BTX-A51 / Edgewood Oncology - LARVOL DELTA

Edgewood Oncology Announces New Efficacy Data From Investigator-Sponsored Study of BTX-A51 in Preclinical Models of Liposarcoma (Businesswire) - "The presentation...highlights new mechanistic and efficacy data in patient-derived cell lines and xenograft models. One of the most significant findings from the presentation is that CK1α is an essential gene for the growth of liposarcomas based on genome-scale RNAi perturbation analysis. The study also used RNAi knockdown and targeted small molecules to confirm that inhibition of CK1α, CDK7, and CDK9 has synergistic impacts on LPS cell survival. As a single agent, BTX-A51 blocked MDM2 and induced P53 expression, stimulating potent apoptosis in LPS models while significantly inhibiting tumor growth in patient-derived xenografts at well tolerated dose levels."

Preclinical • Liposarcoma

Preclinical efficacy of the CK1 alpha/CDK7/CDK9 inhibitor BTX-A51 in CIC-rearranged sarcoma (AACR 2025) - "Treatment with BTX-A51 induces caspase 3-mediated apoptotic cell death through combined stabilization of p53 and inactivation of oncogenic drivers. Together with ongoing in vivo studies, our data will provide a compelling preclinical rationale for the evaluation of BTX-A51 in patients with CIC-rearranged sarcoma."

Preclinical • Burkitt Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Oncology • Sarcoma • Solid Tumor • CASP3 • CASP7 • CDK7 • CHEK2 • CSNK1A1 • MCL1 • MYC • RB1

First-in-class casein kinase 1 alpha inhibitors for overcoming treatment related resistance in AML and pancreatic cancer (AACR 2025) - "Targeting of CK1 kinases in resistant cancers is a novel concept - several preclinical studies showed the potential of CK1δ/ε targeting to overcome/avoid resistance - e.g. to potentiate Gemcitabine efficacy in pancreatic cancer, or Enzalutamide in prostate cancer...These inhibitors exhibited sub-nanomolar activity against CK1α, translating into superior on-target activity in cells compared to the previously reported BTX-A51 compound... Our findings highlight the therapeutic potential of selective CK1α inhibition for treating Venetoclax-resistant AML. Furthermore, the data suggest that dual targeting of CK1α/δ/ε may help overcome resistance in specific cancers, such as Gemcitabine-resistant pancreatic cancer and melanoma.This project is co-financed with state support from the Technology Agency of the Czech Republic within the TN Program for the Support of Applied Research, Experimental Development, and Innovation of the National Competence Center (2018 - 2028); project..."

IO biomarker • Acute Myelogenous Leukemia • Genito-urinary Cancer • Hematological Malignancies • Leukemia • Melanoma • Oncology • Pancreatic Cancer • Prostate Cancer • Solid Tumor

Therapeutic potential of combined targeting of casein kinase 1 alpha (CK1 alpha) and CDK7/9 with the inhibitor BTX-A51 in human liposarcomas (AACR 2025) - P1 | "These data have confirmed CK1α, CDK9, and CDK7 as essential for LPS cells and indicate that BTX-A51 has potent preclinical efficacy in LPS, through combined inhibition of CK1α, CDK9, and CDK7. Our data form the scientific foundation for our ongoing pilot clinical trial evaluating BTX-A51 in patients with advanced WDLPS or DDLPS (NCT06414434)."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Liposarcoma • Oncology • Sarcoma • Solid Tumor • BBC3 • CDK4 • CDK7 • CSNK1A1 • MDM2 • TP53

An Open Label Study of BTX-A51 in Patients with ER+/HER2- GATA3 Mutant and Wild Type Metastatic Breast Cancer (SABCS 2024) - P1 | "The study is currently recruiting patients with ER+/HER2- negative metastatic breast cancer (NCT04872166). Contact information for people with a specific interest in the trial: zung@edgewoodonc.com"

Clinical • Metastases • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CDK7 • CDK9 • ER • GATA3 • HER-2 • MCL1 • MDM2 • TP53

Phase I First-in-Human Dose Escalation Study of the oral Casein Kinase 1α and Cyclin Dependent Kinase 7/9 inhibitor BTX-A51 in advanced MDS and AML. (PubMed, Res Sq) - "Ex-vivo studies confirmed higher efficacy of BTX-A51 on RUNX1 -mutated myeloblasts and demonstrate synergy with azacitidine and venetoclax. Although the overall efficacy was modest, this study lays the groundwork for future studies with improved patient selection and combination approaches."

Journal • Metastases • P1 data • Acute Myelogenous Leukemia • Myelodysplastic Syndrome • CDK7 • RUNX1

A PILOT STUDY OF BTX-A51 IN PATIENTS WITH METASTATIC AND/OR RECURRENT LIPOSARCOMAS CHARACTERIZED BY MDM2 AMPLIFICATIONS (CTOS 2024) - P1 | "N/A Trial in Progress."

Clinical • Metastases • Liposarcoma • Oncology • Sarcoma • Solid Tumor • CDK4 • CDK7 • CDK9 • CDKN1A • GDF15 • MCL1 • MDM2 • TP53

Novel casein kinase 1 alpha inhibitors for the treatment of resistant AML and solid tumors (EORTC-NCI-AACR 2024) - "Targeting of CK1 kinases in resistant cancers is a novel concept – several preclinical studies have demonstrated the potential of CK1δ/ε inhibition to overcome/avoid resistance – e.g. to potentiate the efficacy of Gemcitabine in pancreatic cancer, efficacy of CDK4/6 inhibitors in breast cancer or Enzalutamide in prostate cancer...These newly discovered compounds showed improved on-target CK1α activity, and the in vitro and in vivo efficacy and safety that were superior to the previously published BTX-A51 competitor compound, demonstrating for the first time the potential of selective CK1α inhibition... Our data confirm the attractiveness of the concept based on selective pharmacological inhibition of the kinase CK1α, in particular for the treatment of Venetoclax-resistant AML and Gemcitabine-resistant pancreatic cancer. The project was supported by National Institute for Cancer Research (Programme EXCELES: LX22NPO5102), and CasInvent Pharma."

IO biomarker • Acute Myelogenous Leukemia • Breast Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Oncology • Pancreatic Cancer • Prostate Cancer • Solid Tumor

BTX-A51 in Patients with Liposarcoma (clinicaltrials.gov) - P1 | N=12 | Recruiting | Sponsor: Michael Wagner, MD | Not yet recruiting ➔ Recruiting

Enrollment open • Liposarcoma • Oncology • Sarcoma • Solid Tumor

Design, Synthesis, and Biological Evaluation of 2,4-Diaminopyrimidine Derivatives as Potent CDK7 Inhibitors. (PubMed, ACS Med Chem Lett) - "Starting from BTX-A51, a CK1α inhibitor that also targets CDK7 and CDK9, we designed and synthesized a series of 2,4-diaminopyrimidine derivatives as potent CDK7 inhibitors...Compound 22 effectively inhibited the phosphorylation of RNA polymerase II and CDK2 and resulted in G1/S phase cell cycle arrest and apoptosis in MV4-11 cells. It appears to be a promising lead compound for the development of a CDK7 inhibitor for cancer therapy."

Journal • Oncology • CDK2 • CDK9

BTX-A51 in Patients With Liposarcoma (clinicaltrials.gov) - P1 | N=12 | Not yet recruiting | Sponsor: Michael Wagner

Metastases • New P1 trial • Liposarcoma • Oncology • Sarcoma • Solid Tumor

Edgewood Oncology Announces First Patients Dosed in Phase 2a Study of BTX-A51 in Genetically-Defined Breast Cancer (Businesswire) - "Edgewood Oncology...announced that the first two patients with metastatic breast cancer were treated with BTX-A51, a multi-specific kinase inhibitor of casein kinase 1 alpha (CK1α) and cyclin-dependent kinases 7 and 9 (CDK7 and CDK9), that synergistically targets master regulators of cancer....The ongoing Phase 2a trial of BTX-A51 is a multicenter, open-label, nonrandomized, multiple dose study evaluating the safety, toxicity, pharmacokinetics and preliminary efficacy of BTX-A51 in patients with ER+/HER2- metastatic breast cancer with and without GATA3 mutations."

Trial status • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Solid Tumor

Targeting casein kinase 1 alpha (CK1 alpha) and transcriptional CDKs (CDK7/9) in human liposarcomas (AACR 2024) - "Our results suggest that BTX-A51 has potent preclinical efficacy in treating LPS, primarily through inhibition of CK1α and CDK9. Future mechanistic studies will further clarify mechanisms of BTX-A51-mediated apoptosis, as well as the contribution of CDK7 inhibition to anti-tumor activity. Our data justify a planned clinical trial that will evaluate the efficacy of BTX-A51 in patients with advanced WDLPS or DDLPS."

Liposarcoma • Oncology • Sarcoma • Solid Tumor • CDK4 • CDK7 • CSNK1A1 • MCL1 • MDM2

Edgewood Oncology Announces Positive Efficacy Data From Investigator-Sponsored Study of BTX-A51 in Preclinical Models of Liposarcoma (Businesswire) - "BTX-A51 is a first-in-class, small molecule, multi-selective kinase inhibitor of casein kinase 1 alpha (CK1α) as well as the transcriptional regulators cyclin-dependent kinases 7 and 9 (CDK7 and CDK9) that synergistically co-targets master regulators of cancer to promote programmed cell death, or apoptosis....The data demonstrate that BTX-A51 has preclinical efficacy in treating patient-derived LPS in cell lines and human xenograft models and provides insight into the synergy gained by inhibiting both CK1α and CDK9."

Preclinical • Liposarcoma • Oncology • Solid Tumor

Edgewood Oncology Emerges From Stealth with $20 Million in Series A Financing to Advance BTX-A51 in Patients with Hematologic Malignancies and Genetically-Defined Solid Tumors (Businesswire) - "Edgewood Oncology...emerged from stealth with $20 million in Series A financing backed by Alta Partners to advance the clinical development of BTX-A51 in acute myeloid leukemia (AML) and a precision medicine approach to breast cancer....Edgewood initiated a study of BTX-A51 in combination with azacitidine in R/R AML patients in December 2023. The aim of this Phase 2, multicenter, open-label study is to evaluate the response rate (CR, CRh and CRi) as well as the safety, toxicity and pharmacokinetics of BTX-A51 in combination with azacitidine in patients with R/R AML....Edgewood is expecting to initiate a Phase 2 study in breast cancer patients with a genetically-defined profile in Q2 2024."

Financing • New P2a trial • Acute Myelogenous Leukemia • Breast Cancer

BTX-A51-002: A Study of BTX-A51 in People With Advanced Solid Tumor or Non-Hodgkin Lymphoma (clinicaltrials.gov) - P1 | N=116 | Recruiting | Sponsor: Edgewood Oncology Inc. | Trial completion date: May 2025 ➔ May 2027 | Trial primary completion date: May 2024 ➔ May 2026

Metastases • Trial completion date • Trial primary completion date • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

A Study of BTX-A51 in People With Relapsed or Refractory Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome (clinicaltrials.gov) - P1 | N=80 | Recruiting | Sponsor: Edgewood Oncology Inc. | N=50 ➔ 80 | Trial completion date: Mar 2025 ➔ Mar 2027 | Trial primary completion date: Mar 2023 ➔ Mar 2026

Combination therapy • Enrollment change • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Safety and efficacy of casein kinase 1α and cyclin dependent kinase 7/9 inhibition in patients with relapsed or refractory AML: A first-in-human study of BTX-A51. (ASCO 2022) - P1 | "Baseline characteristics include median age 75 years, median number of prior therapies 3, 97% received prior treatment with venetoclax, 97% had prior HMA, and 43% had prior induction failure. In this FIH study, monotherapy BTX-A51 demonstrated an acceptable safety profile and promising antileukemic activity in pts with heavily pretreated R/R AML. The 21 mg dose administered 3x/wk for 4 wk was identified as the RP2D. RUNX1 mutations were enriched among responders and pts attaining > 50% BM blast reduction."

Clinical • P1 data • Acute Myelogenous Leukemia • Anemia • Febrile Neutropenia • Hematological Disorders • Hepatology • Hypotension • Liver Failure • Neutropenia • CDK7 • MCL1 • RUNX1

SAFETY AND EFFICACY OF CASEIN KINASE 1Α AND CYCLIN DEPENDENT KINASE 7/9 INHIBITION IN PATIENTS WITH RELAPSED OR REFRACTORY AML: A PHASE 1, FIRST-IN-HUMAN STUDY OF BTX-A51 (EHA 2022) - "Baseline characteristics include median age 75 years, median number of prior therapies 3, 97% received prior treatment with venetoclax, 97% had prior HMA, and 43% had prior induction failure. The 21 mg dose administered 3x/wk for 4 wk was identified as the RP2D. RUNX1 mutations were enriched among responders and pts attaining >50% BM blast reduction."

Clinical • P1 data • Acute Myelogenous Leukemia • Anemia • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Hepatology • Hypotension • Leukemia • Liver Failure • Myelodysplastic Syndrome • Neutropenia • Oncology • CDK7 • CDK9 • MCL1 • MDM2 • RUNX1

[VIRTUAL] Trial in Progress: A Phase I Trial of BTX-A51 in Patients with Relapsed or Refractory AML or High-Risk MDS (ASH 2020) - P1 | "The antiapoptotic gene Mcl1 is overexpressed in AML cell lines resistant to venetoclax...For the first cycle, patients will receive tumor lysis syndrome prophylaxis with allopurinol and intravenous fluids and be closely monitored...Key exclusion criteria are receipt of cancer chemotherapy (other than hydroxyurea) within 2 weeks prior to the start of study drug, transplantation within 3 months prior to screening, active graft-versus-host disease requiring systemic immunosuppressive medications, and a white blood cell count > 20 × 109/L...Correlative objectives include determining the changes in SEs and SE-driven expression of antiapoptotic genes by chromatin immunoprecipitation and RNA-sequencing. Recruitment is ongoing and this trial is registered on clinicaltrials.gov: NCT04243785"

Clinical • P1 data • Acute Myelogenous Leukemia • Graft versus Host Disease • Hematological Malignancies • Immunology • Leukemia • Myelodysplastic Syndrome • Oncology • Transplantation • CDK7 • MCL1 • MDM2 • TP53

BTX-A51-002: A Study of BTX-A51 in People With Advanced Solid Tumor or Non-Hodgkin Lymphoma (clinicaltrials.gov) - P1; N=116; Recruiting; Sponsor: BioTheryX, Inc.; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

BioTheryX Announces First Patient Dosed with BTX-A51 in Phase 1 Clinical Trial in Patients with Advanced Solid Tumors (PRNewswire) - “BioTheryX, Inc…announced the dosing of the first patient in a dose escalation clinical trial of BTX-A51 in advanced solid tumor malignancies that are dependent upon MYC, one of the most commonly known oncogenic drivers.”

Trial status • Oncology • Solid Tumor

BTX-A51 for R/R AML or high-risk MDS (YouTube) - "Eytan Stein, MD...discusses the details of a Phase I trial (NCT04243785) of BTX-A51 safety for use in relapsed/refractory (R/R) acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS). BTX-A51 inhibits CK1a;, CDK7 and CDK9, to increase p53 protein levels and decrease key oncogene transcription (Myc and Mcl1), resulting in selective apoptosis of cancer cells. The open-label study will determine the maximum tolerated dose in a dose-escalation phase, followed by a dose-expansion phase to identify dose-limiting toxicities and evidence of efficacy."

Interview • Video

BioTheryX Announces $92M Series E Financing to Accelerate Development of Targeted Protein Degradation Pipeline and Technology Platform in Oncology (PRNewswire) - "BioTheryX, Inc...announced a $92 million Series E financing led by Farallon Capital Management...The proceeds from the financing will be used to advance...BTX-1188, toward clinical development. BioTheryX also plans to advance the clinical development of its lead multi-kinase inhibitor, BTX-A51, for the treatment of acute myeloid leukemia, myelodysplastic syndromes and solid tumors....'With this financing, we are well positioned to execute our plans to bring our first molecular glue program BTX-1188 into the clinic by the end of 2021, expand our platform of molecular glues, PROTACs and monovalent degraders and progress our lead program BTX-A51 through Phase 1.'"

Clinical • Financing • Acute Myelogenous Leukemia • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • Solid Tumor

A Study of BTX-A51 in People With Advanced Solid Tumor or Non-Hodgkin Lymphoma (clinicaltrials.gov) - P1; N=116; Not yet recruiting; Sponsor: BioTheryX, Inc.

Clinical • New P1 trial • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor