Orum’s new program in immuno-oncology achieves simultaneous blockade of PD-1/PD-L1 pathway and delivery of a Cbl-b inhibitor using anti-PD-1-Cbl-bi conjugates and demonstrates enhanced T cell activation in vitro compared to anti-PD-1 alone, even in the presence of immunosuppressive factors
ORM-6151 shows superior tolerability and robust single-dose efficacy, both in vitro and in vivo compared to CC-90009 or Mylotarg™, suggesting the potential for an improved therapeutic option in AML that appropriately balances efficacy with safety and tolerability of a clinically validated GSPT1 degradation mechanism
Orum has identified pharmacodynamic biomarkers as predictors of efficacy to support clinical development of ORM-5029 in HER2-expressing solid tumors
BOSTON & DAEJEON, South Korea--(BUSINESS WIRE)-- 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:
The delivery of Cbl-b inhibitor (Cbl-bi) conjugated to anti-PD-1 antibody enhances the saturating, maximum activation of anti-PD-1 antibody by 300% in PD-1/PD-L1 blockade assay.
Anti-PD-1-Cbl-bi conjugates enhance T cell responses of mixed lymphocyte reaction in a dose-dependent manner and overcome suppressive effects of TGF-β and Treg cells compared to antibody alone in vitro.
Anti-PD-1-Cbl-bi conjugates enhance ex vivo activation of tumor-associated T cells from human cancer patients compared to antibody alone or when treated with antibody and unconjugated Cbl-bi.
Anti-PD-1-Cbl-bi conjugates delay the growth of melanoma tumors in hPD-1 transgenic mice, with corresponding increase in intratumoral transcript levels of CD3e, granzyme B, and perforin in the tumor.
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:
ORM-6151 shows robust in vitro activity in p53 wild-type and mutant cell models.
In ex-vivo AML blasts, ORM-6151 demonstrates efficacy superior to CC-90009, a small-molecule GSPT1 degrader, or Mylotarg, an FDA-approved treatment for AML.
Compared to CC-90009 or Mylotarg, ORM-6151 exhibits minimal cytotoxic activity to healthy hematopoietic progenitor cells in vitro.
A single treatment of ORM-6151 at 3 mg/kg regresses MV4-11 tumors in vivo mouse model with 9/9 complete response (CR), and a single dose of 1 mg/kg produced equivalent antitumor effect as SOC doublet given at optimal repeated dose.
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:
Orum identified the depletion of GSPT1 as a target-proximal pharmacodynamic biomarker in ORM-5029 treated in vitro and in vivo samples.
Loss of GSPT1 drives activation of integrated stress response and upregulation of ATF3 and DDIT3 mRNA and these responses are also seen following treatment with ORM-5029, in both in vitro BT-474 cells and in vivo HCC1568 mouse model.
PD responses correlate with degree and duration of response in an in vivo model treated with ORM-5029.
The posters are available to download through the links below:
PD-1-Cbl-bi TPS² preclinical poster:
ORM-6151 preclinical poster:
ORM-5029 predictive biomarker poster:
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-bi) conjugated to anti-PD-1 antibody. By delivering Cbl-bi 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 .
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 for clinical efficacy, potency, and tolerability of Orum’s products; the potential for conducting and successfully completing clinical trials, translation of preclinical and non-human data to the clinical and human contexts, obtaining favorable trial results, conducting later-phase trials, obtaining regulatory approval of product candidates for sale, successfully commercializing product candidates, and improving the cancer treatment for more patients; the types of cancer that might be treated by Orum products; the successful prediction of patient responses and efficacious doses; and the preferability of Orum products to others available 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 Orum may not be able to maintain and enforce its intellectual property; the risk that product candidates may not be successfully commercialized or adopted; the availability of financing; 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.
