed and out-licensed programs • Clinical supply for combination studies and development expertise Supportive Partnerships
Our Platform 4 We combine leading protein engineering capabilities and deep insights into molecular drivers of disease to develop medicines that drive local biology to produce superior clinical outcomes for patients
A Novel Therapeutic Class with Favorable Drug- Like Properties • Human – Derived from lipocalins (human extracellular binding proteins) • Small – Monomeric, monovalent, small size (~18 kDa vs ~150kDa mAbs) • Stable – Inhalable delivery • Simple – Bi/multispecific constructs • Proprietary – Broad IP position on platform and derived products Translational Science Expertise to Deploy Platform in Meaningful Way • Immunology expertise underpins IO and respiratory focus • A leader in 4-1BB and costim biology • Patient phenotyping efforts for improved stratification and novel intervention points in, e.g., asthma Anticalin® Proteins as Therapeutic Modalities 5 Anticalin Protein Target
Our Pipeline 6 IMMUNO-ONCOLOGY CANDIDATE TARGETS INDICATION PARTNER OUR COMMERCIAL RIGHTS DISCOVERY PRECLINICAL PHASE I PHASE II Cinrebafusp Alfa (PRS-343) 4-1BB/HER2 HER2-High GC** n/a Worldwide HER2-Low GC** PRS-344/S095012 4-1BB/PD-L1 n.d. US Rights; ex-US Royalties PRS-352 n.d. n.d. Royalties PRS-342/BOS-342 4-1BB/GPC3 n.d. Royalties Seagen Programs‡ Co-stim Agonist n.d. US Co-Promotion Option; Royalties ‡3 bispecific programs in collaboration with Seattle Genetics, with Pieris retaining a US co-promotion option for the second program ** Phase 2 study includes HER2-high arm in combination with ramucirumab and paclitaxel and HER2-low arm in combination with tucatinib; drug supply agreements with Lilly and Seagen, respectively RESPIRATORY CANDIDATE TARGETS INDICATION PARTNER OUR COMMERCIAL RIGHTS DISCOVERY PRECLINICAL PHASE I PHASE II PRS-060/AZD1402 IL4-Rα Asthma Worldwide Profit-Share Option Proprietary Programs n.d. n.d. n/a Worldwide AstraZeneca Programs* n.d. n.d. Worldwide Profit-Share Options Genentech Programs+ n.d. n.d. Royalties *4 respiratory programs in collaboration with AstraZeneca, 2 of which carry co-development and co-commercialization options for Pieris +Collaboration includes 1 respiratory program and 1 ophthalmology program
Collaboration Snapshot 7 • PRS-060/AZD1402 + 4 additional programs • Upfront & milestones to date: $70.5M • $10M equity investment from AstraZeneca • Eligible to receive up to approximately $5.4B in potential milestone payments plus royalties • Retained co-development and co- commercialization (US) options on PRS- 060 and up to 2 additional programs • Boston Pharmaceuticals holds exclusive license for PRS-342 • Upfront & milestones to date: $10M • Eligible to receive up to approximately $353M in potential milestone payments • Entitled to tiered royalties • 1 respiratory program + 1 ophthalmology program • Upfront & milestones to date: $20M • Eligible to receive over $1.4B million in potential milestone payments • Entitled to tiered royalties • Genentech has option to select additional targets in return for an option exercise fee • 3-program IO bispecific partnership • Upfront & milestones to date: $35M • Eligible to receive up to approximately $1.2B in potential milestone payments plus royalties • $13M equity investment from Seagen • Tucatinib drug supply for phase 2 combination trial of cinrebafusp alfa in HER2-low gastric cancer • PRS-344: PD-L1/4-1BB antibody-Anticalin bispecific, for which Pieris holds full U.S. rights • Upfront & milestones to date: ~$40M • Eligible to receive up to approximately $447M in potential milestone payments • Entitled to tiered royalties
Anticalin Technology Advantages: Differentiated Respiratory Platform 8 • Lipocalin templates deployed by Pieris in respiratory programs are abundant in the human lung and can permeate lung epithelium • 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 regimens • Control of particle size distribution in critical size range in both “wet” and “dry” formulations to enable tailored delivery to discrete lung regions
PRS-060/AZD1402: IL-4Rα Antagonist 9 PRS-060/AZD1402Candidate Inhibiting IL4-Rα (disrupts IL-4 & IL-13 signaling) Function/MoA Moderate-to-severe asthmaIndications Phase 2a in moderate asthmaticsDevelopment Co-development and U.S. co-commercialization options, including gross margin share Commercial Rights PRS-060/AZD1402
PRS-060 Phase 2a Trial 10 Patient Population: Moderate controlled asthmatics Primary Endpoint: Safety and tolerability Number of Patients: ~45 Part 1 Patient Population: Moderate uncontrolled asthmatics with blood eosinophil count of ≥ 150 cells/μL and FeNO ≥ 25 ppb at screening Primary Endpoint: Improvement of FEV1 over four weeks relative to placebo Number of Patients: ~360 Part 2 Study is sponsored and funded by AstraZeneca Enrollment initiated 1Q 2021 Dry powder formulation, administered b.i.d. over four weeks Up to three dose levels plus placebo
High-value Target 4-1BB & the Advantages of Anticalin-based Bispecifics • Drives meaningful clinical benefit through proliferative, killing and durability impact on tumor-specific T cells • Improves metabolic fitness for increased survival of T cells • Designed to efficiently activate 4-1BB on tumor-specific T cells, avoiding undesirable activation in the liver • Initial clinical data are supportive of this approach • Multiple 4-1BB-based follow-on programs Our Solution 11 • Despite activity, inefficient mAb approaches have led to systemic 4-1BB activation, resulting in hepatic toxicity Historical Challenges 4-1BB
Cinrebafusp Alfa (PRS-343): Proprietary Lead IO Asset 12 Cinrebafusp alfa (PRS-343)Candidate Tumor-targeted 4-1BB agonism and HER2 antagonism Function/MoA HER2-high and HER2-low gastric cancerIndications Initiating phase 2Development Fully proprietaryCommercial Rights HER2-Targeting Antibody 4-1BB-Targeting Anticalin Proteins
Cinrebafusp Alfa Phase I Summary • Acceptable profile observed at all doses tested with no dose-limiting toxicities • Clinical benefit at active dose levels (≥2.5 mg/kg), including confirmed complete response and several confirmed partial responses • Dose-dependent immune activation and 4-1BB modulation in both HER2-high and HER2-low expressing patients • Durable anti-tumor activity in heavily pre-treated patient population, including "cold" tumors • Moving into phase 2 in HER2-high and HER2- low gastric cancer • As lead IO program, cinrebafusp alfa provides key validation of 4-1BB franchise and follow-on programs, including PRS-344 and PRS-342 13
Cinrebafusp Alfa Phase 1 Monotherapy Study 14 Study Objectives Primary: Characterize Safety Profile Identify MTD or RP2D Secondary: Characterize PK/PD & Immunogenicity Preliminary anti-tumor activity Key Eligibility Criteria Inclusion: Metastatic HER2+ solid tumors Breast & Gastric/GEJ ≥ 1 prior anti-HER2 Tx Measurable disease (RECIST v1.1) ECOG 0 or 1 Exclusion: Symptomatic or unstable brain metastasis Abnormal cardiac EF (< 45%) 0.0005 mg/kg 0.05 mg/kg 0.15 mg/kg (n = 5) 0.5 mg/kg (n = 7) 1.0 mg/kg (n = 6) 2.5 mg/kg (n = 6) 5 mg/kg (n = 9) 8 mg/kg (n = 26) 12 mg/kg (n = 3) 18 mg/kg (n = 9) (n = 7) Accelerated Titration Dose Escalation Study Design Q3W Q2W QW, Q2W & Q3W active dose range 13b 12b 11, 11b, 11c, obi 10 9 8 7 6 5
Phase 1 Monotherapy Baseline Characteristics (N = 78) 15 Characteristic n (%) Age, Median (range) 63 (24–92) Gender F 46 (59%) M 32 (41%) ECOG PS 0 19 (24%) 1 59 (76%) Prior Therapy Lines 1 11 (14%) 2 10 (13%) 3 16 (21%) 4 12 (15%) 5+ 29 (37%) Median # of anti-HER2 Tx Breast 6 Gastric 2 Primary Cancer Type n (%) Gastroesophageal 34 (44%) Breast 16 (21%) Colorectal 12 (15%) Gynecological 9 (12%) Bladder 2 (3%) Pancreatic 1 (1%) Other – Cancer of Unknown Origin 2 (3%) Other – Salivary Duct 1 (1%) Melanoma 1 (1%) Data cut-off: 25-Feb-21
Phase 1 Monotherapy Treatment Related Adverse Events at Active Doses (≥ 2.5 mg/kg) 16 Data cut-off: 25-Feb-21 Treatment Related Adverse Events (TRAEs occurring in > 1 patient; n = 53) All Grades n (%) Grade 1-2 n (%) Grade 3-4 n (%) Infusion related reaction 13 (25%) 9 (17%) 4 (8%) Nausea 7 (13%) 7 (13%) Chills 6 (11%) 6 (11%) Vomiting 6 (11%) 6 (11%) Dyspnoea 4 (8%) 4 (8%) Fatigue 4 (8%) 4 (8%) Arthralgia 3 (6%) 2 (4%) 1 (2%) Decreased appetite 3 (6%) 3 (6%) Non-cardiac chest pain 3 (6%) 3 (6%) Asthenia 2 (4%) 2 (4%) Diarrhoea 2 (4%) 2 (4%) Dizziness 2 (4%) 2 (4%) Headache 2 (4%) 2 (4%) Paraesthesia 2 (4%) 1 (2%) 1 (2%) Pruritus 2 (4%) 2 (4%) Pyrexia 2 (4%) 2 (4%) Rash 2 (4%) 2 (4%) 1 Gr 3 Ejection Fraction dec and 1 Gr 3 Heart Failure; both events occurred in one patient and resolved w/o sequelae.
Summary of Responses in Phase 1 Monotherapy Study 17 Cohort 13b 12b 11c Obi 11b 11 10 9 Total Best Response 18 mg/kg, Q2W 12 mg/kg, Q2W 8 mg/kg, QW 8 mg/Kg, Q2W 8 mg/kg, Q2W 8 mg/kg, Q3W 5 mg/kg, Q3W 2.5 mg/kg, Q3W Evaluable Patients 8 2 5 4 7 4 7 5 42 CR 1 - - - - - - - 1 PR 1 - - - 3 - - - 4 SD 3 - 1 2 3 3 3 2 17 ORR 25% 0% 0% 0% 43% 0% 0% 0% 12% DCR 63% 0% 20% 50% 86% 75% 43% 40% 52% Data cut-off: 25-Feb-21
Cinrebafusp Alfa Phase 1 Monotherapy Efficacy Data: Analysis of Patients Treated at Active Doses 18 Overall Population Data cut-off: 25-Feb-21 *Manual update for CUP patient from Medidata 9-Apr-21 *
Cinrebafusp Alfa Phase 1 Monotherapy Efficacy Data: Analysis of Patients Treated at Active Doses 19 GC/GEJ & Colorectal Cancers Data cut-off: 25-Feb-21
Durable Responses with Cinrebafusp Alfa Among Heavily Pre-treated Population 20 Data cut-off: 25-Feb-21 Overall Population
Cinrebafusp Alfa Shows Dose-dependent Activity Across Key Pharmacodynamic Parameters 21 S e ru m ( s 4 -1 B B ) T u m o r (C D 8 + ) Mann-Whitney U TestConnects group averages Dose at 8 mg/kg incorporates patients treated at Q1W, Q2W, or Q3W Median Data cut-off: 25-Feb-21
Cinrebafusp Alfa Activates Adaptive and Innate Immunity in the Tumor 22 Data cut-off: 25-Feb-21 p = 0.002 CD8+ Cells p = 0.0115 CD8+Ki67+ Cells p = 0.0051 NK Cells p = 0.1551 GrzB+ Cells Denotes group averages Median Unpaired One-Tailed Welch`s Biopsy Pre-dose Biopsy Post-dose (Cycle 2 Days 2-8) PRS-343 (Cycle 2 Day 1) PRS-343 (Cycle 1 Day 1) p=0.0782 Based on preclinical and clinical data, serum concentration of > 20 µg/ml defines active dose range beginning at 2.5 mg/kg (Cohort 9)
Single-Agent Activity in Both “Hot” and “Cold” Tumors 23 Data cut-off: 25-Feb-21 PD-L1 status and CD8+ T cells levels in tumor biopsies Several patients with clinical benefit have low/negative PD-L1 status and low CD8 T cell numbers PR SD CR * Threshold informed by (Tumeh et al., 2014 and Blando et al., 2019) Cold Tumor Hot Tumor & PD-L1 High CD8 High/PD-L1 Low/Negative CD8 Low/PD-L1 High *
Signs of Preclinical and Clinical Activity in the HER2-Low Setting 24 PRS-343 increases soluble 4-1BB in HER2-low-expressing patients Baseline On-tx 0 5 10 40 60 Her 2 IHC 2+ Her 2 IHC 1+ PRS-343 enhances T cell activation in in vitro co-cultures with HER2-low tumor cell lines1 1Hinner et al Clin Can Res 2019 Her 2 IHC 2+ Her 2 IHC 1+ Patient with SD Patient with PD F o ld c h a n g e I L 2 ( L o g 2 ) Normalized HER2 expression JIMT-1 MDA-MB-453 ZR-75-1 MKN7 MKN45 Data cut-off: 25-Feb-21
Case Studies: PR in Gastric Cancer and CR in Rectal Cancer Patient Profile, Treatment History and Treatment Outcome 25 Rectal Cancer Patient with Complete Response • 59-year-old male; initial diagnosis in March 2017 • Rectal cancer with cardiac and lung mets • Treated with 18 mg/kg Q2W of PRS-343 • Foundation One Her2 amplification; verified in-house to be IHC 3+; MSS, TMB low Prior Treatment includes: • Folfiri/Avastin • 5FU/Avastin maintenance • Irinotecan/Avastin & SBRT Gastric Cancer Patient with Partial Response • 80-year-old woman; initial diagnosis in June 2017 • Gastric adenoca with mets to liver, LN and adrenals • Treated with 8 mg/kg Q2W of PRS-343 • HER2 IHC 3+; PD-L1 positive (CPS=3) ; NGS: ERBB2 amplification Prior Treatment includes: • Trastuzumab, Pembrolizumab + Capecitabine/oxaliplatin • Nivolumab with IDO1 inhibitor (investigational drug) Pre C D 8 + T c e lls (n /m m 2 ) 0 100 200 300 400 500 600 700 Post CD8 fold change: 2.3 CD8 pre [n/mm2]: 238 2 3 4 8 1 5 0 2 4 6 s 4 1 B B F o ld C h a n g e t o B a s e li n e T i m e p o i n t ( d a y s ) B a s e l i n e P r e C 2 Pre C D 8 + T c e lls (n /m m 2 ) Post CD8 fold change: 5.7 CD8 pre [n/mm2]: 38 0 50 100 150 200 250 B a s e lin e C 4 P o s t- tr e a tm e n t B a s e lin e C 6 P o s t- tr e a tm e n t 2 4 8 15 Pre C2 0 1 2 3 s4 1B B Fo ld C ha ng e to P re do se Timepoint (days) Baseline
Case Study: PR in Cancer of Unknown Primary Patient Profile, Treatment History and Treatment Outcome 26 Data cut-of: 25-Feb-21 Lesions Lesion Site Lesion Size (mm) Pre-treatment Post-treatment Cycle 2 Cycle 4 Cycle 6 Target 1 Lung, right lower lobe mass 25 13 0 0 Total 25 13 0 0 % Change from Baseline -48% -100% -100% Non-target 1 Lung, bilateral pulmonary masses Present Not assessed Present Present Non-target 2 Lymph nodes, mediastinal and hilar Present Not assessed Present Present Overall Response PR PR PR Patient Profile 82-year-old male Initial diagnosis October 2019 Carcinoma of Unknown Primary Stage 4 HER2 amplification via MD Anderson NGS; MSS- stable; TMB unknown Treatment History Open Radical Prostatectomy Radiation Carboplatin + gemcitabine Ba se lin e C1 d2 C1 d3 C1 d4 C1 d8 C1 d1 5 Pr e C 2 Pr e C 3 C3 d2 C3 d3 C3 d4 C3 d8 C3 15 0 5 10 15 Timepoint (days) Fo ld c ha ng e to b as el in e s 4 -1 B B S e ru m Data cut-off: 25-Feb-21
Case Study: SD in Colorectal Cancer Patient Profile, Treatment History and Treatment Outcome 27 Lesions Lesion Site Lesion Size (mm) Pre-treatment Post-treatment Cycle 2 Cycle 4 Cycle 6* Target 1 Lung, right upper lobe pulmonary nodule 10 8 8 - Target 2 Lung, right lower lobe pulmonary nodule 12 11 11 - Total 22 19 19 - % Change from Baseline -14% -14% - Non-target 1 Lung, multiple pulmonary nodules Present Present Present - CEA <1.9 1.1 1.3 - Patient Profile 56-year-old female Initial diagnosis Jan 2009 Stage 4 Colorectal Adenocarcinoma Cancer Archival HER2 3+ MSI stable; KRAS, NRAS, BRAF wt Treatment History 9 prior lines of therapy, including: Folfiri Folfox + Avastin 5-FU + bevacizumab trastuzumab/pertuzumab Investigational agent (immune stimulator antibody conjugate (ISAC) with antibody similar to trastuzumab s 4 -1 B B S e ru m Ba se lin e C1 d2 C1 d3 C1 d4 C1 d8 C1 d1 5 Pr e C 2 Pr e C 3 C3 d2 C3 d3 C3 d4 C3 d8 C3 15 0 5 10 15 Timepoint (days) Fo ld c ha ng e to b as el in e Data cut-off: 25-Feb-21 *Data not yet available due to COVID-related delays
Cinrebafusp Alfa Clinical Development Plan 28 Go/No-Go Analysis Gastric Cancer 2L+ A R M A HER2-High (IHC3+ or IHC2+/ISH+) Cinrebafusp Alfa + Ramucirumab + Paclitaxel Phase 2 Details add. 20 – 40 pts add. 20 – 40 pts and Part BPart A N = ~ 20 pts N = ~ 20 pts Gastric Cancer 2L+ A R M B HER2-Low (IHC2+/ISH- or IHC1+) Cinrebafusp Alfa + Tucatinib Recommended Phase 2 Dose: Two-cycle loading dose of 18 mg/kg (Q2W), followed by an 8 mg/kg dose (Q2W) in subsequent cycles High bar based on ORR, durability, and safety
Cinrebafusp Alfa Opportunity in HER2-High & HER2-Low Gastric Cancer 29 1st Line 2nd Line 3rd Line Cinrebafusp Alfa Initial Focus *HER2-Low = IHC2+/ISH- or IHC1+ US Incidence: ~800 EU5 Incidence: ~1,500 JP Incidence: ~2,600 US Incidence: ~1,500 EU5 Incidence: ~2,800 JP Incidence: ~5,000 US Incidence: ~2,600 EU5 Incidence: ~5,200 JP Incidence: ~9,500 US Incidence: ~3,700 EU5 Incidence: ~7,400 JP Incidence: ~13,400 US Incidence: ~2,100 EU5 Incidence: ~4,000 JP Incidence: ~7,000 US Incidence: ~1,100 EU5 Incidence: ~1,700 JP Incidence: ~4,900 1) Meta Analysis of 12 studies (10,287 patients; Range 12.3-26.9%) 2) Eric Van Cutsem, et al., Gastric Cancer (2015) 18:476–484 ~17%1 HER2-high Patients ~24%2 HER2-low* Patients Total US, EU5 & JP Incidence (HER2+ & HER2-Low): ~35,000
Scientific Rationale for Combining Cinrebafusp Alfa & SoC 30 • Reduces tumor bulk • Releases antigen • Improves T cell : tumor target ratio Paclitaxel – Chemotherapy • Normalizes vascularization • Alters tumor barrier to T cell penetration • Reduces Tregs & inhibits TAMs Ramucirumab – Anti-Angiogenic1-3 • Increases T cell survival and metabolic fitness in the TME • Induces T cell memory • Drives T cell expansion • Induces anti-tumor cytolytic activity Cinrebafusp Alfa – 4-1BB Agonist 1 - Allen et al., Science Translational Medicine 2017 2 - Juang et al. Front Immunology 2018 3 - Tada et al., Journal for Immunotherapy of Cancer 2018
Scientific Rationale for Combining Cinrebafusp Alfa & Tucatinib 31 • Upregulates or stabilizes tumor cell surface HER2 expression2,3,4 • Increases clustering potential of cinrebafusp alfa on tumor cells to drive enhanced 4-1BB cross-linking Tyrosine kinase inhibitors (tucatinib) • Inhibits HER2 signaling AND activates tumor-specific T cells in tumor microenvironment Cinrebafusp Alfa – Dual MoA • Enhances inhibition of HER2 signaling by concurrent binding to HER2 on the tumor cell surface and TKI inhibition of the internal kinase signaling domain1 • In vitro, combination leads to significantly increased T cell activation in the presence of HER2-Low cell lines Complements Both MoAs 1 - Baselga J., Lancet, 2012; 2 - Maruyama T., et al, Anticancer Res., 2011 3 - Scaltriti M., et al, Oncogene, 2009 4 - Hartmans, et al, Oncotarget,, 2017
Cinrebafusp Alfa and Tucatinib Combination Enhances T-cell Activation 32 0. 00 04 2 0. 00 13 0. 00 38 0. 01 1 0. 03 4 0. 10 0. 31 0. 93 2. 8 8. 3 25 0. 00 04 2 0. 00 13 0. 00 38 0. 01 1 0. 03 4 0. 10 0. 31 0. 93 2. 8 8. 3 25 0. 00 04 2 0. 00 13 0. 00 38 0. 01 1 0. 03 4 0. 10 0. 31 0. 93 2. 8 8. 3 25 0. 00 04 2 0. 00 13 0. 00 38 0. 01 1 0. 03 4 0. 10 0. 31 0. 93 2. 8 8. 3 25 0. 00 04 2 0. 00 13 0. 00 38 0. 01 1 0. 03 4 0. 10 0. 31 0. 93 2. 8 8. 3 25 0. 00 04 2 0. 00 13 0. 00 38 0. 01 1 0. 03 4 0. 10 0. 31 0. 93 2. 8 8. 3 25 0 50 100 150 200 #19074 | MKN-7 Concentration [nM] IL -2 [p g/ m l] bg12 0. 00 04 2 0. 00 13 0. 00 38 0. 01 1 0. 03 4 0. 10 0. 31 0. 93 2. 8 8. 3 25 0. 00 04 2 0. 00 13 0. 00 38 0. 01 1 0. 03 4 0. 10 0. 31 0. 93 2. 8 8. 3 25 0. 00 04 2 0. 00 13 0. 00 38 0. 01 1 0. 03 4 0. 10 0. 31 0. 93 2. 8 8. 3 25 0. 00 04 2 0. 00 13 0. 00 38 0. 01 1 0. 03 4 0. 10 0. 31 0. 93 2. 8 8. 3 25 0. 00 04 2 0. 00 13 0. 00 38 0. 01 1 0. 03 4 0. 10 0. 31 0. 93 2. 8 8. 3 25 0. 00 04 2 0. 00 13 0. 00 38 0. 01 1 0. 03 4 0. 10 0. 31 0. 93 2. 8 8. 3 25 0 100 200 300 #19074 | HT-29 Concentration [nM] IL -2 [p g/ m l] bg1bg2 PRS-343 PRS-343 + tucatinib Tras-IgG4 Tras-IgG4 + tucatinib urelumab urelumab + tucatinib 0. 00 04 2 0. 00 13 0. 00 38 0. 01 1 0. 03 4 0. 10 0. 31 0. 93 2. 8 8. 3 25 0. 00 04 2 0. 00 13 0. 00 38 0. 01 1 0. 03 4 0. 10 0. 31 0. 93 2. 8 8. 3 25 0. 00 04 2 0. 00 13 0. 00 38 0. 01 1 0. 03 4 0. 10 0. 31 0. 93 2. 8 8. 3 25 0. 00 04 2 0. 00 13 0. 00 38 0. 01 1 0. 03 4 0. 10 0. 31 0. 93 2. 8 8. 3 25 0. 00 04 2 0. 00 13 0. 00 38 0. 01 1 0. 03 4 0. 10 0. 31 0. 93 2. 8 8. 3 25 0. 00 04 2 0. 00 13 0. 00 38 0. 01 1 0. 03 4 0. 10 0. 31 0. 93 2. 8 8. 3 25 0 1000 2000 3000 #19074 | SK-BR-3 Concentration [nM] IL -2 [p g/ m l] bg1 bg2 0. 00 04 2 0. 00 13 0. 00 38 0. 01 1 0. 03 4 0. 10 0. 31 0. 93 2. 8 8. 3 25 0. 00 04 2 0. 00 13 0. 00 38 0. 01 1 0. 03 4 0. 10 0. 31 0. 93 2. 8 8. 3 25 0. 00 04 2 0. 00 13 0. 00 38 0. 01 1 0. 03 4 0. 10 0. 31 0. 93 2. 8 8. 3 25 0. 00 04 2 0. 00 13 0. 00 38 0. 01 1 0. 03 4 0. 10 0. 31 0. 93 2. 8 8. 3 25 0. 00 04 2 0. 00 13 0. 00 38 0. 01 1 0. 03 4 0. 10 0. 31 0. 93 2. 8 8. 3 25 0. 00 04 2 0. 00 13 0. 00 38 0. 01 1 0. 03 4 0. 10 0. 31 0. 93 2. 8 8. 3 25 0 50 100 150 200 250 #19074 | ZR-75-1 Concentration [nM] IL -2 [p g/ m l] bg12 PRS-343 PRS-343 + tucatinib Tras-IgG4 Tras-IgG4 + tucatinib urelumab urelumab + tucatinib Increased IL-2 secretion observed when cinrebafusp alfa was combined with fixed dose tucatinib in a co-culture assay with SK-BR-3 (high HER2), MKN-7, ZR-75-1 (medium HER2) and HT-29 (low HER2) tumor cell lines SK-BR-3 (HER2+++) MKN-7 (HER2++) HT-29 (HER2+) ZR-75-1 (HER2++) Human T cell Co-Culture Activation Assay
Cinrebafusp Alfa and Tucatinib Combination Leads to Enhanced 4-1BB Signaling 33 PRS-343 PRS-343 + tucatinib Tras-IgG4 Tras-IgG4 + tucatinib urelumab urelumab + tucatinibPRS-343 PRS-343 + tucatinib Tras-IgG4 Tras-IgG4 + tucatinib urelumab urelumab + tucatinib Increased 4-1BB signaling observed when cinrebafusp alfa was combined with fixed dose tucatinib in a reporter assay with SK-BR-3 (high HER2), MKN-7, ZR-75-1 (medium HER2) and HT-29 (low HER2) tumor cell lines 0 .0 0 1 0 .0 0 4 0 .0 1 1 0 .0 3 4 0 .1 0 3 0 .3 0 9 0 .9 2 6 2 .7 7 8 8 .3 3 3 2 5 0 .0 0 1 0 .0 0 4 0 .0 1 1 0 .0 3 4 0 .1 0 3 0 .3 0 9 0 .9 2 6 2 .7 7 8 8 .3 3 3 2 5 0 .0 0 1 0 .0 0 4 0 .0 1 1 0 .0 3 4 0 .1 0 3 0 .3 0 9 0 .9 2 6 2 .7 7 8 8 .3 3 3 2 5 0 .0 0 1 0 .0 0 4 0 .0 1 1 0 .0 3 4 0 .1 0 3 0 .3 0 9 0 .9 2 6 2 .7 7 8 8 .3 3 3 2 5 0 .0 0 1 0 .0 0 4 0 .0 1 1 0 .0 3 4 0 .1 0 3 0 .3 0 9 0 .9 2 6 2 .7 7 8 8 .3 3 3 2 5 0 .0 0 1 0 .0 0 4 0 .0 1 1 0 .0 3 4 0 .1 0 3 0 .3 0 9 0 .9 2 6 2 .7 7 8 8 .3 3 3 2 5 0 200000 400000 600000 800000 Concentration [nM] R L U bg1 bg2 0 .0 0 1 0 .0 0 4 0 .0 1 1 0 .0 3 4 0 .1 0 3 0 .3 0 9 0 .9 2 6 2 .7 7 8 8 .3 3 3 2 5 0 .0 0 1 0 .0 0 4 0 .0 1 1 0 .0 3 4 0 .1 0 3 0 .3 0 9 0 .9 2 6 2 .7 7 8 8 .3 3 3 2 5 0 .0 0 1 0 .0 0 4 0 .0 1 1 0 .0 3 4 0 .1 0 3 0 .3 0 9 0 .9 2 6 2 .7 7 8 8 .3 3 3 2 5 0 .0 0 1 0 .0 0 4 0 .0 1 1 0 .0 3 4 0 .1 0 3 0 .3 0 9 0 .9 2 6 2 .7 7 8 8 .3 3 3 2 5 0 .0 0 1 0 .0 0 4 0 .0 1 1 0 .0 3 4 0 .1 0 3 0 .3 0 9 0 .9 2 6 2 .7 7 8 8 .3 3 3 2 5 0 .0 0 1 0 .0 0 4 0 .0 1 1 0 .0 3 4 0 .1 0 3 0 .3 0 9 0 .9 2 6 2 .7 7 8 8 .3 3 3 2 5 0 200000 400000 600000 800000 Concentration [nM] R L U bg1 bg2 0 .0 0 1 0 .0 0 4 0 .0 1 1 0 .0 3 4 0 .1 0 3 0 .3 0 9 0 .9 2 6 2 .7 7 8 8 .3 3 3 2 5 0 .0 0 1 0 .0 0 4 0 .0 1 1 0 .0 3 4 0 .1 0 3 0 .3 0 9 0 .9 2 6 2 .7 7 8 8 .3 3 3 2 5 0 .0 0 1 0 .0 0 4 0 .0 1 1 0 .0 3 4 0 .1 0 3 0 .3 0 9 0 .9 2 6 2 .7 7 8 8 .3 3 3 2 5 0 .0 0 1 0 .0 0 4 0 .0 1 1 0 .0 3 4 0 .1 0 3 0 .3 0 9 0 .9 2 6 2 .7 7 8 8 .3 3 3 2 5 0 .0 0 1 0 .0 0 4 0 .0 1 1 0 .0 3 4 0 .1 0 3 0 .3 0 9 0 .9 2 6 2 .7 7 8 8 .3 3 3 2 5 0 .0 0 1 0 .0 0 4 0 .0 1 1 0 .0 3 4 0 .1 0 3 0 .3 0 9 0 .9 2 6 2 .7 7 8 8 .3 3 3 2 5 0 200000 400000 600000 800000 Concentration [nM] R L U bg1 bg2 0 .0 0 1 0 .0 0 4 0 .0 1 1 0 .0 3 4 0 .1 0 3 0 .3 0 9 0 .9 2 6 2 .7 7 8 8 .3 3 3 2 5 0 .0 0 1 0 .0 0 4 0 .0 1 1 0 .0 3 4 0 .1 0 3 0 .3 0 9 0 .9 2 6 2 .7 7 8 8 .3 3 3 2 5 0 .0 0 1 0 .0 0 4 0 .0 1 1 0 .0 3 4 0 .1 0 3 0 .3 0 9 0 .9 2 6 2 .7 7 8 8 .3 3 3 2 5 0 .0 0 1 0 .0 0 4 0 .0 1 1 0 .0 3 4 0 .1 0 3 0 .3 0 9 0 .9 2 6 2 .7 7 8 8 .3 3 3 2 5 0 .0 0 1 0 .0 0 4 0 .0 1 1 0 .0 3 4 0 .1 0 3 0 .3 0 9 0 .9 2 6 2 .7 7 8 8 .3 3 3 2 5 0 .0 0 1 0 .0 0 4 0 .0 1 1 0 .0 3 4 0 .1 0 3 0 .3 0 9 0 .9 2 6 2 .7 7 8 8 .3 3 3 2 5 0 50000 100000 150000 200000 600000 800000 1000000 Concentration [nM] R L U bg1 bg2 SK-BR-3 (HER2+++) MKN-7 (HER2++) HT-29 (HER2+) ZR-75-1 (HER2++) (4-1BB Reporter Cell Assay)
PRS-344/S095012: Meaningfully Building on Localized MoA of Cinrebafusp Alfa 34 PRS-344Candidate Localized 4-1BB agonism with PD-L1 antagonism Function/MoA N.D.Indications 2021 IND expected (in co-dev with Servier)Development Opt-in for co-development with full U.S. commercial rights; royalty on ex-U.S. sales Commercial Rights PD-L1-Targeting Antibody 4-1BB-Targeting Anticalin Proteins
PRS-344 Drives Strong Anti-tumor Activity in Anti-PD-L1 mAb- resistant Mouse Model 35 • Dose-dependent anti-tumor response that leads to significant extension of survival • Superior to equimolar doses of anti-PD-L1 mAb treatment alone h-4-1BB knock-in mice subcutaneously implanted with MC-38-huPD-L1 cells Tumor Growth Survival 0 10 20 30 40 50 0 20 40 60 80 100 0 5 10 15 20 25 30 35 0 1000 2000 3000 4000 *** ********* * ** * PRS-344/S095012 (1 mg/kg) anti-4mAb 3mg/kg Vehicle control PRS-344/S095012 (10 mg/kg) PRS-344/S095012 (0.01 mg/kg) anti-PD-L1 mAb (7.7 mg/kg) anti-PD-L1 mAb (0.8 mg/kg) PRS-344/S095012 (0.1 mg/kg) Days after implantationDays after implantation Vehicle Anti-PD-L1 - 7.7 mg/kg Anti-PD-L1 – 0.77 mg/kg Urelumab analog – 3 mg/ PRS-344/S095012 - 10 mg/kg PRS-344/S095012 - 1 mg/kg PRS-344/S095012 - 0.1 mg/kg PRS-344/S095012 - 0.01 mg/kg
Financial Overview (As of 3/31/21) 36 non-dilutive capital from partnerships since 2017>$175M $66.8M (~$120M proforma*) Cash & Cash Equivalents $0.0 Debt 59.7M* CSO *Excludes $23M from PRS-060 phase 2a milestone and AstraZeneca equity investments (along with ~3.6M common shares issued), $10 million from Boston Pharmaceuticals and $20 million from Genentech
Appendix
PRS-060 Phase I
PRS-060 Phase I Multiple Ascending Dose Trial Ascertain PK/PD with a reliable biomarker to confirm local target engagement and inform Phase II dosage regimen Strategic Objectives Dosing patients with mild asthma with elevated FeNO levels (≥35 ppb), to receive inhaled PRS-060 or pbo b.i.d.* over a 10-day period Trial Design Highlights Pieris is sponsoring the trial, AstraZeneca is reimbursing Pieris for all associated costs Initiated in July 2018 Evaluating safety, tolerability, PK, PD and will also evaluate FeNO reduction vs. placebo Measuring safety, tolerability and FeNO changes days 1-10,17, and 40 *q.d. on Day 10
Phase 1b Interim Results: Favorable Safety Profile 40 • All doses of AZD1402/PRS-060 tested in the study were well tolerated • No treatment-related serious AEs were observed System organ class AE Preferred Termsb Placebo (N = 12) n (%) m AZD1402/PRS-060c (N = 30) n (%) m Overall (N = 42) n (%) m Gastrointestinal disorders Dry mouth Nausea 4 (33.3) 4 1 (8.3) 1 1 (8.3) 1 13 (43.4) 14 2 (6.7) 2 3 (10.0) 3 17 (40.5) 18 3 (7.1) 3 4 (9.5) 4 Infections and infestations Upper respiratory tract infection 1 (8.3) 1 1 (8.3) 1 7 (23.3) 8 3 (10.0) 4 8 (19.0) 9 4 (9.5) 5 Nervous system disorders Headache Presyncope 5 (41.7) 9 3 (25.0) 6 0 13 (43.4) 18 5 (16.7) 7 4 (13.3) 6 18 (42.9) 27 8 (19.0) 13 4 (9.5) 6 Respiratory, thoracic and mediastinal disorders Cough Rhinorrhoea Wheezing 6 (50.0) 6 1 (8.3) 1 2 (16.7) 2 2 (16.7) 2 14 (46.7) 15 4 (13.3) 4 1 (3.3) 1 4 (13.3) 5 20 (47.6) 21 5 (11.9) 5 3 (7.1) 3 6 (14.3) 7
Phase 1b Interim Results: Robust FeNO Reduction 41 PRS-060 Relative FeNO Reduction (Emax Analysis) PRS-060, mg (delivered) n Reduction vs. placebo, % (95% CI) p-value 2 6 24.0 (1.8–41) 0.04 6 6 24.3 (2.7–41) 0.03 20 12 36.4 (22–48) <0.0001 60 6 30.5 (10–46) 0.005 Placebo 12 PRS-060 Relative FeNO Reduction (ANCOVA Analysis) Mean change from baseline in FeNO levels at 0.5h (A) and 2h (B) post-dose on Day 10 in participants with mild asthma
Phase 1b Interim Results: Pharmacological Versatility 42 pSTAT6 levels over time following inhalation of PRS-060 No systemic target engagement and minimal systemic exposure was observed at the 2mg dose, suggesting that local target engagement by the drug is sufficient to reduce airway inflammation Pharmacological versatility, given low- dose FeNO reduction with no observed systemic activity (pSTAT6) versus high-dose FeNO reduction with systemic activity
Cinrebafusp Alfa – Biomarkers
Soluble 4-1BB (s4-1BB): Blood-based Biomarker of Cinrebafusp Alfa Engagement 44 • s4-1BB is an alternatively spliced form of 4-1BB receptor lacking the transmembrane encoding exon (Setareh et al., 1995; Shao et al., 2008) • s4-1BB is released by leukocytes in an activation-dependent manner (Michel et al., 2000; Salih et al., 2001; Schwarz et al., 1996) • s4-1BB is produced with a slightly delayed kinetic to pathway activation. Hypothesized role is as a negative regulator, keeping 4-1BB-mediated co-stimulation in check s4-1BB utility as a pathway specific biomarker provides ability to track cinrebafusp target engagement and activity using serum samples
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