inobrodib (CCS1477) / CellCentric - LARVOL DELTA

CellCentric secures $120 million investment to advance inobrodib for treating multiple myeloma (CellCentric Press Release) - "CellCentric...announced the completion of a $120 million Series C funding round...The funding will further support the advancement of CellCentric’s novel oral p300/CBP inhibitor, inobrodib, for the treatment of multiple myeloma.​..Proceeds from the Series C financing will be used to support: Initiation of a Phase II/III study in heavily pretreated multiple myeloma patients, with the potential to support an accelerated approval; Support development activities for a Phase III program, to start mid-2026; Initiation of trials starting Q2 2025, including the combination of inobrodib with bi-specific antibodies, as well as inobrodib in a maintenance setting."

Financing • New P2/3 trial • New P3 trial • Multiple Myeloma

Study to Evaluate CCS1477 in Advanced Tumours (clinicaltrials.gov) - P1/2 | N=350 | Active, not recruiting | Sponsor: CellCentric Ltd. | Recruiting ➔ Active, not recruiting | Trial completion date: Dec 2024 ➔ Aug 2025 | Trial primary completion date: Dec 2024 ➔ Aug 2025

Enrollment closed • Monotherapy • Trial completion date • Trial primary completion date • 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

A PHASE I/IIA STUDY TO EVALUATE INOBRODIB IN PATIENTS WITH ADVANCED HEMATOLOGICAL MALIGNANCIES: DOSE EXPANSION COHORTS OF INOBRODIB IN COMBINATION WITH POMALIDOMIDE/DEXAMETHASONE IN RELAPSED/REFRACTORY MULTIPLE MYELOMA (EHA 2025) - "Combination with IMiDs such as pomalidomide and lenalidomide showed impressive synergy, and this is associated with enhanced targeting of IRF4, a well-established oncogenic driver in MM.Inobrodib represents a novel and differentiated approach and offers a potential new therapeutic option for patients who have relapsed or are refractory to current standard of care therapies. Expansion arms with 20, 30, or 40mg Ino twice daily (4 days on / 3 days off schedule) plus standard doses of pomalidomide and dexamethasone to select optimal dose for pivotal trials are currently enrolling."

Clinical • Combination therapy • Metastases • P1/2 data • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology • IRF4

EP300 INHIBITION ALLEVIATES ACUTE-ON-CHRONIC LIVER FAILURE BY REDUCING ACOD1 EXPRESSION IN SCAR-ASSOCIATED MACROPHAGES (DDW 2025) - "EP300 inhibitor CCS1477 attenuates ACLF progression via the transcriptional repression of ACOD1...(F, G) Chromatin accessibility (ATAC-seq), Ep300, and H3K27ac (ChIP-seq) at Acod1 after 0 h, 2 h, and 6 h stimulation in BMDMs. (H) Graphic abstract."

Fibrosis • Hepatology • Immunology • Liver Failure • CD9 • EP300 • RIPK1

Combining CBP/p300 and PARP inhibitors to enhance anti-tumor efficacy in lethal prostate cancer (AACR 2025) - "In mechanistic studies, increased expression of DNA damage markers in mCRPC cells treated with CCS1477 alongside the PARPi olaparib indicated delayed DNA damage repair. Spatial transcriptomics will identify molecular signatures distinguishing responders from non-responders, advancing precision medicine in diverse populations. In conclusion, our findings indicate that CBP/p300 inhibition in combination with PARP inhibitors may have stronger anti-tumor effects than single-agent therapies, offering a promising novel therapeutic option to improve outcomes for mCRPC patients."

Clinical • Late-breaking abstract • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR

Therapeutic targeting of the p300/CBP bromodomain enhances the efficacy of immune checkpoint blockade therapy. (PubMed, Oncogene) - "By reducing PD-L1 expression and modulating the immunosuppressive TME, CCS1477 creates a more favorable environment for tumor-infiltrating lymphocytes, significantly enhancing the efficacy of immune checkpoint blockade (ICB) therapy. Notably, these effects were observed in both prostate cancer and melanoma models, underscoring the broad therapeutic potential of p300/CBP bromodomain inhibition in improving ICB outcomes."

Checkpoint inhibition • IO biomarker • Journal • Genito-urinary Cancer • Melanoma • Oncology • Prostate Cancer • Solid Tumor • CSF1 • IL6

Preclinical development and characterization of IACS-16559, a dual bromodomain inhibitor of CBP/EP300, and its potential in AML subtypes (AACR 2025) - "Clinical validation of bromodomain inhibition of paralogs CBP and EP300 is undergoing in multiple clinical trials, including both hematological diseases and solid tumors, using EP31670, CCS1477 and TT125-802, while selective CBP or EP300 inhibition is being explored preclinically. However, in contrast, long-term treatment in the MLL-AF9 (MOLM14) model resulted in antagonistic effects. These findings underscore the complexities of combinatorial therapeutic development and emphasize the critical need for careful selection of robust therapeutic combinations and consideration of the genetic background in the target disease."

Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • BRD4 • EP300

Tolerability and Clinical Activity of Novel First-In-Class Oral Agent, inobrodib (CCS1477) With Pom-Dex in RRMM (BSH 2025) - No abstract available

Clinical • Multiple Myeloma

CellCentric Expands US Presence with New Office in Boston (CellCentric Press Release) - "CellCentric, a clinical stage biotechnology company, today announces the opening of a new office in Boston, marking a significant step in expanding its presence in the United States. This will increase the company’s drug development capacity, progressing its novel drug treating multiple myeloma, inobrodib. Located in Burlington, Boston, Massachusetts, the US presence will enhance the company’s ability to access talent and foster further clinical collaborations, as the company accelerates towards registration studies for its first-in-class oral drug."

Commercial • Multiple Myeloma

The clinical-grade CBP/ p300 inhibitor CCS1477 represses the global NRF2-dependent cytoprotective transcription program and re-sensitizes cancer cells to chemotherapeutic drugs. (PubMed, Free Radic Biol Med) - "Furthermore, in co-culture experiments of KEAP1 mutant cancer cells with primary human T cells, CCS1477 treatment suppressed the acquisition of the T cell exhaustion transcriptional state, which should function to augment the anti-cancer immune response. Thus, CCS1477-mediated inhibition of CBP/ p300 represents a novel therapeutic strategy with which to target the currently untreatable tumours with aberrant NRF2 activation."

Journal • Lung Cancer • Oncology • Solid Tumor • KEAP1

CCS1477-02: Study to Evaluate CCS1477 (inobrodib) in Haematological Malignancies (clinicaltrials.gov) - P1/2 | N=250 | Recruiting | Sponsor: CellCentric Ltd. | Trial completion date: Jun 2025 ➔ Mar 2027 | Trial primary completion date: Jun 2025 ➔ Mar 2027

Monotherapy • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma

Orphan Drug Designations and Approvals (FDA) - Generic Name: Inobrodib, Date Designated: 06/21/2023, Orphan Designation: Treatment of Multiple Myeloma, Orphan Designation Status: Designated

Orphan drug • Multiple Myeloma

Targeting Caseinolytic Mitochondrial Matrix Peptidase, a Novel Contributor to High-risk Behavior, in Multiple Myeloma. (PubMed, Blood) - "CLP endopeptidase inhibition overcame conventional and novel drug resistance, induced apoptosis in primary samples, showed efficacy in vivo, and could be achieved with the clinically relevant agent inobrodib. Finally, regimens combining a CLPP and proteasome inhibitor showed enhanced efficacy, as did combinations with inhibitors of intermediary metabolism and autophagy. Taken together, our data indicate that CLPP is a key contributor to transformed plasma cells, a novel mediator of high-risk behavior, and a legitimate target for myeloma therapy whose inhibitors could be rationally combined with current therapeutics to improve outcomes."

Journal • Hematological Malignancies • Monoclonal Gammopathy • Multiple Myeloma • Oncology • Smoldering Multiple Myeloma • SDC1

Concurrent inhibition of p300/CBP and FLT3 enhances cytotoxicity and overcomes resistance in acute myeloid leukemia. (PubMed, Acta Pharmacol Sin) - "Targeting p300/CBP with A485 or CCS1477 retained the efficacy of quizartinib, suggesting marked synergy when combined with p300/CBP inhibitors in quizartinib-resistant AML models, as well as primary FLT3-ITD+ AML samples. These results demonstrate a potential therapeutic strategy of combining p300/CBP and FLT3 inhibitors to treat FLT3-ITD and FLT3-TKD AML."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CREBBP • EP300 • FLT3 • MYC • STAT5

The important role of the histone acetyltransferases p300/CBP in cancer and the promising anticancer effects of p300/CBP inhibitors. (PubMed, Cell Biol Toxicol) - "Importantly, two p300/CBP bromodomain inhibitors, CCS1477 and FT-7051, as well as the dual p300/CBP and BRD4 bromodomain inhibitor NEO2734 have entered Phase I and IIa clinical trials in patients with advanced and refractory hematological malignancies or solid tumors. Taken together, the identification of p300/CBP as critical drivers of tumorigenesis and the development of p300/CBP inhibitors and proteolysis-targeted-chimaera protein degraders represent promising avenues for clinical translation of novel cancer therapeutics."

Journal • Review • Developmental Disorders • Hematological Disorders • Hematological Malignancies • Oncology • Solid Tumor • Targeted Protein Degradation • BRD4 • CREBBP

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

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 • Bone Marrow Transplantation • Hematological Disorders • Hematological Malignancies • Leukemia • Myeloproliferative Neoplasm • Oncology • CALR • CREBBP • EP300 • HSF1 • MYC • STAT3 • STAT5

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

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

Next-Generation Novel Therapies in Multiple Myeloma (ICBMT 2024) - "A wealth of therapeutic options have been approved for the treatment of newly diagnosed (ND) and relapsed/refractory (RR) multiple myeloma (MM) over the past two decades, with proteasome inhibitors (bortezomib, carfilzomib, ixazomib), immunomodulatory drugs (IMiDs; thalidomide, lenalidomide, pomalidomide), and monoclonal antibodies (mAbs; including the CD38 mAbs daratumumab and isatuximab, as well as the SLAMF7-targeting mAb elotuzumab) currently forming the backbone of treatment approaches in each setting. Additional targeted therapies have further enhanced the armamentarium, including, previously, the histone deacetylase inhibitor panobinostat, and, more recently, the nuclear export inhibitor selinexor 1 and the peptide–drug conjugate (PDC) melflufen. 2,3 Furthermore, novel immune-based treatment options such as the antibody–drug conjugate (ADC) belantamab mafodotin, the BCMA-targeting CAR T-cell therapies idecabta-gene vicleucel (ide-cel) and ciltacabtagene autoleucel..."

Hematological Malignancies • Multiple Myeloma • Oncology • Targeted Protein Degradation • CRBN • IRF4 • SLAMF7

Exploring P300/CBP as therapeutic approach for right ventricular dysfunction in PAH (AHA 2024) - "Using human precision-cut RV slices stimulated with phenylephrine and TGFb, we show that P300/CBP inhibition attenuates fibrosis [Masson's trichrome staining (MT), p<0.05] and cardiomyocyte (CM) hypertrophy [hematoxylin and eosin staining (HE), p<0.05]. In vivo, administration of CCS-1477 in a PAB rat model reduces fibrosis (MT, p<0.05), CM surface area (HE, p<0.01), and improves RV function (TAPSE, cardiac output, stroke volume, p<0.05).Our finding provide evidence that targeting P300/CBP may represent a promising avenue to counter maladaptive RV remodeling in PAH."

Cardiovascular • Fibrosis • Heart Failure • Immunology • Pulmonary Arterial Hypertension • Respiratory Diseases • BIRC5 • MMP2 • PCNA

Epigenetic Activation of the CMTM6-IGF2BP1-EP300 Positive Feedback Loop Drives Gemcitabine Resistance in Pancreatic Ductal Adenocarcinoma. (PubMed, Adv Sci (Weinh)) - "The combined application of the EP300 inhibitor inobrodib and gemcitabine exerts a synergistic effect on PDAC. Overall, these findings reveal that the EP300-CMTM6-IGF2BP1 positive feedback loop facilitates gemcitabine resistance via epigenetic reprogramming and the combined use of inobrodib and gemcitabine represents a promising strategy for overcoming chemoresistance in PDAC, warranting further investigation in clinical trials."

Journal • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • Targeted Protein Degradation • CMTM6 • EP300 • IGF2BP1

Integrating text mining with network models for successful target identification: in vitro validation in MASH-induced liver fibrosis. (PubMed, Front Pharmacol) - "EP300 gene-silencing was found to significantly reduce collagen by 37%; compound intervention studies performed in human primary hepatic stellate cells and the hepatic stellate cell line LX-2 showed significant inhibition of collagen to the extent of 81% compared to the TGFβ-stimulated control (1 μM inobrodib in LX-2 cells)...The directionality of the network ensures adherence to physiologically relevant signaling cascades, while the inclusion of clinical data boosts its translational power and ensures identification of the most relevant disease pathways. In silico knockouts thus provide crucial molecular insights for successful target identification."

Journal • Preclinical • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • EP300 • TGFB1

Exploring P300/CBP as therapeutic targets for pulmonary arterial hypertension and right ventricular failure (ERS 2024) - "In the PAB rat model, CCS-1477 improves RV function (TAPSE, CO, SV) and reduces fibrosis (MT). Our finding suggests that targeting P300/CBP may represent a promising avenue to tackle both lung and RV maladaptive remodeling in PAH."

Cardiovascular • Fibrosis • Immunology • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • BIRC5 • MMP2 • PCNA • PLK1

Study to Evaluate CCS1477 in Advanced Tumours (clinicaltrials.gov) - P1/2 | N=350 | Recruiting | Sponsor: CellCentric Ltd. | Trial completion date: Mar 2024 ➔ Dec 2024 | Trial primary completion date: Mar 2024 ➔ Dec 2024

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