Potent Pre-Clinical and Early Phase Clinical Activity of EP300/CBP Bromodomain Inhibitor CCS1477 in Multiple Myeloma

CCS1477 (also known as inobrodib) is a potent and selective inhibitor of the bromodomains of EP300 and CBP, two homologous histone acetyltransferases with critical roles in cellular growth and differentiation.

In preclinical analyses we find that CCS1477 induces potent growth inhibition though inducing cell cycle arrest at low nanomolar concentrations (GI50<100nM) across a panel of 12 human myeloma cell lines, including lenalidomide refractory lines. In vivo, in an OPM-2 human myeloma cell line NOD-SCID xenograft model, there was dose dependent inhibition of tumour growth, with 20mg/kg daily eliciting tumour regression and sustained inhibition of tumour growth for two weeks beyond the end of treatment.

RNA sequencing of tumours recovered from mice after five days of CCS1477 treatment revealed substantial down regulation of transcription factor genes including MYB, MYC, IRF4, E2F1 and FOXM1; and GSEA showed significant enrichment among down regulated genes of gene sets associated with both MYC and E2F targets, consistent with drug-induced proliferative arrest.

In the OPM-2 model, ChIP sequencing showed that EP300 binding peaks were predominantly distributed over transcription factor binding motifs for IRF, Runt, bHLH, bZIP and MYB/SANT factor classes. Within six hours of 100nM CCS1477 treatment there was a localized but significant reduction of EP300 recruitment to intronic FGFR3 sites: FGFR3 is placed under the control of the active IGH promoter in the intergenic t(4;14) in OPM-2 cells. By 48 hours, in keeping with CCS1477-induced inactivation of IRF4 (a critical regulator of plasma cell differentiation required for myeloma cell growth) there was extensive genome-wide redistribution of EP300 binding away from sites with IRF4 motifs, while sites with other motifs remained occupied.

In our ongoing phase I/IIa clinical trial investigating the safety and efficacy of CCS1477 in advanced haematological malignancies (NCT04068597), we have treated four heavily pre-treated relapsed/refractory myeloma patients at the recommended phase 2 dose (35mg PO twice daily, four days a week). Of these, two exhibited objective responses with substantial reductions in serum or urinary M-protein, with one patient achieving a PR and the other exhibiting a complete remission after four months. Both patients remain on treatment as of the submission of this abstract. Treatment was well tolerated, with moderate thrombocytopaenia being an anticipated on-target side effect.

Finally, we evaluated the activity of CCS1477 in an OPM-2 xenograft model in combination with existing standard of care agents in myeloma and observed additive or synergistic growth inhibitory activity with each of bortezomib, lenalidomide and vorinostat in combination with CCS1477.

These encouraging data suggest strong promise for the clinical utility of CCS1477 in the treatment of multiple myeloma as monotherapy and/or in combination with standard of care agents.

Brooks:Kesmalea Therapeutics Ltd: Consultancy; CellCentric Ltd: Current equity holder in private company, Ended employment in the past 24 months. Pegg:CellCentric Ltd: Current Employment, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: WO2018073586A1; Phoremost: Consultancy, Membership on an entity's Board of Directors or advisory committees. West:AstraZeneca: Current equity holder in publicly-traded company; CellCentric Ltd: Current Employment, Current equity holder in private company. Knurowski:CellCentric Ltd: Current Employment, Current equity holder in private company. Frese:CellCentric Ltd: Current Employment. Clegg:AstraZeneca: Current equity holder in publicly-traded company; CellCentric Ltd: Current Employment. Searle:Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Abbvie: Honoraria. Somervaille:Abbvie: Consultancy; Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Imago Biosciences: Research Funding; Oryzon Genomics: Consultancy; CellCentric Ltd: Research Funding.