HER2 x GSPT1

BOSTON & DAEJEON, South Korea--(BUSINESS WIRE)-- Orum Therapeutics (“Orum”), a clinical-stage private biotechnology company pioneering Dual-Precision Targeted Protein Degradation (TPD² ™) and Targeted Protein Stabilization (TPS² ™), today announced that they have entered into a definitive agreement under which Bristol Myers Squibb has acquired Orum’s ORM-6151 program. ORM-6151 is a first-in-class, anti-CD33 antibody-enabled GSPT1 degrader that has received the FDA’s clearance for Phase 1 for the treatment of patients with acute myeloid leukemia or high-risk myelodysplastic syndromes. “We believe this agreement with Bristol Myers Squibb, a global leader in cancer with a strong legacy in protein degradation, validates Orum’s unique Dual-Precision Targeted Protein Degradation approach, which we pioneered to improve the therapeutic window and realize the full potential of targeted protein degraders through precision delivery to cancer cells via antibody drug conjugates,” said Sung Joo Lee, Ph.D., CEO of Orum Therapeutics. “We are excited that Bristol Myers Squibb has acquired our ORM-6151 program with proprietary GSPT1 degraders, first-in-class targeted protein degraders with the potential to make an impact for patients with cancer.” Under this transaction, Bristol Myers Squibb has acquired Orum’s ORM-6151 program for an upfront payment of $100 million, and Orum Therapeutics is eligible to receive milestone payments for a total deal value of $180 million. Further details were not disclosed. Perella Weinberg Partners acted as financial advisor, and Sterne Kessler Goldstein & Fox, and Skadden, Arps, Slate, Meagher & Flom LLP served as legal advisor to Orum Therapeutics. About Orum’s GSPT1 Platform Using the TPD² Approach Orum’s GSPT1 platform uses the company’s unique Dual-Precision Targeted Protein Degradation (TPD²) approach to build novel targeted protein degraders combined with the precise tumor cell delivery mechanisms of antibodies to generate innovative, first-in-class, tumor-selective TPDs for the treatment of cancer. Orum has developed new molecular glue degrader payloads to specifically degrade an intracellular target protein within cancer cells via the E3 ubiquitin ligase pathway. Conjugated to antibodies, the payloads are designed to be delivered specifically to cancer cells and degrade the intracellular target protein GSPT1 and cause tumor cell death. About Orum Therapeutics Orum Therapeutics is a private, clinical-stage biotech pioneering the development of cell-specific, targeted protein degraders (TPD²) and stabilizers (TPS²) with the precision of antibody targeting to improve cancer treatment for more patients. The lead therapeutic candidate from the TPD² GSPT1 platform, ORM-5029, is in clinical development for the treatment of HER2-expressing solid tumors. The TPS² approach uses proprietary Cbl-b inhibitor payloads conjugated to immune cell- or tumor cell-targeting antibodies. Orum is located in Boston, US, and Daejeon, South Korea. For more info, visit . Orum Therapeutics Forward-Looking Statements This press release contains forward-looking statements that are based on the current expectations and beliefs of Orum Therapeutics, Inc. (“Orum”). Statements in this release regarding matters that are not historical facts, including, but not limited to, statements relating to the potential therapeutic value of Orum’s products and TPD² approach; the potential for conducting and successfully completing clinical trials; the types of cancer that might be treated by Orum products; and the potential for the receipt of milestone payments from the sale of ORM-6151 are forward-looking statements. These forward-looking statements are based on management’s expectations and assumptions as of the date of this release and are subject to numerous risks and uncertainties, which could cause actual results to differ materially from those expressed or implied by such statements. These risks and uncertainties include, without limitation, the uncertain and continually changing impacts and expected duration of the COVID-19 pandemic; the uncertainty of success in research and development activities; risks related to clinical trials, including potential delays, safety issues, or negative results; competition from alternative therapies; the risk that product candidates may not be successfully commercialized or adopted; and risks related to the recruitment and retention of key employees, fluctuating markets and economic conditions, health care reform, prices, and reimbursement rates. The forward-looking statements in this presentation speak only as of the date of this release, and Orum undertakes no obligation to update or revise any of the statements. Orum cautions investors not to place considerable reliance on the forward-looking statements contained in this release.

BTX-9341 demonstrated potent degradation of CDK4/6 and tumor growth regression in resistant cells in preclinical breast cancer models, along with robust blood brain barrier penetration SOS1 degraders exhibited antiproliferative effects and inhibited tumor cell growth in a broad range of KRAS-mutated cell lines SAN DIEGO, May 25, 2023 /PRNewswire/ -- Biotheryx, Inc., a biopharmaceutical company discovering and developing a portfolio of first-in-class protein degraders with a focus on validated targets in cancer and inflammatory disease, today announced two poster presentations at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, being held June 2–6, 2023, in Chicago, Illinois and online. The presentations highlight preclinical data for bifunctional degraders of CDK4/6, including development candidate BTX-9341, for the treatment of estrogen receptor positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-), and of son of sevenless homolog 1 (SOS1) for the treatment of KRAS mutant cancers. "These new preclinical data demonstrate the potential of our bifunctional CDK4/6 and SOS1 degraders to potently degrade their targets, ultimately effectively inhibiting tumor growth together with the strength of Biotheryx's PRODEGY platform to efficiently design first-in-class degraders," said Philippe Drouet, President and Chief Executive Officer of Biotheryx. "Besides these encouraging efficacy results, BTX-9341, our oral CDK4/6 development candidate, exhibited superior blood brain barrier penetration versus inhibitors and good tumor exposure when dosed orally. We look forward to advancing BTX-9341 towards clinical development to overcome drug resistance challenges faced by patients with solid tumors such as ER+/HER2- breast cancer." 2023 ASCO Annual Meeting Presentation Details: Title: Discovery of CDK4/6 bifunctional degraders for ER+/HER2- breast cancer and triple negative breast cancer Presenter: Hannah Majeski, Ph.D., Principal Scientist – Biology Abstract #: 1083 Session: Breast Cancer – Metastatic Session Date and Time: Sunday, June 4, 2023, at 8:00 a.m. CDT Highlights: CDK4/6 inhibitors are used to treat ER+/ HER2- breast cancer, but some patients have exhibited innate resistance, and many are shown to develop acquired resistance after three years on therapy. BTX-9341, discovered and developed by Biotheryx's proprietary PRODEGY platform, is a potent, Cereblon- and proteasome-dependent degrader of CDK4 and CDK6 in multiple breast cancer cell lines. BTX-9341 demonstrated in vitro CDK4 and CDK6 degradation in multiple breast cancer cell lines and potent inhibition of cell proliferation. This potency was shown to be superior to CDK4/6 inhibitors, due to Cereblon-mediated target degradation. The CDK4/6 bifunctional degraders were active in a CDK4/6 inhibitor resistant cell line and in multiple PDX CDK4/6 inhibitor resistant organoid models. BTX-9341 exhibited good tumor exposure when dosed orally, and induced a dose-dependent reduction in CDK4, CDK6 and pRB levels in MCF7 xenograft tumors. This resulted in dose dependent tumor growth inhibition, tumor regression and superior efficacy compared to CDK4/6 inhibitors. BTX-9341 and its analogue bifunctional degraders have also shown blood brain barrier penetration and superior inhibition of tumor growth in an MCF7 intracranial mouse model compared to a CDK4/6 inhibitor. The combination of the enhanced efficacy, activity in CDK4/6 inhibitor resistant models and blood brain barrier penetration demonstrate the potential for CDK4/6 degraders in a range of potential cancer indications. Title: Development of bifunctional CRBN-SOS1 degraders for treatment of mutant KRAS cancers Presenter: Kyle Begovich, Ph.D., Senior Scientist – Biology Abstract #: 3151 Session: Developmental Therapeutics – Molecularly Targeted Agents and Tumor Biology Session Date and Time: Saturday, June 3, 2023, at 8:00 a.m. CDT Highlights: KRAS is the most frequently mutated cancer-causing oncogene and is mutated in over 20% of all human cancers, including an estimated 90% of pancreatic cancer, 45% of colorectal cancer and 30% of lung cancer. Combination therapeutic approaches are likely needed to avoid drug resistance in the treatment of KRAS mutant cancers, such as coupling KRAS inhibition with a blockade of its guanine exchange factor (GEF), SOS1, to keep KRAS in its inactive state as well as prevent upstream pathway reactivation. Biotheryx's SOS1 bifunctional degraders demonstrated antiproliferative effects across a range of KRAS-mutant cell lines. Treatment with SOS1 degraders in KRAS-mutant xenograft models resulted in greater than 90% degradation of SOS1 in tumors and subsequently led to significant tumor growth inhibition as a single agent. SOS1 degraders also exhibited synergistic effects with other RAS/MAPK pathway inhibitors, such as KRAS G12C, KRASG12D, EGFR and MEK inhibitors in in vitro studies as well as in KRAS-mutant xenograft models. These data support the potential of SOS1 degradation as a valuable treatment option for a range of KRAS mutant cancers, as a monotherapy and in combination with other RAS-MAPK pathway inhibitors. Following the presentations at the meeting, PDF copies of the presentations and posters will be available in the "Publications and Presentations" section of Biotheryx's website. About Biotheryx, Inc. Biotheryx is a biopharmaceutical company discovering and developing a portfolio of first-in-class protein degraders, including bifunctional degraders and molecular glues. Our initial focus is on deploying the differentiated potential of degraders towards validated targets in cancer and inflammatory disease. Members of our founding and scientific teams previously developed the first U.S. Food and Drug Administration (FDA) approved modulators of Cereblon, the most widely validated E3 ligase involved in protein degradation, and we have applied our expertise in Cereblon binding to build our proprietary PRODEGY platform. Our pipeline of bifunctional degraders includes BTX-9341, the first-ever degrader of CDK4/6 for solid tumors, and the first-ever degraders of SOS1 for pan-KRAS mutant cancers and PDE4 for inflammatory diseases. Our pipeline of molecular glues includes BTX-1188, a rationally designed, dual-targeting molecular glue degrader of GSPT1 and IKZF1/3 for acute myeloid leukemia and solid tumors, and undisclosed oncology targets through our research collaboration and license agreement with Incyte. For more information, please visit and engage with us on LinkedIn. SOURCE Biotheryx, Inc.

BOSTON, MA, USA & DAEJEON, South Korea I April 18, 2023 I Orum Therapeutics , a clinical-stage private biotechnology company pioneering cell-specific targeted protein degradation (TPD² ™) and targeted protein stabilization (TPS² ™), today announced new preclinical data for three of Orum’s therapeutic programs: ORM-5029, which is a proprietary GSPT1 degrader conjugated to HER2-targeting antibody pertuzumab; ORM-6151, which delivers GSPT1 degrader to CD33+ tumors; and its new immuno-oncology program for a Cbl-b inhibitor (Cbl-bi) conjugated to anti-PD-1 antibody pembrolizumab. The data were presented in three posters at the 2023 American Association for Cancer Research (AACR) Annual Meeting. “We are pleased to present new data supporting clinical development of two programs from our TPD² GSPT1 Degrader Platform, which was developed to improve the therapeutic window and realize the full potential of GSPT1 degraders through precision delivery to cancer cells via antibody drug conjugates,” said Peter Park, Ph.D., Chief Scientific Officer of Orum Therapeutics. “We are also excited to unveil at AACR our new TPS² platform, which has the potential to achieve the full promise of Cbl-b inhibitors through T cell-specific delivery. With this novel approach, we show that we can limit unwanted systemic exposure, including the risk of toxicity associated with c-Cbl inhibition, prolong the activation of exhausted PD-1+ T cells, and provide resistance to negative environmental cues such as TGF-β or regulatory T cells. We believe our approach of harnessing the power of protein degraders and stabilizers with the precision of antibody targeting will improve the treatment of cancer for more patients.” Details of the data presented are as follows: Title: A novel antibody-enabled Dual-precision Targeted Protein Stabilization (TPS²) that augments anti-tumor immune response by targeting Cbl-b inhibitor to exhausted T cells while blocking checkpoint molecule, PD-1 Presenter: Joanne Lim, Ph.D. Abstract Number: 4436 Summary: Cbl-b inhibition results in stabilization of intracellular proteins downstream of the T cell activation pathways. Using a murine model well-established to be refractory to anti-PD-1 antibody treatment, we demonstrated that anti-PD-1-Cbl-b inhibitor approach increased effector T cell markers in the tumor and delayed tumor growth. Presented Data: Title: ORM-6151: A first-in-class CD33-antibody enabled GSPT1 degrader for AML Presenter: James Palacino, Ph.D. Abstract Number: 2700 Summary: ORM-6151 shows robust single-dose efficacy, both in vitro and in vivo with superiority or comparability to standard of care (SOC) agents. In addition, in vitro testing demonstrated superior tolerability to healthy bone marrow progenitor cells, suggesting better tolerability. Responses in representative TP53 wild-type and mutant AML models demonstrated comparable activity, indicating the potential for responses in a large percentage of AML patients with poor treatment options. Presented Data: Title: Development of RNAscope multiplex-based assay for exploratory pharmacodynamic biomarkers assessment in breast cancer patients from Phase I clinical trial of ORM-5029, a potent GSPT1 degrader Presenter: Shikha Saini, Ph.D. Abstract Number: 2118 Summary: To fulfill the need to develop pharmacodynamic biomarkers as predictors of efficacy to support clinical development of ORM-5029, Orum identified a novel GSPT1 antibody for detection of depletion following treatment with ORM-5029. GSPT1 depletion and subsequent activation of the integrated stress response are both seen following in vitro or in vivo treatment with ORM-5029. Degree of pharmacodynamic (PD) change correlates with depth and duration of in vivo response. Orum is currently developing a multiplexed (IF/ISH/ISH) assay to track PD responses in patients, with an aim to better predict responses and efficacious doses. Presented Data: The posters are available to download through the links below: PD-1-Cbl-bi TPS² preclinical poster: https://docsend.com/view/enn7dddfbbn74sr2 ORM-6151 preclinical poster: https://docsend.com/view/gkrqtx49dwmthe28 ORM-5029 predictive biomarker poster: https://docsend.com/view/dqym6ks36t73qz7k About Orum’s TPS² Approach Orum’s Dual-precision Targeted Protein Stabilization (TPS²) approach combines novel payloads with the precise cell delivery mechanism of antibodies to increase the levels of intracellular target proteins in a cell-type-specific manner for oncology and immuno-oncology. The first program applying the TPS² approach is a Cbl-b inhibitor (Cbl-b i ) conjugated to anti-PD-1 antibody. By delivering Cbl-b i specifically to exhausted T cells, the conjugate is designed to restore effector T cell function, where PD-1 checkpoint blockade alone is insufficient, while also enabling T cells to overcome the immunosuppressive mechanisms in a tumor microenvironment. About Orum’s GSPT1 Platform Using the TPD² Approach Orum’s GSPT1 platform uses the company’s unique Dual-precision Targeted Protein Degradation (TPD²) approach to build novel targeted protein degraders combined with the precise tumor cell delivery mechanisms of antibodies to generate innovative, first-in-class, cell-specific TPDs for the treatment of cancer. Orum has developed new molecular glue degrader payloads to specifically degrade an intracellular target protein within cancer cells via the E3 ubiquitin ligase pathway. Conjugated to antibodies, the payloads are designed to be delivered specifically to cancer cells and degrade the intracellular target protein GSPT1 and cause tumor cell death. About Orum Therapeutics Orum Therapeutics is a private, clinical-stage biotech pioneering the development of tumor-directed targeted protein degraders (TPD²) and stabilizers (TPS²) with the precision of antibody targeting to improve cancer treatment for more patients. The first therapeutic candidates from the TPD² GSPT1 platform, ORM-5029 and ORM-6151, are in clinical development for the treatment of solid tumors and hematologic cancers, respectively. The first program applying the TPS² approach is a Cbl-b inhibitor conjugated to anti-PD-1 antibody. Orum is located in Boston, US, and Daejeon, South Korea. For more info, visit www.orumrx.com . SOURCE: Orum Therapeutics