mivebresib (ABBV 075) / AbbVie - LARVOL DELTA

SORAFENIB REVERSES VENETOCLAX SECONDARY RESISTANCE IN ACUTE MYELOID LEUKAEMIA VIA DOWNREGULATION OF THE RAS-RAF-MEK-ERK SIGNALLING PATHWAY (EHA 2025) - "Peripheral leukemic cells were analysed via flow cytometry, haematological parameters were monitored through blood counts, and spleen size was measured post-treatment.High-throughput in vitro drug sensitivity screening identified six venetoclax-synergistic agents from thirty-one candidates: ruxolitinib, sorafenib, A1331852, mivebresib, quizartinib, and nilotinib. Sorafenib reverses secondary venetoclax resistance in AML by inhibiting the Ras-Raf-MEK-ERK pathway and downregulating anti-apoptotic proteins (BCL-2, MCL-1, BCL-XL), thereby synergising with venetoclax to inhibit resistant leukaemic cells. This study provides a promising therapeutic strategy for overcoming venetoclax resistance in AML."

IO biomarker • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • BCL2 • BCL2L1 • MCL1

Multipronged DNA Damage Response Inhibition Enhances the Therapeutic Efficacy of [177Lu]Lu-PSMA-617 in Castration-Resistant Prostate Cancer (SNMMI 2025) - " In vitro cytotoxicity was evaluated in a panel of prostate cancer (PCa) cell lines (PC3-PIP, LNCaP, and 22Rv1) treated with the PARP inhibitor Talazoparib (TAZ), or BET inhibitor ABBV-075, or their combination (0.3 nM–1 mM) using a presto-blue assay. ABBV-075 showed nanomolar cytotoxicity with IC50s (100-300 nM) in PC3-PIP, LNCaP, and 22Rv1 cells. Interestingly, only AR-sensitive 22Rv1 cells responded to TAZ (IC50= 0.7 µM). Synergistic effects were observed for specific TAZ + ABBV-075 treatment combinations in the treated cells (CI>10; HAS and Loewe models)."

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

Synergistic Combination of Radiopharmaceutical Therapy and DNA Damage Repair Inhibition for Triple Negative Breast Cancer (SNMMI 2025) - " Cytotoxicity was determined in 4T1 cells treated with 0.3 nM -1 mM Talazoparib (TAZ: PARPi), ABBV-075 (BETi), or combined with RPT ([177Lu]Lu-NM600). Cell viability was assessed at 24 h, 48 h, 72 h, and 96 h after treatment. IC50s were determined, and combination effects were evaluated between treatments using established synergy models. ABBV-075 showed similar nanomolar cytotoxicity at 72 and 96 h post-treatment (IC50s: 369 vs. 414 nM). Therefore, 300 nM will be used as the reference concentration of ABBV-075 for all subsequent in-vitro combinations."

Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRCA1 • BRCA2 • RAD51

Novel therapeutic strategies targeting MECOM rearranged AMLs discovered by unbiased drug screen (AACR 2025) - "Co-targeting with BETi and other identified sensitivities such as the IAP family inhibitor (LCL161) or Bcl-xL inhibitor (navitoclax or A1155463) also exhibited synergistic lethality in 3q26.2-r AML cell lines and PD AML cells. Co-treatment of mivebresib with dactolisib or LCL161 was superior than each drug alone in reducing AML burden and improving survival. These findings demonstrate promising preclinical activity of novel BETi-based combination with IAP or Bcl-xL inhibitor against AML with EVI1 overexpression."

Acute Myelogenous Leukemia • Oncology • BCL2L1 • GATA2 • MECOM • MYC • PIK3CA • TNFA • XIAP

An oncohistone-driven H3.3K27M/CREB5/ID1 axis maintains the stemness and malignancy of diffuse intrinsic pontine glioma. (PubMed, Nat Commun) - "Intriguingly, disrupting CREB5 super-enhancers with ABBV-075 significantly reduces its expression and inhibits H3.3K27M DIPG tumor growth. Combined treatment with ABBV-075 and a BRG1 inhibitor presents a promising therapeutic strategy for clinical translation in H3.3K27M DIPG treatment."

Journal • Brain Cancer • CNS Tumor • Diffuse Intrinsic Pontine Glioma • Glioma • Oncology • Pediatrics • Solid Tumor • CREB5 • ID1 • SMARCA4

Exploring BET inhibitors as promising agents for solitary fibrous tumor (Sarcoma-RC 2025) - "RNA-seq was performed on Illumina NovaSeq X. Results Among seven BETis tested in SFT cells, Mivebresib and BMS-986158 exhibited the lowest IC50 values (INT-SFT: 10.8 nM and 6.23 nM; IEC139: 12.5 nM and 28.8 nM) and, in contrast to other BETis, induced apoptosis at 50 nM (INT-SFT: 32% and 45.9%; IEC139: 27.5% and 34.3%)...Combining BETis with PARPi rucaparib or ATRi berzosertib showed synergistic effects, enhancing apoptotic responses and DNA damage accumulation...In vivo, Mivebresib markedly reduced tumor growth in SFT PDX models, supporting its potential as a targeted therapy. Legal entity responsible for the study The authors."

Oncology • Sarcoma • Solid Tumor • CCND1 • CDKN1A • NAB2 • STAT6

Identification of BET Inhibitors (BETi) Against Solitary Fibrous Tumor (SFT) Through High-Throughput Screening (HTS). (PubMed, bioRxiv) - "Consequently, combining BET inhibitors with PARP (Poly (ADP-ribose) polymerase) or ATR inhibitors significantly enhanced anti-proliferative effects in SFT cells. Taken together, our study established BET inhibitors Mivebresib and BMS-986158 as promising anti-SFT agents."

Journal • Hematological Disorders • Hematological Malignancies • Oncology • Sarcoma • Solid Tumor • NAB2 • STAT6

Efficacy of Combinations of Targeted Agents Against Dependencies in Mecom Rearranged AML Identified By Unbiased Chemical and CRISPR Screens (ASH 2024) - "Treatment of 3q26.2-r AML cell lines for 96-hours with ORY001 (LSD1i; 3-100 nM), RGFP966 (HDAC3i; 0.5-10 µM) or GNE-781 (CBP/p300i; 10-1000 nM) induced moderate, dose-dependent cell death, as determined by flow cytometry...Treatment of the luciferized 3q26.2-r PD AML242 model, engrafted in NSG mice, with mivebresib (0.5 mg/kg, daily 5x per week), dactolisib (20 mg/kg, daily 5x per week) or LCL161 (65 mg/kg, daily 5x per week) reduced AML burden and increased survival compared to vehicle-treated mice (p < 0.05)...These treatments resulted in reduction of EVI1 and c-Myc levels, associated with preclinical differentiation and apoptotic activity in the 3q26.2-r AML cell models. Further in vivo evaluation of the efficacy of BETi or LSD1i-based combinations against 3q26.2-r AML is warranted."

Clinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BRD4 • CD86 • GATA2 • HDAC3 • ITGAM • MECOM • MYC • PIK3CA • XIAP

Efficacy and safety of venetoclax combination therapy for relapsed/refractory acute myeloid leukemia: a systematic review and meta-analysis (BMC Cancer) - "Out of 58 identified articles, seven were included in the meta-analysis. The pooled complete remission (CR) rate was 15.4%, and the composite complete remission (CRc) rate was 35.7%. The partial remission (PR) rate was 2.6%, while the non-remission (NR) rate was 24.4%. The minimal residual disease status in CRc patients (MRD-CRc) rate was 39.4%, and the morphologic leukemia-free state (MLFS) rate was 10.3%....Subgroup analysis based on combined drugs revealed varying CR and CRc rates. the combination of venetoclax and azacitidine + demonstrates superior outcomes, displaying the highest rates of CR at 31.3% and CRc at 62.7%. In contrast, venetoclax and idasanutlin exhibits a moderate CR rate of 6.1% and a CRc rate of 26.5%, while venetoclax and mivebresib shows the lowest CR rate at 3.3% and a moderate CRc rate of 8.0%."

Retrospective data • Acute Myelogenous Leukemia

Efficacy and safety of venetoclax combination therapy for relapsed/refractory acute myeloid leukemia: a systematic review and meta-analysis. (PubMed, BMC Cancer) - "In conclusion, while venetoclax combination therapies, particularly with azacitidine + , show promise in achieving favorable treatment responses in relapsed/refractory AML patients, a comprehensive evaluation of safety profiles is essential. Nevertheless, it is essential to underscore the markedly increased incidence rates of febrile neutropenia and thrombocytopenia observed among adverse events."

Clinical • Combination therapy • Journal • Retrospective data • Review • Acute Myelogenous Leukemia • Colorectal Cancer • Fatigue • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Leukemia • Neutropenia • Oncology • Thrombocytopenia

Targeting the DNA Damage Response Boosts Radiopharmaceutical Therapy Efficacy in Castration-Resistant Prostate Cancer (EANM 2024) - "Aim/Introduction: 177Lu-PSMA-617 radiopharmaceutical therapy (RPT) is an encouraging treatment for men with metastatic castration-resistant prostate cancer (CRPC)...In vitro, cytotoxicity was determined in PC3-PIP, LNCaP, and 22Rv1 cells treated with 0.3 nM-1 mM Talazoparib (TAZ: PARPi), JQ1 or ABBV-075 (BETi), or combinations... Our studies demonstrate the potential of pharmacological DDR inhibition to boost radiobiological response in CRPC. Our preclinical data strongly supports the clinical feasibility of combining TAZ and ABBV-075, two clinical-stage drugs, and RPT in CRPC patients."

Clinical • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Metastatic Castration-Resistant Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor • BRCA1 • BRCA2 • PARP1 • RAD51

Identification of targetable epigenetic vulnerabilities in uveal melanoma. (PubMed, bioRxiv) - "RNA sequencing revealed a notable overlap between the genes and pathways affected by HDAC and BET inhibition, including the reversal of gene signatures linked to high metastatic risk and upregulation of genes associated with a neuronal phenotype. Together, we found that UM cells are particularly vulnerable to class I HDAC and BET inhibition, and highlight the BET inhibitor mivebresib as a promising candidate for further clinical evaluation."

Journal • Eye Cancer • Melanoma • Oncology • Solid Tumor • Targeted Protein Degradation • Uveal Melanoma • BAP1

Transcriptional repression of double-strand DNA damage repair potentiates targeted alpha therapy efficacy in advanced prostate cancer. (EANM 2024) - "In vitro, cytotoxicity was determined in PC3-PIP, LNCaP, and 22Rv1 cells treated with BETi (JQ1 or next-generation inhibitor ABBV-075: 0.3 nM-1 mM). DDR disruption through BETi proved a promising strategy to boost 225Ac's lethality in CRPC cells. Combining BETi with 225Ac-ART-101 or other TAT agents is mechanistically justified and merits further therapeutic optimization and toxicological evaluations toward its potential clinical implementation."

Clinical • Metastases • Castration-Resistant Prostate Cancer • Dental Disorders • Genito-urinary Cancer • Metastatic Castration-Resistant Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor • Xerostomia • BRCA1 • BRCA2 • RAD51

The ROCK-1/2 inhibitor RKI-1447 blocks N-MYC, promotes cell death, and emerges as a synergistic partner for BET inhibitors in neuroblastoma. (PubMed, Cancer Lett) - "Synergistic effects from RKI-1447 and the BET inhibitor, ABBV-075, were confirmed in various neuroblastoma models, including zebrafish...BET inhibitors have shown preclinical efficacy against neuroblastoma, but acquired resistance has limited their therapeutic benefit. We reveal that the combination of ROCK and BET inhibitors offers a promising treatment approach that can potentially mitigate resistance to BET inhibitors and reduce toxicity."

Journal • CNS Tumor • Neuroblastoma • Oncology • Solid Tumor • MYC • MYCN

BRD4 plays an antiaging role in the senescence of renal tubular epithelial cells. (PubMed, Transl Androl Urol) - "At first, we used a D-galactose (D-gal) and BRD4 inhibitor (Abbv-075) to replicate kidney senescence in vivo...The findings also suggest that BRD4 inhibitors have potential nephrotoxic effects for oncology treatment. BRD4 may be a potential therapeutic biomarker and drug target for aging-related kidney diseases, which warrants additional studies."

Journal • Chronic Kidney Disease • Nephrology • Oncology • Renal Disease • BRD4 • CDKN1A

MYC family amplification dictates sensitivity to BET bromodomain protein inhibitor Mivebresib (ABBV-075) in small-cell lung cancer. (PubMed, Mol Cancer Res) - "Further characterization of genome-wide binding of MYC, MYCN, and MYCL1 uncovered unique enhancer and epigenetic preferences. Implications: Our study suggests that chromatin landscapes could establish cell states with unique gene expression programs, conveying sensitivity to epigenetic inhibitors such as mivebresib."

Journal • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • MYCL • MYCN

Combination strategies to overcome radioresistance in metastatic Castration-Resistant Prostate Cancer (SNMMI 2024) - "Purpose/Background: Radiopharmaceutical therapy (RPT) with [177Lu]Lu-PSMA-617 (Pluvicto®) constitutes an effective therapeutic approach for treating metastatic castration-resistant prostate cancer (mCRPC), the lethal form of prostate cancer (PCa)...3 nM - 1 mM) of Talazoparib (TAZ: PARPi), or JQ1 or ABBV-075 (BETi) or combination of TAZ + BETi, and cell viability was measured via PrestoBlue Assay... Our studies demonstrate the potential of pharmacological DDR disruption to sensitize PCa cells to 177Lu radiation. From both DDR pathway inhibitions, BETi emerged as the most potent sensitizer strategy warranting further exploration. Because ABBV-075 has been established in the Phase I trial, this combination strategy is highly and readily translatable."

Metastases • Genito-urinary Cancer • Metastatic Castration-Resistant Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor • BRCA1 • BRCA2 • PARP1 • RAD51

Identifying novel therapies from unbiased screens in AML with MECOM re-arrangement (AACR 2024) - "Consistent with this, co-treatment of mivebresib with SMAC mimetic birinapant or IAP inhibitor LCL161 was synergistically lethal against 3q26.2-r cells. Co-targeting the other identified druggable vulnerabilities from the drug screen with BETi (mTOR/PI3K with BGT-226 and dactolisib, Bcl-xL with navitoclax and A1155463, as well as CBP/p300 (with GNE781, identified through the CRISPR screen), exerted synergistic lethality in 3q26.2-r AML cells...These findings demonstrate promising preclinical activity of BETi and IAP protein or mTOR/PI3K antagonists in the cellular models of AML with EVI1 overexpression. This supports the rationale to determine in vivo efficacy of these BETi-based combinations against this therapy-resistant AML sub-type."

Acute Myelogenous Leukemia • Oncology • BCL2L1 • BRD4 • CASP3 • CDK4 • HEXIM1 • MCL1 • MECOM • mTOR • MYC • PIK3CA • XIAP

Therapeutic Potential of Bromodomain and Extra-Terminal Domain Inhibitors for Synovial Sarcoma Cells. (PubMed, Cancers (Basel)) - "Additionally, knockdown of SS18-SSX, which upregulates BCL2, reduced the sensitivity to ABBV-075. These findings suggest the potential utility of BET inhibitors targeting the SS18-SSX-regulated intrinsic apoptotic pathway as a promising therapeutic strategy for SS."

IO biomarker • Journal • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • Synovial Sarcoma • BCL2 • BCL2L1 • CDK4 • CDK6 • CDKN1A • SS18

Development and Efficacy of a Novel Bromodomain and Extraterminal Domain Degrader K-256 in MYC/BCL2-Related Lymphoma (ASH 2023) - "The GI50 of K-256 in SU-DHL4 and SU-DHL6 was 12.8 nM and 7.50 nM, respectively, and K-256 induced cell death at lower concentrations than existing drugs (vs. JQ1, OTX-015, and ABBV-075, p < 0.0001; vs. dBET6 and ARV-771, p < 0.01)...As expected, the combination of K-256 with venetoclax also demonstrated synergistic effects in PDX cells, similar to those observed in cell lines (CI of 0.515 to 0.762 for inhibiting cell proliferation; 0.085 to 0.995 for inducing apoptosis)... The novel BET degrader, K-256, bound to BET proteins at lower concentrations than existing BET inhibitors and degraders, strongly suppressing MYC expression, primarily via BRD4 degradation. Additionally, K-256 demonstrated superior therapeutic effects in MYC/BCL2-related PDX models both in vitro and in vivo, suggesting that this novel drug could be a promising therapeutic agent for MYC/BCL2-related lymphoma. Its translation to future clinical applications warrants further consideration."

Clinical • IO biomarker • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • BRD2 • BRD3 • BRD4 • BRDT • MYC

Actionable Findings from an Unbiased Drug Screen for Novel Single Agent and Combination Therapies Against AML with Mecom Re-Arrangement (ASH 2023) - "This was consistent with previous reports that BET inhibitors (e.g., OTX015, mivebresib or ABBV-075 and JQ1) are effective against 3q26.2-r AML cell lines, patient-derived (PD) AML cells and PDX models...In follow-up experiments, XIAP/cIAPs inhibitors birinapant (10-1000 nM) or SM-164 (30-1000 nM), chosen based on the MIPE screen outcomes, induced significantly more dose-dependent apoptosis in 3q26.2-r versus the other AML cell lines...Treatment with the dual mTOR/PIK3CA inhibitor NVP-BGT226 (1-30 nM) or navitoclax or Bcl-xL-specific BH3 mimetic A-1155463 also exerted lethality and synergistically induced apoptosis with mivebresib in AML cells with inv3/t(3; 3)...Co-treatment with birinapant and tegavivint also synergistically induced apoptosis in 3q26.2-r AML cells...Additionally, compared to each drug or vehicle control, co-treatment with birinapant and the BETi OTX015 (30 mg/kg/day, by oral gavage) was more effective in reducing AML burden in the xenograft model...."

Combination therapy • Acute Myelogenous Leukemia • Oncology • BCL2L1 • BRD4 • CASP3 • CDK4 • CTNNB1 • GATA2 • HEXIM1 • MCL1 • MECOM • MYC • PIK3CA • SF3B1 • XIAP

Rational therapeutic combination of Bromodomain and Extra-Terminal domain (BET) inhibitor and Fibroblast Growth Factor Receptor (FGFR) inhibitor for treatment of invasive lobular carcinoma (SABCS 2023) - " We demonstrated that iBET significantly inhibited ILC cell growth in both 2D and 3D culture, with the greatest potency demonstrated by JQ1 and Mivebresib (ABBV-075). Our results provide evidence that iBET, either alone or in combination with erdafitinib, is remarkably effective at inhibiting ILC growth, both in vitro and in vivo and represents a rational therapeutic strategy for recurrent ILC patients in the future."

Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • BRD2 • BRD3 • CDH1 • ER • FGFR • FGFR3

Epigenetic Cooperativity as a Therapeutic Vulnerability in Cancer. (PubMed, Cancer Res) - "As a result, combined treatment of NC tumors with tazemetostat and the BET inhibitor mivebresib produces marked antitumor therapeutic synergy in vitro and in vivo, associated with enhanced suppression of RB1 function through convergent remodeling of NC gene expression. This study advances epigenetic cooperativity as a distinct mode of gene expression dysregulation in NC and nominates a compelling combination epigenetic strategy for investigation in clinical trials for patients. See related article by Huang et al., p. 3956."

Journal • NUT Midline Carcinoma • Oncology • BRD4 • CDKN2A • EZH2 • RB1

EFFICACY OF BET INHIBITORS IN SOLITARY FIBROUS TUMOR: AN IN VITRO EVALUATION (CTOS 2023) - " Three different BET inhibitors, Mivebresib, Pelabresib, and ABBV-744, were evaluated to determine their antitumor activity in SFT cell lines...In addition, a synergistic effect was observed between BET inhibitors and Rucaparib, a commonly used PARP inhibitor (Combination Index of 0.42 and 0.27 for INT-SFT and IEC139 respectively)... BET inhibitors demonstrated efficacy and specificity for SFT in vitro models, potentially through targeting the HR pathway. Further investigations, including in vivo experiments, are necessary to elucidate the underlying mechanisms and evaluate clinical efficacy. The knowledge gained from these studies can lay the groundwork for potential clinical trials that will enable us to assess their safety, efficacy, and potential side effects in the context of SFT."

Preclinical • Leiomyosarcoma • Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor • H2AX • NAB2 • RAD51 • STAT6

Selectivity Mechanism of Pyrrolopyridone Analogues Targeting Bromodomain 2 of Bromodomain-Containing Protein 4 from Molecular Dynamics Simulations. (PubMed, ACS Omega) - "This study determined the effectiveness of pyrrolopyridone analogues to selectively inhibit BD2 using a pan-BD inhibitor (ABBV-075) and a selective-BD2 inhibitor (ABBV-744). These results suggest that the R3 and R5 regions of pyrrolopyridone analogues can be modified to improve the selectivity between BRD4-BD1 and BRD4-BD2. The selectivity of BD2 inhibition by pyrrolopyridone analogues can be used to design novel BD2 inhibitors based on a pyrrolopyridone core."

Journal • BRD4