inobrodib (CCS1477) / CellCentric - LARVOL DELTA

DoMMino-1: Inobrodib, Pomalidomide and Dexamethasone in Relapsed or Refractory Multiple Myeloma (clinicaltrials.gov) - P2 | N=100 | Recruiting | Sponsor: CellCentric Ltd. | Not yet recruiting ➔ Recruiting

Enrollment open • Hematological Malignancies • Multiple Myeloma • Oncology

p300/CBP co-ordinate with the metazoan INO80 complex in haematological malignancies, providing synthetic lethal opportunities. (LCC 2026) - "Tim Somervaille and Oliver Sinclair have led preclinical and early-phase clinical evaluation of inobrodib (CCS1477; herein CCS)...ChIP-seq analyses revealed a significant co-localisation of mINO80 and p300 at oncogenic driver genes known to be perturbed by CCS treatment of MM cells, such as IRF4, the central TF that drives MM. Together, these findings suggest a novel synthetic lethal therapeutic approach to target the mINO80 complex in combination with CCS."

Synthetic lethality • Tumor mutational burden • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Oncology • HDAC3 • IRF4 • TMB • UCHL5

p300/CBP co-ordinate with the metazoan INO80 complex in haematological malignancies, providing synthetic lethal opportunities. (LCC 2026) - "Tim Somervaille and Oliver Sinclair have led preclinical and early-phase clinical evaluation of inobrodib (CCS1477; herein CCS)...ChIP-seq analyses revealed a significant co-localisation of mINO80 and p300 at oncogenic driver genes known to be perturbed by CCS treatment of MM cells, such as IRF4, the central TF that drives MM. Together, these findings suggest a novel synthetic lethal therapeutic approach to target the mINO80 complex in combination with CCS."

Synthetic lethality • Tumor mutational burden • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Oncology • HDAC3 • IRF4 • TMB • UCHL5

Tolerability and Clinical Activity of Novel First-in-Class Oral Agent, Inobrodib (CCS1477), in Combination with Pomalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma (ASH 2024) - P1/2 | "The combination is tolerable, with no overt overlapping toxicity, based on the anticipated safety profile of inobrodib and pom/dex doublet. Preliminary PD data, safety and efficacy will be used to support dose expansion and dose optimisation decisions in the current study, before a pivotal trial is initiated."

Clinical • Combination therapy • IO biomarker • Anemia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Multiple Myeloma • Neutropenia • Oncology • Thrombocytopenia • IRF4

Discovery of CZL-077 as a potent, selective, and orally active p300/CBP bromodomain inhibitor with improved in vivo antitumor efficacy. (PubMed, Eur J Med Chem) - "Compared to CCS1477, it shows comparable in vivo efficacy in the OPM-2 xenograft model and demonstrates more potent antitumor activity in the 22RV1 xenograft model, with tumor growth inhibition values of 56.2% and 72.8%, respectively. Overall, CZL-077 is a promising candidate for the treatment of human cancer as a p300/CBP BRD inhibitor."

Journal • Preclinical • Oncology • CREBBP

Evaluating inobrodib (CCS1477) in combination with teclistamab or elranatamab in patients with Relapsed/Refractory multiple myeloma; Specific cohorts within a Phase I/IIa study evaluating inobrodib in patients with advanced hematological malignancies (ASH 2025) - P1/2 | "This Phase I/II study (Study CCS1477-02) of Ino with pomalidomide and dexamethasone (InoPd) showed high response rates (75% ORR) with a manageable safety profile in heavily pre-treated relapsed/refractory multiple myeloma (RRMM), all of which were refractory to their last line of therapy. Serial blood and bone marrow samples are being collected for exploratory biomarker analysis to understand mechanisms of response to treatment or disease progression. These cohorts will be opened in approximately 8 sites in the UK and US."

Clinical • Combination therapy • IO biomarker • Metastases • P1/2 data • Hematological Malignancies • Multiple Myeloma • Myelodysplastic Syndrome • Oncology • IRF4

P300/CBP acetyltransferase inhibition and degradation disrupt oncogenic transcriptional programs and reveal epigenetic vulnerabilities in multiple myeloma (ASH 2025) - "Inobrodib (CCS1477), a selective P300/CBP bromodomaininhibitor, has shown promising early clinical activity in relapsed/refractory MM, highlighting thetherapeutic relevance of this axis. However, the effects of more direct P300/CBP targeting—via catalyticinhibition or protein degradation—on chromatin structure and MM lineage survival programs remainincompletely defined.Aims:We aimed to characterize the transcriptional and epigenetic effects of catalytic inhibition and targeteddegradation of P300/CBP in MM, identify determinants of resistance and sensitivity, and explore rationalepigenetic drug combinations.MM cell lines were treated with selective small-molecule P300/CBP catalytic inhibitors (A-485, A-241), thebromodomain inhibitor GNE-781, the P300/CBP degrader dCBP-1, the HDAC3 inhibitor RGFP966, and theKDM6 demethylase inhibitor GSK-J4...Collectively, these findings establish P300/CBP as a critical epigenetic dependency in MM, essential formaintaining enhancer..."

IO biomarker • Hematological Malignancies • Multiple Myeloma • Targeted Protein Degradation • HDAC3 • IRF4 • KDM6A • NCOR1 • SLAMF7 • TNFRSF17

Randomized phase II dose optimization study of inobrodib (CCS1477), in combination with pomalidomide and dexamethasone in relapsed/refractory multiple myeloma (RRMM) (ASH 2025) - P1/2 | "Background Inobrodib (CCS1477/Ino) is a first-in-class potent, selective, and orally bioavailable inhibitor of thebromodomains of p300 and CBP, two closely related histone acetyl transferases with oncogenic roles inhematological malignancies. Recruitment is ongoing, with 36 of 60 (60%) planned patients enrolled as of the data cut-off (7 July 2025); full enrollment is expected by September 2025. Initial data combining all three dose levels aresummarized below. Comprehensive dose-specific data for all patients will be presented at theconference."

Clinical • Combination therapy • IO biomarker • P2 data • Hematological Malignancies • Infectious Disease • Multiple Myeloma • Neutropenia • Thrombocytopenia • IRF4

In silico structural biology studies inform the identification of "druggable" pockets in previously understudied dependencies with tumor type/lineage-selective roles. (ASH 2025) - "Knowninhibitors for individual MM-preferential dependencies (e.g. the p300 inhibitor inobrodib) were alsoidentified as putative binders to "druggable" pockets that were nominated in unbiased manner by our insilico pipeline: such observations further support the notion that our pipeline can reliably identify bothligand-binding pockets for "druggable" targets and compounds binding to those specific pockets...Our study highlights the importance of machine learning-based pipelines for assessment of primarysequence regions, 3D structurally-defined binding pockets and their interaction with putative smallmolecule ligands to identify candidate binders to MM-preferential dependencies. Identification ofstructurally and functionally important binding regions provides essential groundwork for ongoingdocking screens with large chemical libraries and innovative machine learning-based docking approachesthat involve both existing compounds and synthetic datasets of..."

Hematological Malignancies • Multiple Myeloma • Oncology • Solid Tumor

Histone acetyltransferase p300/CBP as a therapeutic target to ameliorate gvhd-induced inflammatory memory (ASH 2025) - "We found that GVHD induces epigenetic remodeling in ISCs through a p300/CBP-dependentmanner, in which IFN-γ activates p300/CBP, leading to H3K27ac enrichment at target genes involved inIFN-γ responses. Given the emerging efficacy of p300/CBP inhibitors in various hematologicalmalignancies (Nicosia L: Cancer Cell 2023, Welsh SJ: Blood Cancer Discov 2024), these agents representpromising therapeutic candidates for GVHD by suppressing inflammatory memory in ISCs, whilepotentially preserving GVL effects and additionally exerting direct anti-tumor activity."

Epigenetic controller • Graft versus Host Disease • Hematological Malignancies • Immunology • CREBBP • EP300 • IFNG

IRF4 maintenance in multiple myeloma is conserved in de novo-derived inobrodib resistance, conferring cross resistance to immunomodulatory drugs (ASH 2025) - P1/2 | "Given that both pomalidomide and inobrodib act via IRF4 downregulation, combination treatmentappears to be an effective strategy to target patients refractory against either drug. Additionally, wepropose that direct targeting of IRF4 activity may be a fruitful avenue for further investigation where IMiDand inobrodib treatment is unsuccessful."

Clinical • Immunomodulating • Hematological Malignancies • Multiple Myeloma • IKZF1 • IRF4

CellCentric Presents Positive Phase 2 Dose Optimization Data for Inobrodib in Multiple Myeloma at ASH Annual Meeting (CellCentric Press Release) - "Among evaluable patients at this data cut (n=44, to a minimum of 60), the emerging objective response rate (ORR) was 69% for patients allocated to the 20mg cohort. Early analyses indicate more dose interruptions and de-escalations at higher doses, yielding emerging ORRs to date of 54% for 30mg and 33% for 40mg of inobrodib. Across all cohorts, responses continue to deepen and lengthen. Specifically, among heavily pretreated (median five lines of prior therapy) pom-refractory patients who had previously failed on BCMA and/or TCE therapy, deep and durable ORRs were observed with 60% at 20mg and 75% at 30mg....'Following recent discussions with the FDA, we look forward to initiating pivotal registration studies next year'."

New trial • P2 data • Multiple Myeloma

Crebbp Inhibition Potentiates JAK2 Inhibition in Post-MPN Acute Myeloid Leukemia (ASH 2024) - "Here, we demonstrate through genome-wide CRISPR screens in post-MPN AML line HEL treated with four different JAK2 inhibitors (i.e. ruxolitinib, momelotinib, pacritinib and fedratinib) that depletion of CREBBP sensitizes cells to JAK2 inhibition...In both human and murine models of post-MPN AML, the combination treatment of ruxolitinib plus CREBBP/EP300 inhibitor SGC-CBP30 or CCS1477 substantially induced apoptosis and cell cycle arrest at G1...Overall, our results demonstrate that CREBBP/EP300 inhibition potentiates JAK2 inhibition in post-MPN AML by further attenuating MYC expression and activity, and repressing JAK/STAT and other pathways associated with JAK2 inhibitor persistence. Therefore, we propose CREBBP inhibition as a potential therapeutic strategy to potentiate JAK2 inhibition in post-MPN AML."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myeloproliferative Neoplasm • Oncology • CALR • CREBBP • EP300 • HSF1 • MYC • STAT3 • STAT5

Tolerability and Clinical Activity of Novel First in Class Oral Agent, Inobrodib (CCS1477), in Combination with Pomalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma (ASH 2023) - P1/2 | "Initial dose escalation cohorts enrolled 15 RRMM pts with a median age of 71 yrs (range 41-80). Median prior lines of therapy was 5 (range 3-9). Median follow-up was 56 days (range 13-189), with a median number of 3 cycles received (range 1-7)."

Clinical • Combination therapy • IO biomarker • Anemia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Multiple Myeloma • Neutropenia • Oncology • Thrombocytopenia

Targeting CREB-Binding Protein (CREBBP) Overcomes Resistance to Azacitidine and Venetoclax Therapy in Acute Myeloid Leukemia (AML) (ASH 2023) - "While clinical outcomes of VEN combined with hypomethylating agents (decitabine or azacitidine - AZA) have been promising, a substantial subset of patients remains refractory or experiences relapse following treatment with these regimens...Importantly, co-treatment with either A485 or CCS1477 and VEN/AZA synergistically abrogated cell proliferation and clonogenic potential of THP1 cells, effectively overcoming resistance (Figure 1)...Targeting this molecular pathway holds the promise of offering a potential therapeutic approach to improve treatment outcomes for AML patients, particularly those facing resistance to current therapies. Understanding and harnessing CREBBP's influence could pave the way for developing personalized and effective strategies to combat this challenging hematological malignancy."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • CREBBP • GLI2 • KMT2A

Preclinical and Early Clinical Results Indicate a Role for the Oral p300/CBP Inhibitor Inobrodib (CCS1477) in T-Cell Lymphoma (ASH 2023) - P1/2 | "Together these data support the further development of inobrodib for the treatment of peripheral T cell lymphoma. Expansion continues with a focus on T-cell lymphomas, which may be driven by IRF4 and GATA3."

Preclinical • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Oncology • Peripheral T-cell Lymphoma • Solid Tumor • T Cell Non-Hodgkin Lymphoma • Thrombocytopenia • EP300 • GATA3 • IRF4

Investigating the Therapeutic Potential of the Novel CBP/p300 Protein Degrader CBPD409 in Multiple Myeloma (ASH 2024) - P1/2 | "However, whether CBPD-409 exhibits better anti-myeloma efficacy as compared to CCS-1477 has still to be elucidated.Aim : To determine the in vitro and in vivo impact of CBPD-409 monotherapy, and to evaluate its potential synergy with the standard of care treatment dexamethasone (Dex) in MM cells.Methods : MM cell lines U266 and MM1.S, and peripheral blood mononuclear cells (PBMCs) obtained from healthy donors, were exposed to CBPD-409 or CCS-1477 for 72h, as to establish the therapeutic window of CBPD-409. CBPD-409 significantly reduced tumour burden in the MM1.S xenograft model of myeloma, demonstrating in vivo efficacy. Future studies will examine the impact of CBPD-409 on proliferation and CBP/p300 downstream signalling pathways in primary MM cells."

Genito-urinary Cancer • Hematological Malignancies • Multiple Myeloma • Oncology • Oral Cancer • Prostate Cancer • Solid Tumor • Targeted Protein Degradation • ANXA5 • CREBBP • MYC

Activity of Orally Available CBP/p300 Degraders in Pre-Clinical Models of Multiple Myeloma (ASH 2024) - "Some compounds, including inobrodib, have progressed to early-stage clinical trials...With intermittent dosing strategies, advanced compounds lead to potent and sustained loss of CBP and p300 in myeloma cell lines and tumor xenografts and achieve tumor reduction as single agents when delivered orally. With these optimized compounds, we can now address systematically (in vitro and in vivo) the relative consequences of CBP/p300 inhibition and degradation both in tumor cells and normal tissue/hematopoietic cells."

Preclinical • Hematological Malignancies • Multiple Myeloma • Oncology • Targeted Protein Degradation • CRBN • IRF4

CellCentric to Host Investor Event and Present Dose Optimization Data from Phase 2 Study of Inobrodib for Multiple Myeloma at the American Society of Hematology (ASH) Annual Meeting (CellCentric Press Release) - "Preliminary results confirm earlier findings that inobrodib in combination with pomalidomide + dexamethasone (InoPd) for multiple myeloma has promising clinical activity and a tolerable safety profile in a heavily pretreated population. The Company will host a live investor event on December 7, at 8:00 p.m. ET in Orlando following the poster presentation."

P2 data • Multiple Myeloma

The EP300-Targeting Drug CCS1477 Inhibits the Growth and Development of Diffuse Large B-Cell Lymphoma by Promoting Apoptosis and Mitophagy to Reduce Drug Resistance. (PubMed, Anticancer Agents Med Chem) - "By selectively targeting EP300, CCS1477 orchestrates a dual pro-death mechanism involving both intrinsic apoptosis execution and PINK1-driven mitochondrial clearance, resulting in significant inhibition of diffuse large B-cell lymphoma pathogenesis."

Journal • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • EP300 • MYC

CellCentric Announces Completion of Enrollment for Dose Optimization Cohorts in Phase 2 Study for Multiple Myeloma (Newsfile) - "A total of 60 patients have now been enrolled in the MM dose optimization cohorts, evaluating three separate doses of inobrodib (20mg, 30mg, and 40mg) in combination with pomalidomide and dexamethasone. The results will determine the recommended dose for future registration-enabling studies of inobrodib, with initial data are expected by the end of 2025."

Enrollment closed • P1/2 data • Multiple Myeloma

CellCentric Announces First Patients Dosed with Inobrodib in Combination with Bispecific Antibodies in Multiple Myeloma (Newsfile) - "Approximately 40 patients are expected to receive the combination of inobrodib with either bispecific agent. Initial safety evaluation data is expected by the end of 2025."

P1/2 data • Trial status • Multiple Myeloma

Study to Evaluate CCS1477 in Advanced Tumours (clinicaltrials.gov) - P1/2 | N=220 | Completed | Sponsor: CellCentric Ltd. | Active, not recruiting ➔ Completed

Trial completion • Breast Cancer • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • ARID1A • CREBBP • MYC

DoMMino-1: Inobrodib, Pomalidomide and Dexamethasone in Relapsed or Refractory Multiple Myeloma (clinicaltrials.gov) - P2 | N=100 | Not yet recruiting | Sponsor: CellCentric Ltd.

New P2 trial • Hematological Malignancies • Multiple Myeloma • Oncology

Emerging therapeutic agents in multiple myeloma: highlights from the 2024 ASH annual meeting. (PubMed, Biomark Res) - "Key updates include: Cevostamab (FcRH5×CD3) demonstrated a 30.2% overall response rate in patients who underwent BCMA-targeted treatment and 60.6% in BCMA-targeted naïve patients;the triple-step dosing strategy reduced cytokine release syndrome. Lisaftoclax (APG-2575, BCL-2 inhibitor) displayed overall response rates ranging from 61.3 to 100% and ≥ VGPR rates of 32.3-100%, supporting enhanced response depth with favorable safety in combination regimens. Inobrodib (CCS1477, p300/CBP inhibitor) plus lenalidomide achieved a 71% overall response rate in pomalidomide-refractory patients, marking the first oral epigenetic modulator to reverse immunomodulatory drug resistance. Elranatamab (ELRA, BCMA×CD3) combined with carfilzomib and dexamethasone yielded an 83.3% overall response rate with a median duration of response not reached. Mezigdomide (MEZI, CELMoD) showed an 85.7% overall response rate and 17.5-month progression-free survival in..."

Journal • Hematological Malignancies • Inflammation • Multiple Myeloma • Oncology