Bristol Myers Squibb (BMS) has acquired Orum Therapeutics’ ORM-6151 program, 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 (AML) or high-risk myelodysplastic syndromes.[1]

Targeted protein degradation
Traditional the mainstay of drug discovery and development of generally focused on protein–ligand interactions, including enzymes, ion channels, or receptors.  The simple reason being that these proteins typically contain a well-defined ligand-binding site allowing the interaction with small molecules drugs.  However, this focus on the direct regulation of proteins with specific protein activity modulators, like inhibitors, is limited.[2]

In recent years, a variety of targeted protein degradation (TPD) strategies have emerged, promising a novel approach to remove specific disease-associated proteins by exploiting cells’ own destruction machinery.[2] These novel technologies are expanded the scope of targeted protein degradation (TPD), and have expanded the therapeutic options through their catalytic mechanism of action and ability to degrade previously “undruggable” target proteins.[2]

This strategy is especially designed to eradicates so-called problem proteins from cells by hijacking the cellular degradation processes with small molecules. One of these processes includes the ubiquitin-proteasome pathway, an intracellular quality control mechanism that utilizes E3 ubiquitin ligases and associated partners to specifically seek out damaged or misfolded proteins for degradation via the proteasome or “cellular trash can.”

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Small-molecule GSPT1 degraders
Although small-molecule GSPT1 degraders have shown to be potent anti-tumor cytotoxicity, they have a relatively narrow therapeutic index. To increase the efficacy vs. tolerability window of TPDs, scientists at Orum Therapeutics developed their Dual-Precision Targeted Protein Degradation (TPD² ™) and Targeted Protein Stabilization (TPS² ™) technology, which combines the catalytic mechanism of targeted protein degradation with the precision of tumor-targeting therapeutic antibodies.

Platform technology
Orum Therapeutics‘ GSPT1 platform is based on the company’s unique TPD² ™ and TPS² ™ technology. This approach is used 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’s TPD² platform technology is designed in such a way that it overcomes the limitations of the targeted protein degrader with a specifically targeting antibody. Whereas TPDs are typically small molecules that indiscriminately enter many cells throughout the body, covalently attaching these protein degraders to antibodies drives localization to specific (cancer) cells. As a result, these targeted agents improve critical limitations of conventional targeted protein degrader product candidates

Molecular Glue Degrader
Orum Therapeutics, based in Boston, US, and Daejeon, South Korea, has developed ‘molecular glue degrader’ payloads to specifically degrade an intracellular target protein within cancer cells via the E3 ubiquitin ligase pathway. Conjugated to antibodies, these payloads are designed to be delivered specifically to cancer cells and degrade the intracellular target protein GSPT1 and cause tumor cell death.

“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,” explained Sung Joo Lee, Ph.D., Chief Executive Officer 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,” Lee added.

Clinical development
In preclinical development ORM-6151 demonstrated superior tolerability and robust single-dose efficacy, both in vitro and in vivo compared to CC-90009, a novel protein degrader and the first cereblon E3 ligase modulating drug being developed by Bristol Myers Squibb  and gemtuzumab ozogamicin (Mylotarg™; Pfizer), an antibody-drug conjugate used to treat patients diagnosed with acute myeloid leukemia (AML), suggests a potential for an improved therapeutic option in AML that appropriately balances efficacy with safety and tolerability of a clinically validated GSPT1 degradation mechanism.[3]

Data presented in a poster at the 2023 American Association for Cancer Research (AACR) Annual Meeting, confirmed that ORM-6151’s 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.

The investigators showed that based on the initial study results, 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.

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 US $180 million.

Highlight of prescribing information
Gemtuzumab ozogamicin (Mylotarg™; Pfizer)[Prescribing information]

[1] Palacino J, Lee P, Jeong H, Kim Y, Song Y, Permpoon U, Wong W, Bai C, Fishkin N, Takrouri K, Yu E, Yi Y, Skaletskaya A, Chang KH, Kim MS, Kim DY, Choi DK, Park PU. ORM-6151: A First-in-Class, Anti-CD33 Antibody-Enabled GSPT1 Degrader for AML. Blood 2022; 140 (Supplement 1): 3061–3062. doi:
[2] Zhao L, Zhao J, Zhong K, Tong A, Jia D. Targeted protein degradation: mechanisms, strategies and application. Signal Transduct Target Ther. 2022 Apr 4;7(1):113. doi: 10.1038/s41392-022-00966-4. PMID: 35379777; PMCID: PMC8977435.
[3] Hansen JD, Correa M, Alexander M, Nagy M, Huang D, Sapienza J, Lu G, LeBrun LA, Cathers BE, Zhang W, Tang Y, Ammirante M, Narla RK, Piccotti JR, Pourdehnad M, Lopez-Girona A. CC-90009: A Cereblon E3 Ligase Modulating Drug That Promotes Selective Degradation of GSPT1 for the Treatment of Acute Myeloid Leukemia. J Med Chem. 2021 Feb 25;64(4):1835-1843. doi: 10.1021/acs.jmedchem.0c01489. Epub 2021 Feb 16. PMID: 33591756.

Featured Image: Photo of scientists researching in laboratory. Courtesy: 2016 – 2023 © Fotolia/Adobe. Used with permission.

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