On April 10, 2024 Opna Bio, a clinical-stage biopharmaceutical company focused on the discovery and development of novel cancer therapeutics, reported promising preclinical data in two programs, OPN-6602, a dual EP300/CBP inhibitor in multiple myeloma, and OPN-9840, an oral, non-covalent TEAD inhibitor in malignant mesothelioma and metastatic melanoma (Press release, Opna Bio, APR 10, 2024, View Source [SID1234641997]). Data were shared at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, taking place April 5-10, 2024 in San Diego.

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OPN-6602 Significantly Reduced Tumor Growth in Multiple Myeloma Models

OPN-6602 is an orally active, small molecule dual inhibitor of the E1A binding protein p300 (EP300) and CREB-binding protein (CBP) that demonstrated potent in vitro and in vivo anti-tumor activity in preclinical models of multiple myeloma. Multiple myeloma is an aggressive blood cancer derived from malignant plasma cells in the bone marrow.

Significantly reduced tumor growth as single agent (71% tumor growth inhibition, or TGI) in the OPM-2 multiple myeloma cell xenograft model
Demonstrated increased anti-tumor activity (>100% TGI) and sustained duration of response in combination studies with dexamethasone, pomalidomide and mezigdomide
Displayed synergy with dexamethasone and lenalidomide in growth inhibition of MM1.S cells
Showed downregulation of key drivers of the multiple myeloma signaling pathway including MYC, IRF4 and MYB in OPM-2 xenograft tumors
A first-in-human Phase 1 study of OPN-6602 is planned for mid-2024 in patients with multiple myeloma.

"We are excited to begin our Phase 1 study of OPN-6602 in patients with multiple myeloma this summer. While we will study OPN-6602 initially as monotherapy, preclinical data supports testing the compound as a single agent and in combination with standard of care and next generation myeloma therapies," said Jackie Walling, MBChB, PhD, chief medical officer. "The unique pharmacokinetic profile of the compound, with a high c-max and short half-life, in particular, is anticipated to provide a distinct advantage in the combination setting."

OPN-9840 Demonstrated Single Agent Efficacy in Malignant Mesothelioma

OPN-9840 is an oral, non-covalent, pan transcriptional enhanced associate domain (TEAD) inhibitor that demonstrated dose-dependent and on-target in vitro and in vivo efficacy in preclinical models of malignant mesothelioma. Malignant mesothelioma is a rare and aggressive cancer that primarily affects the lining of the lungs or abdomen. In 40% of malignant mesotheliomas, neurofibromatosis 2 (NF2) gene mutations cause dysregulation of the Hippo pathway and increased TEAD-dependent transcription. This aberrant signaling ultimately leads to increased tumor growth and resistance to therapies.

Significantly inhibited tumor growth (88% to >100%) in an NF2-mutant malignant mesothelioma mouse xenograft model. Tumor regression was observed in the 15 mg/kg (2/8 mice) and 50 mg/kg (4/8 mice) dose groups.
OPN-9652, an analog of OPN-9840, showed increased anti-tumor activity (134% TGI) and synergistic inhibition of downstream target genes in a combination study with trametinib
Showed no in vitro cytotoxicity; is well tolerated in vivo while showing potential for blood brain barrier penetration
Additional studies presented through a collaboration with Dr. Andrew Aplin’s laboratory at Thomas Jefferson University demonstrated that Opna TEAD inhibitors enhance BRAF/MEK inhibition in melanoma models by targeting drug-resistant persister cells. Dr. Aplin is a professor in cancer research and deputy director at Jefferson’s NCI-designated Sidney Kimmel Cancer Center.

OPN-9840 is set to begin IND-enabling studies and Opna is currently seeking partnerships for development.

Abstract Information

Title: OPN-6602, a potent dual EP300/CBP bromodomain inhibitor, targets multiple myeloma through concomitant suppression of IRF4 and c-MYC
Abstract Number: #660
Date and time: April 7, 2024; 1:30-5:30 pm PT
Presenter: Bernice Matusow, MS

Title: OPN-9840, a non-covalent potent pan-TEAD inhibitor, exhibits single agent efficacy in preclinical malignant mesothelioma models
Abstract Number: #7264
Date and time: April 10, 2024; 9 am-12:30 pm PT
Presenter: Pan-Yu Chen, PhD

Title: Targeting TAZ-TEAD in minimal residual disease enhances the duration of targeted therapy in melanoma models
Abstract Number: #7201
Date and time: April 10, 2024; 9 am-12:30 pm PT
Presenter: Connor Ott, PhD candidate, Thomas Jefferson University