mivebresib (ABBV 075) / AbbVie - LARVOL DELTA

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

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

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

Identification of BET inhibitors (BETi) against solitary fibrous tumor (SFT) through high-throughput screening (HTS). (PubMed, Neoplasia) - "Consequently, combining BET inhibitors with PARP (Poly (ADP-ribose) polymerase) inhibitors or with ATR inhibitors significantly enhanced anti-proliferative effects in SFT cells. Taken together, this study establishes BET inhibitors Mivebresib and BMS-986158 as promising anti-SFT agents."

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

Inhibition of bromodomain and extra-terminal motif (BET) proteins in pediatric sarcoma: A systematic review of in vitro and in vivo studies. (PubMed, Drug Discov Today) - "Accordingly, we reported that ABBV-744 and RVX-208, which selectively target the BD2 domain, and GNE-987, a specific BRD4 degrader, are the most promising inhibitors. However, ABBV-075, a pan-BETi, also exhibits high efficacy, being effective at low doses. Nevertheless, translating these experimental findings into clinical practice remains difficult because of resistance, toxicity, and inconsistent responses. Future approaches include using biomarkers for patient selection, developing isoform-specific BETi, and designing rational combination therapies to enhance treatment for these aggressive pediatric cancers."

Journal • Preclinical • Review • Oncology • Pediatrics • Sarcoma • Solid Tumor • BRD4

DNA Damage Repair Inhibition boots Radiopharmaceutical Therapy for Triple Negative Breast Cancer (EANM 2025) - "Materials and Methods Cytotoxicity was determined in 4T1 cells treated with 0.3 nM -1 mM Talazoparib (TAZ:PARPi), ABBV-075 (BETi), or combined with RPT ([ 177 Lu]Lu-NM600). Median overall survival was 18, 14, 11, 18, 18, 23, and 28 in the vehicle (n=5), PARPi (n=5), BETi (n=5), [ 177 Lu]Lu-NM600 (n=5), [ 177 Lu]Lu-NM600 + BETi (n=5), [ 177 Lu]Lu-NM600 + PARPi (n=5) and [ 177 Lu]Lu-NM600 + PARPi + BETi (n=5), respectively. Conclusion These findings demonstrated the enhance potency of RPT when combined with clinically relevant PARPi and BETi and the potential this combination therapy to tackle TNBC."

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

Evaluating the Therapeutic Efficacy and Safety of Venetoclax-Based Combination Regimens in Relapsed or Refractory Acute Myeloid Leukemia: A Systematic Review and Meta-Analysis (SOHO 2025) - "Venetoclax-based combinations included various agents such as hypomethylating agents (azacitidine), IDH inhibitors, and investigational drugs like idasanutlin (MDM2 antagonist) and mivebresib (small-molecule pan-BET inhibitor). Venetoclax-based combination regimens demonstrate encouraging efficacy in R/R AML, particularly when combined with azacitidine. However, significant myelosuppressive toxicity highlights the need for careful monitoring."

Retrospective data • Review • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

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

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

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

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

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 Malignancies • Leukemia • Oncology • BCL2 • BCL2L1 • MCL1

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 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