camibirstat (FHD-286) / Foghorn Therap - LARVOL DELTA

BRM/BRG1 is a novel therapeutic target in ZNF384-rearranged mixed phenotype acute leukemia (ASH 2025) - "At the chromatin level, FHD-286 not only results in loss of BRG1 binding but also,interestingly, in loss of ZNF384 binding, suggesting that inhibiton of BRM/BRG1 may specifically affect theZNF384 fusion protein. We have established cell line-derived and patient-derived xenograft models ofZNF384-r MPAL and will confirm our findings in vivo in pre-clinical studies."

Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Targeted Protein Degradation • CCNB1 • CDK1 • CDK6 • EP300 • SMARCA4 • ZNF384

Machine learning-powered integration of global proteomics and ex vivo sensitivity unveils a protein signature predictive of treatment success to AML therapy: Validation in patients treated with FHD-286, a SMARCA2/4 dual inhibitor (ASH 2025) - P1 | "Patients had received a median 3 prior lines of therapy (range 1-7),including venetoclax and hypomethylating agents (100%), high-dose chemotherapy (71%), and stem celltransplant (57%). A clinical trial prospectively assigning patients tospecific treatment arms based on our proteomics signature will launch in 2025. This result highlights theutility of Yatiri Bio's deep learning model to guide AML treatment decisions and improve outcomes andsupports the development of a mass spectrometry-based clinical assay for patient selection in clinicaltrials."

Machine learning • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • SMARCA2 • TP53

Genomic and phenotypic impact of FHD-286–induced inhibition of SMARCA4/2 in patients with relapsed/refractory myeloid malignancies (ASH 2025) - P1 | "FHD-286 monotherapy induced myeloiddifferentiation in patients (pts) with relapsed/refractory (R/R) acute myeloid leukemia (AML) ormyelodysplastic syndrome (MDS), and the addition of decitabine (DAC) produced objective responses.In a multicenter, open-label, Phase 1 dose escalation study (NCT04891757), pts with R/R AML, MDS, orchronic myelomonocytic leukemia received FHD-286 monotherapy or in combination with DAC. FHD-286 induced broad immunophenotypic and transcriptional changes in leukemic blasts, consistentwith decreased stemness and increased myeloid differentiation. In the combination therapy cohort,responders exhibited stronger transcriptional impacts than nonresponders or monotherapy-treated pts.Additional studies will be needed to understand the context in which FHD-286+DAC leads to greaterefficacy, and may support pt enrichment strategies."

Clinical • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • CD34 • ITGAM • KIT • SMARCA4

Preclinical evaluation of SWI/SNF targeting agents in multiple myeloma including t(4; 14) subtypes (ASH 2025) - "AU-24118 log2 IC₅₀ values correlatedwith those of FHD-286 (r=0.62, p=0.0002) and with pomalidomide (r=0.61, p=0.0002), suggesting a sharedbiology. Broad PRISM profiling confirms lineage-specific vulnerability of MM to SWI/SNF inhibition,with in vitro and in vivo validation supporting selective efficacy in high-risk t(4; 14)-positive subtypes. FHD-286, AU-15330, and AU-24118 demonstrated strong in vitro activity, particularly in t(4; 14)-positive HMCLs.This activity was due, in part, to chromatin compaction and decommissioning of lineage and oncogenicenhancers as well as eviction of IKZF1/3 off chromatin. AU-24118 showed high selectivity, with picomolarrange IC₅₀ in sensitive HMCLs."

Preclinical • Hematological Malignancies • Multiple Myeloma • Plasmacytoma • Targeted Protein Degradation • ANXA5 • CRBN • DUSP22 • IKZF1 • IRF4 • NSD2 • POU2AF1 • SMARCA2 • USP22

Notable Efficacy of Co-Treatment with FHD-286, a Dual BRG1/BRM ATP-Ase Inhibitor, and Menin or BET Inhibitor, Decitabine or Venetoclax Against AML with MLL-r or Mutant NPM1 (ASH 2023) - "BRG1 (SMARCA4) and BRM (SMARCA2) are the core ATPase within the multi-protein, ATP-dependent, chromatin remodeling BAF complexes that regulate gene transcription. Finally, co-treatment with FHD-286 and OTX015 or SNDX-5613 (oral gavage) was significantly more effective than each drug alone in reducing the AML burden and overall survival of mice engrafted with a separate PDX model of AML cells with mtNPM1 and FLT3-ITD, without significant toxicity. These findings demonstrate the pre-clinical efficacy of FHD-286-based rational combinations and underscore their promise against AML with MLL1r or mtNPM1."

Clinical • IO biomarker • Acute Myelogenous Leukemia • BCL2 • BRD4 • CASP3 • CD123 • CD33 • CD99 • CDK4 • CDKN1A • CEBPA • CLEC12A • FLT3 • HEXIM1 • IL3RA • ITGAM • MCL1 • MEF2C • MYC • NPM1 • PBX3 • PLK1 • SMARCA2 • SMARCA4

Preliminary Results from a Phase 1 Dose Escalation Study of FHD-286, a Novel BRG1/BRM (SMARCA4/SMARCA2) Inhibitor, Administered As an Oral Monotherapy in Patients with Advanced Hematologic Malignancies (ASH 2023) - P1 | "Enrollment into the single-agent dose escalation phase of the study is complete. Based on nonclinical, translational, and single-agent clinical data, FHD-286 in combination with decitabine or low-dose cytarabine is being evaluated in the combination dose escalation phase of the study."

Clinical • Metastases • Monotherapy • P1 data • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Dental Disorders • Endocrine Disorders • Hematological Malignancies • Hepatology • Leukemia • Myelodysplastic Syndrome • Oncology • Stomatitis • Transplantation • Xerostomia • KMT2A • MECOM • SMARCA2 • SMARCA4

Identifying 'Druggable' Targets and Preclinically Overcoming Non-Genetic/Adaptive Resistance to Menin Inhibitors in AML with MLL1r or mtNPM1 (ASH 2024) - "These MITR cells exhibited cross-resistance to other MIs, including ziftomenib and DS1594b...Notably, in a luciferized MLL1r MITR AML PDX model, compared to treatment with each agent alone, co-treatment with FHD-286 and SNDX-5613 or OTX015 for 8-weeks yielded significantly superior survival of the NSG mice (p < 0.05). These findings demonstrate that co-treatment with FHD-286 overcomes in vitro and in vivo MI-resistance, while significantly improving in vivo efficacy of BETi in the cell-line xenograft and PDX models of MITR AML cells. They also show that combinations of epigenetically targeted agents may be effective in MI-sensitive or -resistant AML with MLL1r or mtNPM1."

IO biomarker • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • BRD4 • CDK6 • CLEC12A • CREBBP • EP300 • FLT3 • HOXA9 • IGF2BP2 • MEF2C • MEIS1 • NPM1 • PBX3 • SMARCA4

Leveraging SMARCA4 Dependency of Mantle Cell Lymphomas to Overcome BTK Inhibitor Resistance (ASH 2024) - "Covalent Bruton tyrosine kinase inhibitors (cBTKi), such as ibrutinib, zanubrutinib, and acalabrutinib, are mainstays of treatment relapsed MCL, and their use is emerging in the front-line setting...We found that pharmacological inhibition of SMARCA4 by FHD-286, an allosteric SMARCA2/4 ATPase inhibitor, which is a clinical stage asset owned by Foghorn Therapeutics and currently under investigation in AML in combination with decitabine and cytarabine, potently induced cytotoxicity in MCL cells at low nanomolar ranges...Consistently, combining FHD-286 with pirtobrutinib led to a substantial synergistic cytotoxic effect in MCL cell lines and primary MCL cells. Altogether, our findings suggest that SMARCA4 plays a tumor maintenance role in MCL. Targeting SMARCA4 can be further exploited as a therapeutic strategy in cBTKi-resistant MCL and may be even more effective in SMARCA4-mutated MCL."

Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CARD11 • CD79A • NR4A1 • RAC2 • SMARCA2 • SMARCA4 • SYK • TP53

Targeting the SWI/SNF Chromatin Remodeling Complex Subunit SMARCA4 in ALL (ASH 2024) - "Validating our hypothesis, pharmacologic SMARCA4 inhibition using two recently developed inhibitors (BRM014 and FHD-286) showed that Ph-like B-ALL was significantly more sensitive to SMARCA4 inhibition compared to KMT2A-R ALL...Furthermore, we demonstrate a direct correlation between high SMARCA4 expression and poor patient outcomes, as well as a clear dependency of Ph-like B-ALL on SMARCA4. Based on our data, applying a SMARCA4 inhibitor-based therapy may specifically benefit patients with Ph-like B-ALL."

Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • T Acute Lymphoblastic Leukemia • CD34 • KMT2A • SMARCA4

Discovery of novel SMARCA2 small molecule inhibitors with best-in-class potency and selectivity for the treatment of SMARCA4-mutant cancers (AACR-NCI-EORTC 2025) - "Multiple Phase 1 clinical trials exploring the SMARCA4/2 dual inhibitor FHD-286 in different indications were discontinued, flagging safety concerns...Here, we identified unique SMARCA2 selective inhibitor series with a best-in-class potency and selectivity profile. Thorough characterization and optimization efforts are ongoing to identify clinical development candidates with the ultimate goal of achieving greater efficacy along with enhanced safety, providing meaningful benefits to patients diagnosed with SMARCA4 deficient cancer."

IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • KRT80 • SMARCA2 • SMARCA4

Pan-RAS Inhibitor RMC-6236 Suppresses Myeloma Growth and Shows Enhanced Efficacy with SWI/SNF Inhibition (IMS 2025) - " We evaluated the anti-myeloma activity of novel pan-RAS inhibitors, RMC-6236 and RMC-7977, across a broad panel of over 50 MM cell lines. Our findings demonstrate that RMC-6236 shows broad and potent anti-tumor activity in RAS- and FGFR3-driven MM by suppressing MAPK and mTORC1 signaling. Its therapeutic efficacy is significantly enhanced in combination with SWI/SNF inhibitor FHD-286. These findings represent a promising therapeutic strategy that supports further clinical investigation in RAS-dependent MM."

Clinical • Hematological Malignancies • Multiple Myeloma • EIF4EBP1 • FGFR3 • KRAS • MAPK1 • NRAS • RPS6 • RPS6KA3 • SLC3A2

Superior Preclinical Efficacy of BRG1/BRM Inhibitor Combined With BET Inhibitor or Decitabine Against MECOM-rearranged (MECOM-r) Acute Myeloid Leukemia (AML) (SOHO 2025) - "Taken together, these findings highlight the promise of FHD-286– based rational combinations, especially with BETi, navitoclax, or decitabine, in exerting significant anti-AML efficacy against cellular models of MECOM-r AML."

Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2L1 • CD93 • CDK4 • GATA2 • ITGAM • KIT • MECOM • MYC • PLK1 • SMARCA4

Selective Sensitivity of Ph-like B-ALL to BRG1 Inhibition Reveals a Novel Targeted Therapy Strategy. (PubMed, bioRxiv) - "The pharmacologic inhibition of BRG1 using two selective inhibitors, BRM014 and FHD-286, revealed marked sensitivity in Ph-like B-ALL cell lines, whereas KMT2A -R B-ALL was resistant...These results support the advancement of BRG1-directed strategies as a viable treatment approach for patients with Ph-like B-ALL, with the potential to improve outcomes in this high-risk population. Higher levels of BRG1 correlate to poor clinical outcomes in Ph-like but KMT2A -R B-ALL Inhibition of BRG1 induces cell cycle arrest in Ph-like cells in vitro and extends the survival of mice in pre-clinical in vivo studies."

Journal • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • CCND3 • CDK4 • CDK6 • CDKN1B • E2F1 • KMT2A • SMARCA4

PRELIMINARY SAFETY, PHARMACOKINETIC, AND CLINICAL ACTIVITY RESULTS WITH FHD-286, A BRG1/BRM INHIBITOR, PLUS DECITABINE IN A PHASE 1 STUDY IN PATIENTS WITH RELAPSED OR REFRACTORY MYELOID MALIGNANCIES (EHA 2025) - P1 | "The median number of prior therapies was 3 (range 1-9), including hypomethylating agents (93%), venetoclax (91%), cytarabine-based regimens (64%), and hematopoietic stem cell transplant (27%). In summary, preliminary data suggest FHD-286+DAC is better tolerated among pts not receiving strong CYP3A4 inhibitors as they increase FHD-286 exposure. FHD-286+DAC is clinically active in pts with R/R AML or MDS."

Clinical • P1 data • PK/PD data • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Chronic Myelomonocytic Leukemia • CNS Disorders • Diabetes • Fatigue • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Hepatology • Infectious Disease • Leukemia • Myelodysplastic Syndrome • Neutropenia • Oncology • Pneumonia • Pulmonary Disease • Respiratory Diseases • Thrombocytopenia • CD34 • ITGAM • SMARCA4

IN VIVO EPIGENETIC CRISPR SCREENING IDENTIFIES SMARCA4 AS A CRITICAL TARGET FOR AUTOIMMUNE BONE MARROW FAILURE (EHA 2025) - "In vitro drug experiments using SWI/SNF small molecule inhibitors FHD-286 and FHT-1015 significantly decreased the cytotoxicity of CD8+ T cells without impairing long-term T cell expansion... This study successfully identified Smarca4 as a critical target for autoimmune bone marrow failure through in vivo epigenetic CRISPR-Cas9 screening, providing novel therapeutic targets and strategies for AA management."

Preclinical • Anemia • Aplastic Anemia • Hematological Disorders • Immunology • CD8 • JAK2 • SMARCA4

Superior preclinical efficacy of BRG1/BRM inhibitor combined with BET inhibitor or decitabine against MECOM-rearranged AML (AACR 2025) - "Finally, as compared to treatment with each drug alone or vehicle control, in PD xenograft (PDX) models of AML cells with MECOM-r, co-treatment with FHD-286 and decitabine or OTX015 significantly reduced AML burden and improved overall survival of the NSG mice, without inducing significant toxicity. Taken together, these findings highlight the promise of FHD-286 treatment alone and in rational combinations in exerting significant anti-AML efficacy against cellular models of AML, especially those with MECOM-r and EVI1 overexpression."

Preclinical • Acute Myelogenous Leukemia • Oncology • CD93 • CDK4 • GATA2 • ITGAM • KIT • MECOM • MYC • PLK1 • SMARCA2 • SMARCA4

MYC-mediated resistance to immune activation by SWI/SNF mutation or chemical inhibition (AACR 2025) - "SWI/SNF ATPase inhibitors (FHD-286, BRD98, and BRM014) and degraders (ACBI1) similarly induce ISGs through a cGAS/STING-dependent mechanism. This study highlights the suppressive effect of MYC overexpression on IFN-I responses in ARID1A-deficient cancers and suggests a potential link to therapeutic resistance in MYC-high tumors. While the precise molecular mechanisms remain to be fully elucidated, these findings provide a foundation for future studies aimed at understanding the interplay between oncogenic drivers and immune signaling pathways, with implications for developing more effective therapeutic strategies."

Oncology • ARID1A • CD8 • CTNNB1 • KRAS • MYC • STING

A Phase 1 Study of FHD-286, a Dual BRG1/BRM (SMARCA4/SMARCA2) Inhibitor, in Patients With Advanced Myeloid Malignancies. (PubMed, Clin Cancer Res) - P1 | "DS was the most frequent serious TRAE. While antileukemic activity was observed, no objective responses were achieved and disease progression frequently occurred within 1-2 treatment cycles. Blast reductions were reported across cytogenetic and mutational profiles, coupled with myeloid differentiation via BRG1/BRM inhibition. This novel mechanism warrants further investigation of FHD-286 in combination with other agents in myeloid malignancies."

Journal • P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Hepatology • Leukemia • Myelodysplastic Syndrome • Oncology • Xerostomia • SMARCA2 • SMARCA4

FHD-286-C-002: FHD-286 as Monotherapy or Combination Therapy in Subjects With Advanced Hematologic Malignancies (clinicaltrials.gov) - P1 | N=144 | Active, not recruiting | Sponsor: Foghorn Therapeutics Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Superior preclinical efficacy of co-treatment with BRG1/BRM and FLT3 inhibitor against AML cells with FLT3 mutations. (PubMed, Blood Cancer J) - "This efficacy is associated with the induction of gene-expression perturbations responsible for growth inhibition, differentiation, as well as a reduced AML-initiating potential of the AML cells. Additionally, co-treatment with FHD-286 and FLT3i exerts superior pre-clinical efficacy against AML cells and patient-derived (PD) xenograft (PDX) models of AML with FLT3 mutations."

Journal • Preclinical • Acute Myelogenous Leukemia • FLT3 • SMARCA2 • SMARCA4

Epigenetic control of tumor associated macrophages – targeting the BAF nucleosome remodeling complex (LCC 2025) - "Subcutaneous growth of MC38 adenocarcinoma was substantially slowed in mice treated with BAF inhibitors (FHD-286 or BRM014) and anti-PD-L1 compared to mice treated with PD-L1 alone...Using depleting and blocking antibodies respectively, we established the tumor growth phenotype was dependent on CD8+ T cells, and partly dependent on CD86, highlighting the role of TAM:CD8+ T cell cross talk in promoting an anti-tumor immune response. Collectively, we discovered the BAF complex is a regulator of tumor-associated macrophages and identified a molecular and cellular mechanism through which myeloid-specific ARID1A-loss boosts anti-tumor immunity."

Epigenetic controller • IO biomarker • Oncology • ARID1A • CD8 • CD86 • ITGAX • MRC1

NRF2 induces cell plasticity during liver tumour initiation (LCC 2025) - "Finally, we have shown that NRF2-driven transdifferentiation is inhibited by FHD-286, a selective inhibitor of BRG1/BRM within the SWI/SNF complex. Overall, our study reveals a novel role for NRF2 in the regulation of cell plasticity during liver tumourigenesis and identifies FHD-286 as a promising therapy for NRF2-driven liver cancers."

Biliary Cancer • Cholangiocarcinoma • Hepatology • Liver Cancer • Oncology • Solid Tumor • NFE2L2 • SMARCA4

Discovery of FHD-286, a First-in-Class, Orally Bioavailable, Allosteric Dual Inhibitor of the Brahma Homologue (BRM) and Brahma-Related Gene 1 (BRG1) ATPase Activity for the Treatment of SWItch/Sucrose Non-Fermentable (SWI/SNF) Dependent Cancers. (PubMed, J Med Chem) - "Herein, we report the discovery of compound 1 (FHD-286) as a potent allosteric inhibitor of the dual ATPase subunits from a high-throughput screening hit with a BRM IC50 of ∼27 μM. FHD-286 is an orally bioavailable compound with antitumor activity in mouse xenograft models of uveal melanoma and acute myeloid leukemia and is being evaluated in Phase 1 clinical trials."

Journal • Acute Myelogenous Leukemia • CNS Disorders • Eye Cancer • Hematological Malignancies • Leukemia • Melanoma • Oncology • Solid Tumor • Uveal Melanoma • SMARCA2 • SMARCA4

Foghorn Therapeutics Provides Update on FHD-286 Clinical Development Program and Strategic Priorities (GlobeNewswire) - "Foghorn Therapeutics Inc...announced today that it has made the decision to discontinue the independent development of FHD-286 in combination with decitabine in patients with relapsed and/or refractory acute myeloid leukemia (AML)....The Company will prioritize its proprietary pipeline and Lilly collaboration programs, including the clinical-stage selective SMARCA2 (BRM) inhibitor FHD-909 (LY4050784)....In the Phase 1 dose escalation trial of FHD-286 in combination with decitabine in relapsed and/or refractory AML, objective clinical responses were observed by standard response criteria. However, the observed response rate did not meet the Company’s threshold to continue development by Foghorn alone. Foghorn expects to report the results at a medical conference in 2025."

Discontinued • P1 data • Pipeline update • Acute Myelogenous Leukemia

Foghorn Therapeutics Provides Third Quarter 2024 Financial and Corporate Update (GlobeNewswire) - "Program Overview and Upcoming Milestones: (i) FHD-286:...AML Phase 1 trial:...Topline safety, tolerability, initial efficacy, and PK/PD data expected by year-end 2024....(ii) Selective CBP degrader program:...Investigational New Drug (IND)-enabling studies are on track to initiate by the fourth quarter of 2024."

P1 data • Preclinical • Acute Myelogenous Leukemia • Solid Tumor