Motixafortide (BL-8040)

Motixafortide targets CXCR4, a chemokine receptor and a well validated therapeutic target that is over-expressed in many human cancers including PDAC. CXCR4 plays a key role in tumor growth, invasion, angiogenesis, metastasis and therapeutic resistance, and CXCR4 overexpression has been shown to be correlated with poor prognosis.

Motixafortide is a short synthetic peptide used as a platform for cancer immunotherapy with unique features allowing it to function as a best-in-class antagonist of CXCR4. It shows high-affinity, long receptor occupancy and acts as an inverse agonist.

In a number of clinical and preclinical studies, motixafortide has been shown to affect multiple modes of action in “cold” tumors, including immune cell trafficking, tumor infiltration by immune effector T cells, and reduction in immunosuppressive cells (such as MDSCs) within the tumor niche, turning “cold” tumors, such as pancreatic cancer, “hot” (i.e., sensitizing them to immune checkpoint inhibitors and chemotherapy).

Motixafortide (BL-8040)

Therapeutic areas

Therapeutic areas

Solid tumors
Stem cell mobilization
Hematological malignances

Mode of action

Mode of action

CXCR4 antagonism

Stage of development

Stage of development

Active clinical development with multiple Phase 2 and Phase 3 studies

Main Indications

Stem cell mobilization

Stem cell mobilization

Acute Myeloid Leukemia (AML)

Acute Myeloid Leukemia (AML)

Solid tumors

Solid tumors

Development

Motixafortide - BL-8040 (formerly known as BKT140 and developed by Biokine Therapeutics Ltd.) is a novel selective inhibitor of the CXCR4 chemokine receptor that is currently being developed for several indications including treatment of solid tumors, mobilization of hematopoietic stem cells (HSCs) for autologous transplantations and hematological malignancies.

The immune-mediated effects of motixafortide are being explored in combination with PD-1/PD-L1 immune checkpoint inhibitors (i.e., Merck’s Keytruda® (pembrolizumab) and Regeneron’s Libtayo® (cemiplimab).

A Phase 3 study was successfully carried out to evaluate the efficacy of motixafortide on top of G-CSF for mobilization of HSCs for autologous transplantation in multiple myeloma patients. In a planned interim analysis, the DMC (Data Monitoring Committee) recommended that patient enrollment be ceased immediately at 122 patients, without the need to recruit all 177 patients originally planned for the study based on statistically significant evidence favoring treatment with motixafortide. This study was based on earlier clinical studies demonstrating the superior capability of motixafortide to mobilize HSCs from multiple myeloma patients and from healthy volunteers 1,2.

Motixafortide is also being developed for the treatment of acute myeloid leukemia (AML). Motixafortide demonstrated direct apoptotic effects on AML blasts. These observations were strengthened by findings from a Phase 2a relapsed/refractory (r/r) AML study in which motixafortide in combination with HiDAC significantly improved overall survival of relapsed/refractory AML patients, compared with historical data.

1Peled et al. The High-Affinity CXCR4 Antagonist BKT140 Is Safe and Induces a Robust Mobilization of Human CD34+ Cells in Patients with Multiple Myeloma. Clin Cancer Res 20; 469-79 (2013).

2Abraham et al. Single Dose of the CXCR4 Antagonist BL-8040 Induces Rapid Mobilization for the Collection of Human CD34 Cells in Healthy Volunteers. Clin Cancer Res 23; 1-12 (2017).