BTX-A51 holds promise in hematological malignancies and genetically-defined solid tumors, which remains the focus of ongoing clinical programs

Pipeline

Clinical Trials Information

NCT04243785

A Study of BTX-A51 in People With Relapsed or Refractory Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome

Read More →

BTX-A51’s synergistic mechanism of action and Phase 1b data provide a strong rationale for targeting hematologic malignancies and genetically-defined solid tumors, including GATA3-mutant breast cancer

Hematologic Malignancies

Acute Myeloid Leukemia (AML)

Despite advances made in the treatment of AML, the prognosis for this patient population remains poor. A significant unmet need exists for improved first-line regimens as well as for patients with relapsed or refractory (R/R) disease.

The vast majority of leukemia cells express a wild-type (non-mutated) p53 protein. However, the expression of mouse double minute 2 homolog (MDM2) and myeloid cell leukemia-1 (MCL-1) in these cells suppresses apoptosis mediated by p53. MCL-1 overexpression is a major mechanism for resistance to the standard-of-care treatment for AML. Preclinical data in acute myeloid leukemia (AML) demonstrate that BTX-A51 robustly increases p53 levels in leukemia cells and activates apoptosis.1

Furthermore, in a first-in-human study, monotherapy BTX-A51 demonstrated a favorable safety profile and encouraging antileukemic activity in patients with heavily pre-treated R/R AML.2 Notably, several complete remissions with incomplete count recovery (CRi’s) were observed along with a reduction of tumor cells in the blood of most patients. Additionally, a wide therapeutic window was observed, underscoring the potential efficacy and safety of this investigational drug. Preclinical data demonstrate that BTX-A51 works synergistically with both azacitidine and venetoclax (publication in development). As a result of these data, BTX-A51 is being evaluated in combination with azacitidine in a Phase 2a study in R/R AML patients.

Genetically-Defined Solid Tumors

GATA3-mutant Breast Cancer

Approximately 10-15% of estrogen receptor positive / human epidermal growth factor receptor 2 negative (ER+/HER2-) breast cancer patients harbor a GATA binding protein 3 (GATA3) mutation. These patients have a poor response to hormonal therapy and therefore a poor prognosis.3 There is no available therapy that is specifically designed to target GATA3-mutant breast cancer. In addition, despite the importance of CDK4/6 inhibitors as a mainstay in treatment, resistance to CDK4/6 inhibitors remains a significant clinical challenge.

GATA3 mutations are mutually exclusive of p53 mutations which means that patients with GATA3 mutations express wild-type (non-mutated) p53 protein.4 In many cases, these tumors also overexpress MDM2 to suppress p53 function, in order to block tumor cell apoptosis. Through inhibition of MDM2 and stabilization of the p53 protein, BTX-A51 may activate apoptosis of GATA3-mutant breast cancer.5

In addition, CDK7 is a master regulator of cell cycle progression and controls the downstream activation of CDK4/6. By inhibiting CDK7, BTX-A51 is expected to also inhibit phosphorylation of downstream targets including CDK4/6 and Rb. Emerging clinical data in breast cancer with a CDK7 inhibitor supports this hypothesis.6

BTX-A51 is being evaluated in a Phase 2a study in ER+/HER2- breast cancer with and without GATA3 mutations.

Liposarcoma

Dedifferentiated liposarcomas (DDLPS) are rare tumors that form in soft tissues and these patients have a poor prognosis and very limited treatment options.

DDLPS is characterized by MDM2 amplification and wild-type (non-mutated) p53 protein. Through inhibition of MDM2 and stabilization of the p53 protein, BTX-A51 may activate apoptosis of DDLPS. To test this hypothesis, BTX-A51 is being evaluated in an investigator sponsored Phase 1b study in unresectable or metastatic DDLPS.

Expanded Access

Edgewood Oncology does not currently have an approved access program for BTX-A51. We encourage patients to speak with their physicians about treatment options that may be right for them.

References

  1. Minzel W, Venkatachalam A, Fink A, Hung E, Brachya G, Burstain I, et al. Small Molecules Co-targeting CKIα and the Transcriptional Kinases CDK7/9 Control AML in Preclinical Models. Cell. 2018;175(1):171–185.

  2. Ball B, Borthakur G, Stein AS, Chan K, Thai DL, and Stein E. 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. J Clin Oncol 40, 2022 (suppl 16; abstr 7030).

  3. Velimirovic M, Gerratana L, Davis AA, Dai SC, Cheng J, Iafrate AJ, et al. Landscape of GATA3 mutations identified from circulating tumor DNA clinical testing and their impact on disease outcomes in estrogen receptor-positive (ER+) metastatic breast cancers treated with endocrine therapies. J Clin Oncol 39, 2021 (suppl 15; abstr 1065).

  4. Li, A, Schleicher SM, Andre F, and Mitri ZA. Genomic Alteration in Metastatic Breast Cancer and Its Treatment. Am Soc Clin Oncol Educ Book 40, 30-43(2020).

  5. Bianco G, Coto-Llerena M, Gallon J, Kancherla V, Taha-Mehlitz S, Marinucci M, et al. GATA3 and MDM2 are synthetic lethal in estrogen receptor-positive breast cancers. Commun Biol. 2022;5(1):373.

  6. Coombes RC, Howell, S, Lord, SR, Kenny L, Mansi, J, Mitri Z, et al. Dose escalation and expansion cohorts in patients with advanced breast cancer in a Phase I study of the CDK7-inhibitor samuraciclib. Nat Commun 14, 4444 (2023).