BTX-A51 / Edgewood Oncology - LARVOL DELTA

BTX-A51 treatment modulates host innate immune responses via NF-κB and β-catenin signaling during Rift Valley fever virus infection in vitro. (PubMed, J Virol) - "BTX-A51 acted concomitantly on the NF-κB and β-catenin pathways to reduce proinflammatory signaling in RVFV-infected cells. Due to many mechanisms of infection being conserved across the Bunyavirales order, these findings also create the potential for BTX-A51 treatment to be tested against different viruses as a tool for pandemic preparedness."

Journal • Preclinical • Hematological Disorders • Infectious Disease • Inflammation • Oncology • Respiratory Diseases

Casein Kinase 1 and CK2 as Therapeutic Targets in Cancer: Molecular Pharmacology, Toxicological Considerations, and Clinical Progress. (PubMed, Mini Rev Med Chem) - "Several CK inhibitors, including CX-4945 (Silmitasertib), CIGB- 300, IC261, D4476, SR-3029, and BTX-A51, have shown promising anticancer activity in various cancer models. Novel dual-therapy approaches targeting CK1/CK2-regulated pathways have further improved the therapeutic specificity and efficacy. CK-targeting therapies are an exciting approach and hold great promise for selectively targeting cancer-causing signaling pathways and advancing cancer precision medicine."

Journal • Oncology

BTX-A51 in Patients With Liposarcoma or CIC-rearranged Sarcoma (clinicaltrials.gov) - P1 | N=24 | Active, not recruiting | Sponsor: Michael Wagner, MD | Trial primary completion date: Jun 2026 ➔ Jan 2027

Trial primary completion date • Liposarcoma • Oncology • Sarcoma • Solid Tumor • MDM2

BTX-A51 in Patients With Liposarcoma or CIC-rearranged Sarcoma (clinicaltrials.gov) - P1 | N=24 | Active, not recruiting | Sponsor: Michael Wagner, MD | Recruiting ➔ Active, not recruiting

Enrollment closed • Liposarcoma • Oncology • Sarcoma • Solid Tumor • MDM2

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

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

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

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

Design, Synthesis, and Structure-Activity Relationship Studies of 7H‑Pyrrolo[2,3‑d]pyrimidine Derivatives as Potent Casein Kinase 1α (CK1α) Inhibitors. (PubMed, ACS Med Chem Lett) - "The structure-activity relationship was systematically summarized, and notably, compound 7a exhibited potent inhibitory activity against CK1α with an IC50 of 10.96 nM, representing a 9-fold increase in potency as compared to BTX-A51, the only CK1α inhibitor currently in clinical development...It also dose-dependently stabilized p53 protein and effectively inhibited the growth of MV4-11 cells. Further optimization of 7a may provide promising CK1α inhibitors with desirable drug-like properties for cancer treatment."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

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, J Hematol Oncol) - P1 | "Although the overall efficacy was modest, this study lays the groundwork for future studies with improved patient selection and combination approaches."

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

BTX-A51 in Patients With Liposarcoma or CIC-rearranged Sarcoma (clinicaltrials.gov) - P1 | N=24 | Recruiting | Sponsor: Michael Wagner, MD | N=12 ➔ 24

Enrollment change • Liposarcoma • Oncology • Sarcoma • Solid Tumor

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

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: [email protected]"

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

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