inobrodib (CCS1477) / CellCentric - LARVOL DELTA

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

Group 3 medulloblastoma transcriptional networks collapse under domain specific EP300/CBP inhibition. (PubMed, Nat Commun) - "Here, we discover that targeting EP300/CBP using the domain-specific inhibitors, A485 (HAT) or CCS1477 (BRD) have different effects in select tumor types...Mechanistically, bromodomain inhibition causes rapid disruption of genetic dependency networks that are required for G3MB growth. These studies provide a domain-specific structural foundation for drug discovery efforts targeting EP300/CBP and identify a selective role for the EP300/CBP bromodomain in maintaining genetic dependency networks in G3MB."

Journal • Brain Cancer • Medulloblastoma • Oncology • Solid Tumor • EP300

Discovery of Highly Potent and Efficient CBP/p300 Degraders with Strong In Vivo Antitumor Activity. (PubMed, J Med Chem) - "Herein, we report the design, synthesis, and biological evaluation of a series of cereblon (CRBN)-recruiting CBP/p300 proteolysis targeting chimeras (PROTACs) based on the inhibitor CCS1477...14g and 14h displayed remarkable antitumor efficacy in the MV4;11 xenograft model (TGI = 88% and 93%, respectively). Our findings demonstrated that 14g and 14h are useful lead compounds and deserve further optimization and activity evaluation for the treatment of human cancers."

Journal • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation • CRBN

Targeting the CBP/p300 axis in lethal prostate cancer impacts DNA repair (AACR 2024) - "In this study, CBP/p300 mediated bromodomain activity is targeted by CCS1477 (inobrodib), a first-in-class bromodomain inhibitor developed by Cell Centric...These collective findings reveal that CBP/p300 govern repair of DNA DSBs by regulating HR, thus modulating genome integrity and promoting CRPC growth. These studies identify CBP/p300 as a driver of PCa tumorigenesis through coordinated control of critical transcriptional events and lay the groundwork to optimize therapeutic strategies for advanced PCa via CBP/p300 inhibition, potentially in combination with AR-directed therapies."

Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • MYC

Discovery of CBPD-409 and CBPD-268 as highly potent and orally efficacious CBP/p300 PROTAC degraders for the treatment of castration-resistant prostate cancer (AACR 2024) - "CBPD-409 exhibits strong and dose/schedule-dependent tumor growth inhibition and is more potent and efficacious than two CBP/p300 inhibitors CCS1477 and GNE-049 and the AR antagonist Enzalutamide. CBPD-268 was well tolerated in mice and rats and displayed a therapeutic index of >10. Taken together, CBPD-409 and CBPD-268 are highly promising CBP/p300 degraders for further extensive evaluations for the treatment of CRPC and other types of human cancers."

Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CRBN

Genetic or pharmacological inactivation of CREBBP sensitizes B-cell acute lymphoblastic leukemia to ferroptotic cell death upon BCL2 inhibition (AACR 2024) - "As anticipated, and validating our screen design, inhibitors of the CREBBP paralogue EP300 (the CREBBP/EP300-specific bromodomain inhibitor Inobrodib and the CREBBP/EP300 acetylase inhibitor A485) exhibited synthetic lethality, consistent with previous reports in B-cell lymphoma. Lastly, we demonstrate that small-molecule inhibition of CREBBP sensitizes B-ALL cells, regardless of genotype, to Venetoclax-induced ferroptosis in vitro and in vivo, providing a potential novel drug combination for broader clinical translation in B-ALL. In summary, we have identified a number of actionable compounds that specifically target CREBBP-mutated high-risk B-ALL, demonstrate a novel mechanism-of-action for the BCL2 inhibitor Venetoclax in B-ALL and propose CREBBP-inhibitors and Venetoclax as a novel treatment combination for B-ALL across genotypes."

IO biomarker • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CREBBP • EP300

Discovery of CBPD-409 as a Highly Potent, Selective, and Orally Efficacious CBP/p300 PROTAC Degrader for the Treatment of Advanced Prostate Cancer. (PubMed, J Med Chem) - "CBPD-409 exhibits strong tumor growth inhibition and is much more potent and efficacious than two CBP/p300 inhibitors CCS1477 and GNE-049 and the AR antagonist Enzalutamide. CBPD-409 is a promising CBP/p300 degrader for further extensive evaluations for the treatment of advanced prostate cancer and other types of human cancers."

Journal • Metastases • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • Targeted Protein Degradation

Characteristics of anticancer activity of CBP/p300 inhibitors - Features of their classes, intracellular targets and future perspectives of their application in cancer treatment. (PubMed, Pharmacol Ther) - "The promising anticancer efficacy in in vitro and mice models led CCS1477 and NEO2734 to clinical trials. However, none of the described inhibitors is perfectly specific to CBP/p300 since they share similarity of a key functional domains with other enzymes, which are critically associated with cancer progression and their antagonists demonstrate remarkable clinical efficacy in cancer therapy. Therefore, we revise the possible and clinically relevant off-targets of CBP/p300 inhibitors that can be blocked simultaneously with CBP/p300 thereby improving the anticancer potential of CBP/p300 inhibitors and pharmacokinetic predicting data such as absorption, distribution, metabolism, excretion (ADME) and toxicity."

Journal • Review • Oncology

Discovery of Novel PROTAC Degraders of p300/CBP as Potential Therapeutics for Hepatocellular Carcinoma. (PubMed, J Med Chem) - "Based upon the clinical p300/CBP bromodomain inhibitor CCS1477, a conformational restriction strategy was used to optimize the linker to generate a series of PROTACs, culminating in the identification of QC-182...Notably, QC-182 potently depletes p300/CBP proteins in mouse SK-HEP-1 xenograft tumor tissue. QC-182 is a promising lead compound toward the development of p300/CBP-targeted HCC therapy."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • CREBBP

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 Disorders • Hematological Malignancies • Leukemia • Oncology • BCL2 • CREBBP • GLI2 • KMT2A

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

CellCentric discloses significant new clinical data, demonstrating inobrodib’s efficacy in ongoing Phase I/IIa clinical trials (CellCentric Press Release) - P1/2 | N=250 | NCT04068597 | Sponsor: CellCentric Ltd. | "CellCentric has announced new clinical data for its oral drug inobrodib at the American Society for Hematology annual meeting (ASH) in San Diego. The data shows over 70% responses (>=MR by IMWG criteria) in last line multiple myeloma patients treated with inobrodib in combination with pom + dex....The results showed inobrodib has a manageable safety profile. All patients demonstrated some signs of clinical activity, with rapid responses: 72% ≥MR by IMWG criteria in both cohorts, and 67% ORR in the 35mg cohort. A significant number of patients across both dosing cohorts remain on treatment after six months."

P1/2 data • Hematological Malignancies • Multiple Myeloma • Oncology