Session: 651. Multiple Myeloma and Plasma Cell Dyscrasias: Basic and Translational: Poster I
Hematology Disease Topics & Pathways:
Research, Fundamental Science, Combination therapy, Translational Research, Drug development, Treatment Considerations
MM is driven by transcriptional reprogramming events that prevent the differentiation of activated B cells to plasma cells (Mahindra 2010). Deregulation of the transcription factor MYC is common and preclinical studies have revealed a central role of MYC in the pathogenesis of MM (Chesi 2008). The inhibition of the lymphocyte-specific transcription factor IRF4 is detrimental to MM cell growth (Shaffer 2008). IRF4 is known to positively regulate MYC expression, and MYC in turn upregulates IRF4 through an autoregulatory loop (Shaffer 2008). Thus, inhibition of CBP/EP300 BRD simultaneously suppresses the expression of IRF4 and MYC, resulting in effective growth inhibition of MM cells (Conery 2016). Recently, pharmacogenomic analysis identified EP300 as a specific highly relevant target for MM (de Matos Simoes 2023). Furthermore, the EP300 pathway has been implicated in resistance to immunomodulatory (IMiD) therapies such as pomalidomide and mezigdomide (Yun 2024).
OPN-6602 is a potent, selective, and orally active small molecule dual CBP/EP300 BRD inhibitor. OPN-6602 demonstrates potent antitumor activity in preclinical studies. OPN-6602 inhibits the binding of acetylated histone peptides to the BRDs of EP300 (IC50 = 27 nM) and CBP (IC50 = 31 nM), with greater than 200-fold selectivity versus BET BRDs (IC50 >8000 nM). The potent inhibition of both EP300 and CBP and selectivity against other BRDs thus underlie the pharmacological effects of OPN-6602.
In a screen of 91 cancer cell lines, OPN-6602 is most active in hematopoietic and lymphoid tumors (GI50 <250 nM). Several MM cell lines including OPM-2, U266, and RPMI 8226 were highly sensitive to OPN-6602 with GI50s ~7-21 nM.
OPM-2 is an MM cell line that is dependent on the expression of EP300/CBP. The efficacy of OPN-6602 in combination with dexamethasone (dex) and/or with pomalidomide (pom) or mezigdomide (mezi) was evaluated in the OPM-2 xenograft model. OPN-6602 at 24 mg/kg QD suppressed tumor growth (71% TGI). Addition of dex significantly increased anti-tumor activity (100% TGI) with 3/6 animals exhibiting tumor regressions. For OPN-6602 triplets with dex + pom or dex + mezi, all animals (n=6) exhibited tumor regressions. Dosing for all groups was discontinued after Day 13 to monitor the duration of response. The triplets OPN-6602 + dex + pom and OPN-6602 + dex + mezi exhibited sustained duration of responses of 30 and >42 days, respectively. In a pharmacodynamic study after 3 days of consecutive dosing in the OPM-2 model, RNASeq analysis demonstrates distinct profiles among OPN-6602, dex, pom, and mezi. Indeed, further downregulation of MYC and IRF4 was observed exclusively with the OPN-6602 triplets compared to OPN-6602 single agent or in combination with dex. Interestingly, when OPN-6602 is excluded from the treatment regimen (i.e dex and pom/mezi), the downregulation of MYC and IRF4 is significantly compromised.
The efficacy of OPN-6602 in combination with dex and/or mezi was further evaluated in the MM1.S xenograft model in SCID mice. Synergistic responses were observed with OPN-6602 at 24 mg/kg as a triplet combining dex + mezi with 5/6 animals exhibiting tumor regressions compared to the doublet dex + mezi combo with 1/6 animals exhibiting tumor regressions.
Preclinical safety of OPN-6602 was evaluated in a 28-day GLP toxicology study in CD-1 mice at doses of 0, 15, 50 and 150 mg/kg/day. The no observed adverse effect level (NOAEL) and the severely toxic dose in 10% of animals (STD10) were 15 and 50 mg/kg/day, respectively. There were no significant changes in white blood cell or platelet counts. Similar findings were observed in a dog GLP toxicology study.
OPN-6602 is currently being evaluated in patients with MM in the Phase I clinical trial OPN6602-C01 (NCT06433947).
Disclosures: Matusow: Opna Bio LLC: Current Employment, Current holder of stock options in a privately-held company. Saghafinia: Opna Bio LLC: Current Employment, Current holder of stock options in a privately-held company. Li: Opna Bio LLC: Consultancy. Kohler: Opna Bio LLC: Consultancy. Chen: Opna Bio LLC: Current Employment, Current holder of stock options in a privately-held company. Nichols: Opna Bio: Current Employment, Current holder of stock options in a privately-held company. Singh: Opna Bio: Current Employment, Current holder of stock options in a privately-held company. Inokuchi: Opna Bio: Current Employment, Current holder of stock options in a privately-held company. Walling: Opna Bio: Consultancy, Current Employment. Bollag: Opna Bio: Current Employment, Current holder of stock options in a privately-held company.
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