Notch-2

CHICAGO--(BUSINESS WIRE)--Cellworks Group Inc., a leader in Personalized Therapy Decision Support and Best-in-Class PTRS, today announced compelling results from a new study demonstrating the ability of the Cellworks Platform to identify patients with high microsatellite instability (MSI-H) who may not respond to immune checkpoint inhibitors (ICIs), despite MSI-H status. Results from the study were showcased in a poster presentation titled, Use of Biosimulation to Predict Immune Checkpoint Inhibitor Resistance in Patients with High Microsatellite Instability as part of the AACR Annual Meeting 2025 taking place April 25-30, 2025 at the McCormick Place Convention Center in Chicago. While immune checkpoint inhibitors (ICIs) such as pembrolizumab are considered a standard-of-care for MSI-H cancers, MSI-H status alone is not a definitive predictor of treatment success. In this study, Cellworks applied its unique mechanistic Computational Biology Model (CBM) to biosimulate patient-specific responses to ICIs. The computational biosimulation process in the study uncovered molecular signatures of resistance in MSI-H patients who were predicted to have poor response to ICIs, providing a deeper understanding of why some MSI-H patients fail to benefit from immunotherapy. Key Findings Efficacy Scores Significantly Higher in MSI-H Patients. MSI-H patients demonstrated significantly higher pembrolizumab efficacy scores compared to microsatellite stable (MSS) patients in both STAD (average ES: 20.5 vs. 3.2, p < 0.001) and CRC (average ES: 13.4 vs. 2.4, p < 0.001). Large Subset of MSI-H Patients Predicted to Have Low ICI Response. Despite being MSI-H, 59% of STAD and 81% of CRC patients were identified as low pembrolizumab responders. Molecular Drivers of Resistance Identified. In MSI-H patients classified as low pembrolizumab responders, higher rates of NOTCH2, EGFR, and EZH2 amplifications, along with TP53 loss-of-function mutations, were identified. In MSI-H/ES-L CRC patients, MYC amplification was significantly enriched ( p < 0.05). “These findings highlight the power of using patient-specific drug response methods to move beyond MSI-H status and identify critical molecular drivers of immune checkpoint inhibitor resistance,” said Dr. James Wingrove, Chief Development Officer at Cellworks and presenting author of the study. “By identifying patients unlikely to respond to ICIs, we can help oncologists personalize treatment strategies and improve outcomes for MSI-H patients who may otherwise receive ineffective therapies.” “This study demonstrates the importance of looking beyond MSI status to understand immune checkpoint inhibitor resistance at a molecular level,” said Dr. Michael Castro, Chief Medical Officer at Cellworks. “Our biosimulation revealed that MSI-H patients with low predicted response to pembrolizumab frequently harbored alterations such as NOTCH2, EGFR, and EZH2 amplifications, as well as TP53 loss-of-function mutations in STAD, and MYC amplifications in CRC. Identifying these resistance-associated biomarkers can help guide clinicians in selecting more effective, personalized treatment strategies for MSI-H patients who may not benefit from ICIs alone.” Study Design Cellworks developed a mechanistic Computational Biology Model (CBM) that can be personalized based on a patient’s tumor-based genomic profile, revealing signaling pathway dysregulation and patient-specific drug response. Output from the model was used to identify MSI-H patients who may have a poorer response to ICIs. Computational biosimulation was performed using real-world retrospective cohorts of 423 STAD patients and 534 CRC patients (TCGA). MSI measurements were provided by TCGA. Efficacy scores based on biosimulated composite cell growth in response to disease and therapy were generated on all patients for pembrolizumab. Molecular rationales for ICI resistance were identified for MSI-H patients with low pembrolizumab efficacy scores. The Cellworks Platform The Cellworks Platform performs computational biosimulation of protein-protein interactions, enabling in silico modeling of tumor behavior using comprehensive genomic data. This allows for the evaluation of how personalized treatment strategies interact with the patient’s unique tumor network. Multi-omic data from an individual patient or cohort is used as input to the in silico Cellworks Computational Biology Model (CBM) to generate a personalized or cohort-specific disease model. The CBM is a highly curated mechanistic network of 6,000+ human genes, 30,000 molecular species and 600,000 molecular interactions. This model along with associated drug models are used to biosimulate the impact of specific compounds or combinations of drugs on the patient or cohort and produce therapy response predictions, which are statistically modeled to produce a qualitative therapy response score for a specific therapy. The Cellworks CBM has been tested and applied against various clinical datasets with results provided in over 125 presentations and publications with global collaborators. About Cellworks Group Cellworks Group, Inc. is a leader in Personalized Therapy Decision Support and Precision Drug Development. The Cellworks Platform predicts therapy response for individual patients and patient cohorts using a breakthrough Computational Biology Model (CBM) and biosimulation technology. Backed by Artiman Ventures, Bering Capital, Sequoia Capital, UnitedHealth Group and Agilent Ventures, Cellworks has the world’s strongest trans-disciplinary team of molecular biologists, cellular pathway modelers and software engineers working toward a common goal – attacking serious diseases to improve the lives of patients. The company is based in South San Francisco, California with a CLIA-certified computational laboratory in Franklin, Tennessee and a research and development facility in Bangalore, India. For more information, visit www.cellworks.life. All trademarks and registered trademarks in this document are the properties of their respective owners.

Study led by experts at Cincinnati Children's sheds light at the cellular level on how heart valve tissues form. Findings eventually may improve survival odds for newborns with heart valve defects. CINCINNATI, July 30, 2024 /PRNewswire/ -- Imagine a future where doctors could detect and treat potentially fatal heart valve defects months before a baby is born. While this future is still a few years away, scientists have made significant progress by creating a detailed map of how human heart valves form. This new map, published July 24, 2024, in Nature Cardiovascular Research, will help guide future heart research. Continue Reading Healthy vs. defective heart valve formation: On the left side, representing healthy valve development, unidirectional blood flow induces Jag1 production in valve endothelial cells (VECs), which activates NOTCH2-mediated Notch signaling when these cells contact Elastin-expressing valve interstitial cells (VICs). This process promotes downstream elastogenesis-related gene expressions. On the right side, representing defective development, a lack of APOE in pulmonary stenosis patients suppresses Notch signaling, leading to elastogenesis defects. Emerging blueprint for replacement valves that can grow Heart valves might be small, but they're incredibly important. Doctors have been replacing damaged heart valves in adults for many years, and sometimes they can save newborns with artificial valve transplants. But these artificial valves aren't perfect. They don't have living cells, so they can't form a completely normal valve. They also don't grow with the child, which means the child might need several risky surgeries as they get older. "Engineered human heart valves with the appropriate cell types for transplantation would avoid repeated surgeries in babies and address the donor valve shortage," says corresponding author Mingxia Gu, MD, PhD, an expert in molecular and cardiovascular biology at Cincinnati Children's. "Now, we've achieved an unprecedented understanding of the cellular composition of human heart valves and how fetal heart valve tissue changes over time. This is a crucial first step for future human valve engineering." How do heart valve leaflets form? The human heart has four valves that control the flow of blood through the heart's chambers. Each valve has two or three thin and fragile-seeming leaflets that open and close more than 2.5 billion times across a lifetime. When a baby is growing in the womb, the cells that make up these leaflets change completely. At 14 weeks, the leaflets are mostly made of complex sugars. By 36 weeks, they turn into three-layered tissues with a mix of flexible and stiff fibers. If these leaflets don't form correctly, it can cause serious heart problems. Heart valve birth defects are rare. The most common type, called bicuspid aortic valve, occurs among an estimated 0.5% to 2% of people. This condition occurs when two of the normal three leaflets of the aortic valve stick together. Those affected need life-long monitoring may require valve replacement surgery at some point. Other conditions that can involve defective heart valves include valve prolapse in Marfan syndrome, a narrow pulmonary valve in tetralogy of Fallot, and a missing aortic valve in hypoplastic left heart syndrome. Unexpected role played by the gene APOE The Cincinnati Children's research team studied healthy and faulty heart valves all the way down to the single-cell level. They documented in unprecedented detail how various cell types signal each other to form valve tissues. In a key finding, the team discovered a cell type that expresses high levels of the gene APOE. This gene needs to work in concert with another gene called NOTCH2 to make the elastin fibers essential for heart valve function. The involvement of APOE was surprising because previously the gene had been known only for its role in atherosclerosis and Alzheimer's disease. The paper further describes signaling "crosstalk" among key genes as they instruct developing cells to form the heart valve tissues. This process continues as the fetus grows and continues after birth until the heart reaches its full adult size. "The finding of APOE as the top regulator in modulating elastin formation during early valve formation could yield a new angle for clinicians to understand heart valve underdevelopment," says co-corresponding author Yifei Miao, MBBS, PhD. How can these findings help people with heart valve defects? Researchers will need several more years to figure out how to use these new discoveries to help people. Knowing which genes are key for making the various parts of heart valves—and which ones function incorrectly in babies with heart valve defects—will provide vital clues for creating future gene or cell therapies. One exciting idea is to use the new atlas to engineer a "human valve" for valve replacement therapy. Currently, replacement valves include mechanical devices, biological ones made from cow or pig tissue, and some human valves obtained from donated organs. The new atlas may help scientists build or "grow" human-tissue valves in the lab. "This atlas provides insights into the similarities and differences among the four human valves, enabling more precise valve engineering and deep understanding of the valve-specific phenotypes in patients," Gu says. "The newly discovered APOE+ valve cell type could be crucial for seeding onto an engineered valve scaffold to mediate elastin fiber formation, which is essential for valve remodeling and function." About the study Cincinnati Children's co-authors also included Ziyi Liu, MD, Yu Liu, PhD, Zhiyun Yu, PhD, Cheng Tan, MD, Nicole Pek, BSc, Anna O'Donnell, BS, MBA, Minzhe Guo, PhD, Katherine Yutzey, PhD, and David Winlaw, MBBS, MD, (now at Lurie Children's Hospital). Co-authors also included experts with the Stanford School of Medicine, the University of Michigan, the University of Washington, and the Icahn School of Medicine at Mount Sinai, New York. Funding sources for this study include support from Additional Ventures (1019125), an Endowed Scholar Award from Cincinnati Children's, two grants from the Chan Zuckerberg Initiative (CZF2019-002440 and CZF2021-237566), and two American Heart Association Predoctoral Fellowship grants (1013861 and 906513). This research was further supported by the Cincinnati Children's Heart Institute Biorepository, the Discover Together Biobank, the Division of Pulmonary Biology, and core research facilities in Pathology and Confocal Imaging. SOURCE Cincinnati Children's Hospital Medical Center

COMPANY TO HOST AN INVESTOR CONFERENCE CALL TODAY, WEDNESDAY, MARCH 29, 2023, AT 8:00 AM EDT Continued advancement of pipeline, including two clinical-stage inhaled respiratory programs and additional therapeutic programs for serious diseases Elarekibep (PRS-060/AZD1402) Phase 2a study for asthma continues to be enrolled by AstraZeneca; clinical data anticipated by mid-2024 PRS-220, inhaled Anticalin protein for idiopathic pulmonary fibrosis (IPF), continues in Phase 1 study; topline results expected in the second half of this year PRS-400, targeting muco-obstructive respiratory disease, advances toward development candidate nomination; additional preclinical data expected this year BOSTON, MA / ACCESSWIRE / March 29, 2023 / Pieris, Inc. (NASDAQ:PIRS), a clinical-stage biotechnology company advancing novel biotherapeutics through its proprietary Anticalin® technology platform for respiratory diseases, cancer, and other indications, reported financial results for the fiscal year ended December 31, 2022, and provided a business update. "Pieris continues to advance potentially transformative clinical and preclinical programs, while remaining committed to cost-effective operations. Our top priority is to obtain data from the elarekibep Phase 2a study in asthma. We are pleased that our partner and study sponsor, AstraZeneca, is significantly increasing operational resources to complete the trial. As an inhaled therapeutic, elarekibep offers the promise of a superior product pro to currently available injectable drugs and further validation of our broader respiratory franchise," said Stephen S. Yoder, President and CEO of Pieris. "Respiratory diseases such as asthma, IPF and chronic obstructive pulmonary disease are underserved by the biopharma industry despite high mortality rates, impaired quality of life, and a significant burden on the healthcare system. We believe Pieris is well positioned to develop differentiated inhaled biologics medicines that could fundamentally alter how respiratory diseases are managed. "Alongside our lead program, elarekibep, Pieris is advancing additional clinical and preclinical programs that could result in meaningful new medicines. We are evaluating opportunities to support the long-term development of these promising therapeutic candidates." Respiratory Pipeline: Elarekibep and AstraZeneca Collaboration: Enrollment is ongoing in the multi-center, placebo-controlled Phase 2a study of dry powder inhaler-formulated elarekibep, an IL-4 receptor alpha (IL-4Rα) inhibitor being developed for the treatment of moderate-to-severe asthma. Topline results measuring placebo-adjusted FEV1 improvement at four weeks are now expected to be reported by the middle of 2024 based on AstraZeneca's most recent projections. AstraZeneca has communicated to the Company that completion of the Phase 2a study remains an important priority and that additional resources have been provided to achieve study completion, including a commitment to adding several new countries and a significant number of additional clinical sites, bringing the total number to more than 100 sites. Elarekibep is validated by dupilumab, an FDA-approved inhibitor of IL-4Rα, that has demonstrated reduced levels of fractional exhaled nitric oxide (FeNO) and clinical efficacy in uncontrolled, moderate-to-severe asthma. Furthermore, recently reported dupilumab Phase 3 study results have shown efficacy in chronic obstructive pulmonary disease (COPD). Previously reported elarekibep Phase 1 results demonstrated reduced FeNO levels in mild asthma patients, and a favorable safety profile. Pieris retains co-development and U.S. co-commercialization rights for elarekibep, exercisable following completion of the ongoing Phase 2a study. Beyond elarekibep, Pieris continues to develop two preclinical programs with AstraZeneca for which it also retains co-development and U.S. co-commercialization options. PRS-220: Pieris continues the development of an inhaled Anticalin protein targeting connective tissue growth factor (CTGF) for the treatment of IPF and other fibrotic lung diseases. In preclinical models, PRS-220 demonstrated superior on-target potency compared to pamrevlumab, an intravenously infused CTGF antagonist in late-stage clinical development. The Company believes that the inhaled route of administration allows for superior lung exposure. These attributes, combined with the convenience of at-home administration via inhalation, result in PRS-220 having best-in-class potential. The Company is currently dosing healthy volunteers in a Phase 1 study of PRS-220 and expects to report results in the second half of this year. Pieris continues to benefit from a meaningful grant from the Bavarian government, which supports early-stage development of this program. PRS-400: Pieris continues to advance PRS-400, an inhaled anti-Jagged-1 Anticalin therapeutic program with potential in a wide range of respiratory diseases driven by mucus hypersecretion. PRS-400 is designed to exert clinical activity by disrupting mucus-mediated pathology in the airways, while avoiding inhibition of healthy mucus production outside of the lungs. Previously presented preclinical data demonstrate that PRS-400 potently inhibits Jagged-1-induced Notch 2 signaling in relevant tissue in the lung. In patients with muco-obstructive respiratory diseases, such as those living with inadequately controlled COPD with chronic bronchitis, PRS-400 has potential to improve clinical outcomes and improve quality of life. PRS-400 is advancing toward development candidate nomination later this year. Immuno-Oncology Pipeline: Pieris's immuno-oncology pipeline continues to progress in a cost-efficient manner with the benefit of its partners. The Company believes that multiple opportunities exist to generate value from this portfolio based on promising preclinical and clinical data. PRS-344/S095012 and Servier Collaboration: Pieris and Servier continue to enroll the escalation portion of the Phase 1/2 study of PRS-344/S095012, a 4-1BB/PD-L1 bispecific MabcalinTM (antibody-Anticalin protein) compound for the treatment of solid tumors, for which Pieris holds full U.S. rights and will receive development milestones and royalties on ex-U.S. sales by Servier. Additionally, Servier discontinued development of PRS-352/S095025, an PD-L1/OX40 bispecific Mabcalin compound, for strategic reasons. Seagen Collaboration: In January 2023, Seagen initiated a Phase 1 study for SGN-BB228 (also known as PRS-346), triggering a $5 million milestone payment to Pieris. SGN-BB228 is a first-in-class CD228/4-1BB bispecific antibody-Anticalin compound designed to provide a potent costimulatory bridge between tumor-specific T cells and CD228-expressing tumor cells. Pieris and Seagen continue to collaborate on two other undisclosed bispecific programs. PRS-342/BOS-342: Boston Pharmaceuticals continues to advance PRS-342/BOS-342, a 4-1BB/GPC3 bispecific Mabcalin compound, toward the clinic, with Phase 1 expected to begin in the coming months. Fiscal Year End Financial Update: Cash Position - Cash, cash equivalents, and investments totaled $59.2 million for the year ended December 31, 2022, compared to a cash and cash equivalents balance of $117.8 million for the year ended December 31, 2021. The decrease was due to funding operations in 2022. The Company believes operations are sufficiently funded for more than the next 12 months. R&D Expense - R&D expenses were $53.0 million for the year ended December 31, 2022, compared to $66.7 million for the year ended December 31, 2021. The decrease was due to lower overall program costs for both elarekibep and cinrebafusp alfa, lower manufacturing costs across other later-stage respiratory and immuno-oncology programs, lower license fees and lower consulting costs. These lower costs were partially offset by higher clinical costs for PRS-220 and PRS-344/S095012, higher pre-clinical costs for PRS-400, and an increase in personnel and travel costs. G&A Expense - G&A expenses were $16.4 million for the year ended December 31, 2022, compared to $16.6 million for the year ended December 31, 2021. The period-over-period decrease was driven primarily by lower personnel, facilities and audit and tax costs, partially offset by higher business development, travel and amortization of deferred costs related to revenue recognition. Other Income - For the year ended December 31, 2022, $8.2 million of grant income was recorded with respect to PRS-220, compared to $3.7 million for the year ended December 31, 2021. The increase was due to higher overall costs incurred on PRS-220 as the program progressed into a Phase 1 clinical study. Net Loss - Net loss was $33.3 million or $(0.45) per share for the year ended December 31, 2022, compared to a net loss of $45.7 million or $(0.71) per share for the year ended December 31, 2021. Conference Call: Pieris management will host a conference call beginning at 8:00 AM EDT on Wednesday, March 29, 2023, to discuss the full-year financial results and provide a corporate update. Individuals can join the call by dialing 877-407-8920 (Toll Free US & Canada) or +1 412-902-1010 (International) at least five minutes prior to the start of the call. Alternatively, a listen-only audio webcast of the call can be accessed here. For those unable to participate in the conference call or listen to the webcast, a replay will be available on the Investors section of the Company's website, . About Pieris Pharmaceuticals: Pieris is a clinical-stage biotechnology company that combines leading protein engineering capabilities and deep understanding into molecular drivers of disease to develop inhaled medicines that drive local biology to produce superior clinical outcomes for patients. Our pipeline is focused on inhalable Anticalin proteins to treat respiratory diseases and locally-activated bispecifics for immuno-oncology. Proprietary to Pieris, Anticalin proteins are a novel class of therapeutics validated in the clinic and by strong partnerships with leading pharmaceutical companies. For more information, visit . Forward-looking Statements: This press release contains forward-looking statements as that term is defined in Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. Statements in this press release that are not purely historical are forward-looking statements. Such forward-looking statements include, among other things, our expected cash runway; our product candidates clinical and therapeutic potential in their intended indications; the advancement of our proprietary and co-development programs into and through the clinic and the expected timing for reporting data; the receipt of royalty and/or milestone payments provided for in our collaboration agreements; making IND filings or achieving other milestones related to our programs, including elarekibep, PRS-220, PRS-400, PRS-344/S095012, SGN-BB228 and PRS-342/BOS-342; the therapeutic potential of our Anticalin platform; the potential addressable market for our product candidates; our continued progress in the area of co-stim bispecifics and inhaled therapeutics; and the advancement and funding of our developmental programs generally. Actual results could differ from those projected in any forward-looking statement due to numerous factors. Such factors include, among others, the amounts of anticipated funding actually received for our continued development programs and our actual reductions in spending as compared to anticipated cost reductions; 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, including in collaboration with other parties, 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 or geopolitical issues, including the conflict in Ukraine; 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 the Securities and Exchange Commission (SEC) available at , including, without limitation, the Company's most recent Annual Report on Form 10-K, the Company's Quarterly Reports on Form 10-Q, and subsequent filings with the SEC. Investor Relations Contact: Pieris Pharmaceuticals, Inc. Investors@pieris.com PIERIS PHARMACEUTICALS, INC. CONDENSED CONSOLIDATED BALANCE SHEETS (in thousands) December 31, 2022 December 31, 2021 Assets: Cash and cash equivalents $ 38,635 $ 117,764 Short term investments 20,534 - Accounts receivable 5,810 3,313 Prepaid expenses and other current assets 8,445 6,548 Total current assets 73,424 127,625 Property and equipment, net 16,992 19,122 Operating lease right-of-use assets 3,705 3,909 Other non-current assets 1,369 2,904 Total Assets $ 95,490 $ 153,560 Liabilities and stockholders' equity: Accounts payable $ 4,154 $ 8,609 Accrued expenses 11,605 16,836 Deferred revenue, current portion 20,824 25,116 Total current liabilities 36,583 50,561 Deferred revenue, net of current portion 18,734 38,403 Operating lease liabilities 12,244 13,841 Total Liabilities 67,561 102,805 Total stockholders' equity 27,929 50,755 Total liabilities and stockholders' equity $ 95,490 $ 153,560 PIERIS PHARMACEUTICALS, INC CONDENSED CONSOLIDATED STATEMENTS OF OPERATIONS (in thousands, except per share data) Year ended December 31, 2022 2021 Revenues $ 25,902 $ 31,418 Operating expenses Research and development 52,982 66,656 General and administrative 16,394 16,593 Total operating expenses 69,376 83,249 Loss from operations (43,474 ) (51,831 ) Interest income 721 4 Grant income 8,173 3,685 Other income (expense), net 1,303 2,404 Net loss $ (33,277 ) $ (45,738 ) Basic and diluted net loss per share $ (0.45 ) $ (0.71 ) Basic and diluted weighted average shares outstanding 74,172 64,547 SOURCE: Pieris Pharmaceuticals, Inc. 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