Orum Therapeutics Unveils AACR 2026 Preclinical Data on ORM-1153 Showing Broad AML Activity and Improved Safety Potential
Orum Therapeutics has unveiled new preclinical findings for its investigational therapy ORM-1153, highlighting its potential as a next-generation treatment for acute myeloid leukemia (AML) and other CD123-positive blood cancers. The data, presented at the AACR Annual Meeting 2026, underscore the therapy’s promising efficacy, improved pharmacological profile, and favorable tolerability in early studies, reinforcing its advancement toward clinical development.
ORM-1153 is a degrader-antibody conjugate (DAC), a novel therapeutic modality designed to selectively deliver a protein-degrading payload directly to cancer cells. This approach represents an evolution beyond traditional antibody-drug conjugates (ADCs), which typically rely on cytotoxic agents to kill cancer cells. Instead, ORM-1153 leverages a targeted protein degradation strategy aimed at eliminating key proteins essential for cancer cell survival. Specifically, the therapy targets CD123, a cell surface marker commonly expressed in AML and other hematologic malignancies, and delivers a proprietary payload that induces degradation of GSPT1, a protein involved in cellular proliferation.
The newly presented data were featured in two separate poster presentations, each shedding light on different aspects of ORM-1153’s design and biological activity. Together, these findings provide a comprehensive view of the therapy’s mechanism of action, preclinical efficacy, and safety profile.
A central focus of the research is the optimized design of ORM-1153. The molecule incorporates a proprietary CD123-targeting antibody engineered to enhance internalization into cancer cells while minimizing interactions with Fc-gamma receptors. This design is intended to reduce unintended engagement with immune cells, thereby lowering the risk of off-target effects and improving overall tolerability. In addition, the linker connecting the antibody to the payload has been optimized for increased stability in plasma, ensuring that the drug remains intact in circulation until it reaches its intended target.
This combination of improved antibody engineering and linker stability appears to translate into meaningful pharmacological advantages. In preclinical models, ORM-1153 demonstrated strong anti-leukemic activity even at low doses. The therapy showed prolonged accumulation within tumor cells, suggesting efficient delivery and retention of the active compound. Notably, researchers observed undetectable levels of free payload in systemic circulation, an encouraging indicator that the drug is not prematurely releasing its active component, which could otherwise lead to toxicity.
Equally important are the findings related to safety and tolerability. In repeat-dose studies conducted in non-human primates, ORM-1153 exhibited a favorable profile, supporting the notion that the therapy could be administered safely in a clinical setting. This is a critical consideration in AML treatment, where many existing therapies are associated with significant toxicity that can limit their use, particularly in older or frail patients.
The second poster presentation expanded on these findings by evaluating ORM-1153 across a range of primary AML patient samples and disease models. The data showed consistent anti-cancer activity across these samples, suggesting that the therapy may have broad applicability in a heterogeneous disease like AML. Importantly, ORM-1153 retained its activity in models characterized by TP53 mutations.
TP53 mutations are among the most challenging features in AML, often associated with resistance to standard therapies and poor clinical outcomes. Patients with these mutations typically have limited treatment options, making the development of effective therapies for this subgroup a significant unmet medical need. The observed activity of ORM-1153 in TP53-relevant models is therefore particularly encouraging, as it indicates the potential to address a population that has historically been difficult to treat.
Company leadership emphasized the significance of these findings in the context of current AML treatment challenges. The data not only demonstrate strong preclinical efficacy but also suggest that ORM-1153 could offer a differentiated safety and tolerability profile compared to existing therapies. By combining targeted delivery with protein degradation, the DAC platform aims to achieve greater selectivity, potentially reducing damage to healthy cells while enhancing anti-tumor effects.
This approach could represent a meaningful advancement over conventional cytotoxic therapies, which often lack specificity and can lead to significant side effects. By contrast, ORM-1153’s mechanism is designed to precisely target cancer cells expressing CD123 and disrupt critical survival pathways through GSPT1 degradation. This dual level of specificity—both in targeting and mechanism—may enable more effective and better-tolerated treatment options for patients.
The broader implications of these findings extend beyond AML. Because CD123 is expressed in multiple hematologic malignancies, ORM-1153 may have potential applications in other blood cancers as well. While the current focus remains on AML, future research could explore its utility in additional indications, further expanding its therapeutic impact.
Looking ahead, the company plans to continue advancing ORM-1153 toward clinical development. The data presented at AACR provide a strong foundation for this progression, supporting the initiation of regulatory activities. A regulatory submission is anticipated in the second half of 2026, marking a key milestone in the therapy’s development timeline.
If successful in clinical trials, ORM-1153 could offer a new treatment paradigm for AML patients, particularly those with limited options due to resistant disease or unfavorable genetic profiles. Its innovative design and promising preclinical performance position it as a potential next-generation therapy in the evolving landscape of targeted cancer treatments.
In summary, the preclinical data presented for ORM-1153 highlight several key strengths: robust anti-leukemic activity at low doses, improved pharmacological properties through optimized design, minimal systemic exposure to free payload, and a favorable safety profile in repeat-dose studies. Additionally, its demonstrated activity across diverse patient samples and in TP53-mutant models underscores its potential for broad clinical utility.
These findings collectively support the continued development of ORM-1153 and reinforce the promise of degrader-antibody conjugates as a novel and potentially transformative approach in oncology. As the therapy moves closer to clinical evaluation, it represents an important step forward in the quest to develop more effective and tolerable treatments for patients with AML and related diseases.
About ORM-1153
ORM-1153 is a CD123-targeting degrader-antibody conjugate developed using Orum’s Dual-Precision TPD²® approach. The molecule is built from two proprietary elements, a GSPT1-degrading payload and an anti-CD123 antibody engineered for high internalization efficiency, conjugated with a cleavable β-glucuronide linker. By combining tumor-selective antibody delivery with targeted protein degradation, ORM-1153 is designed to induce cancer cell death through degradation of GSPT1, a protein implicated in cell survival, including in TP53-mutant AML, while minimizing effects on normal tissues.
Orum’s unique Dual-Precision Targeted Protein Degradation (TPD²) approach builds novel targeted protein degraders combined with the precise cell delivery mechanisms of antibodies to generate innovative, first-in-class, cell-selective TPDs for the treatment of cancer and other serious diseases. Orum has developed new targeted protein 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 target cells and precisely degrade the intracellular target protein of interest.
Orum Therapeutics is a public biotech pioneering the development of cell-specific, targeted protein degraders (TPD²) with the precision of antibody targeting to develop the next generation of degrader antibody conjugates (DACs) for oncology and beyond. The company is advancing its GSPT1-directed TPD² programs and developing novel degrader payloads to expand the potential of targeted protein degradation. Orum’s novel targeted protein degrader payloads are designed to selectively degrade key intracellular proteins, offering a highly targeted approach to treating difficult-to-treat diseases. Orum is located in Daejeon, South Korea, and Lexington, MA, US.
