Motixafortide (BL-8040)

Motixafortide (formerly known as BL-8040/BKT140) is a novel selective inhibitor of the CXCR4 chemokine receptor. CXCR4, is a well validated therapeutic target that is involved in the mobilization and trafficking of hematopoietic stem cells, immune cells and cancer cells from the bone marrow and the lymph nodes to the peripheral blood. Motixafortide is being developed as a platform for several indications including mobilization of hematopoietic stem cells (HSCs) for autologous transplantations, treatment of solid tumors, and other hematological malignancies.

Motixafortide’s unique features including high-affinity, long receptor occupancy and inverse agonist activity position it as the best-in-class antagonist of CXCR4.

Motixafortide (BL-8040)

Without BL-8040

Limited availability ofimmune cells

Immune cells circulate in periphery and tumor

Poor immune cell infiltration

Fibroblastic cells at tumor edge produce CXCL12, which isolates effector immune cells at the tumor edge

Immunosuppressive TME

CXCL12 secreted by the tumor creates immunosuppression

With BL-8040


Increased numbers of immune cells (NK, B and T cells) circulate in periphery and tumor


Effector immune cells no longer held at tumor edge & traffic into tumor


Blockade of CXCR4 on immune-suppressor cells reduces their attraction & infiltration into the tumor, relieving immunosuppression and possibly acting synergistically with checkpoint inhibitor agents; BL-8040 modulates the TME and the ratio between effector/suppressor cells towards a proinflammatory profile

Solid tumors

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.

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).

Under a clinical collaboration with MSD, known as Merck in the U.S. and Canada, in the field of cancer immunotherapy, initiated in 2016,we conducted a Phase 2a open-label, multi-center study (COMBAT/KEYNOTE-202) in two parts.

Dual combination part of the study (Cohort 1): Cohort 1 of COMBAT focused on proof of mechanism for the combination of motixafortide and KEYTRUDA® (pembrolizumab), MSD’s anti-PD-1 therapy, in patients with metastatic pancreatic adenocarcinoma (treatment lines 2-5). Proof of mechanism was demonstrated in this cohort and data were presented at the 2018 ASCO Gastrointestinal Cancers Symposium (ASCO GI) and ASCO-SITC in January 2018.

Triple combination part of the study (Cohort 2): Based on Cohort 1’s promising data, and to optimize potential efficacy, we expanded the study to include a triple combination arm investigating the safety, tolerability and efficacy of motixafortide, KEYTRUDA and chemotherapy (Cohort 2). Preliminary results from the triple combination were presented at ESMO IO in Geneva in 2019 and final results were announced in December 2020 - both showing substantial improvement across all study endpoints, including OS, PFS, and ORR, in the most challenging PDAC patient population, all diagnosed at stage 4 of the disease. Final data was published in Clinical Cancer Research in 2021 .

Summary of COMBAT Results triple combination (Cohort 2)

Improvement across all efficacy parameters compared to best matching population benchmark

  • Prolonged mOS and mPFS
  • Improved Confirmed ORR
  • Responses and stable disease were generally durable

Favorable safety compared to SOC (Onivyde label) - the triple combination was generally well tolerated, showing also favorable safety by low incidence of neutropenia and infections in treated patients.

Efficacy data is summarized below:

Median Overall Survival (mOS) 6.5 months 4.7 months 1
Median Progression Free survival (mPFS) 4.0 months 2.7-3.1 months 2,3
Confirmed Objective Response Rate (cORR) 13.2% 7.7% 3
Disease Control Rate (DCR) 63.2% 29-52% 2,4

1 Macarulla Mercade et al, Pancreas 2020
2 Petrelli el al Eu J Cancer 2017
3 Onivyde prescribing information
4 Wang Gilliam Eu J Cancer 2019

We are exploring various alternatives to execute a randomized trial to further confirm this promising data before advancing to a phase 3 trial.

Other Studies

In October 2020, an investigator-initiated Phase 2 study, led by Columbia University, was initiated to evaluate motixafortide in combination with the anti-PD-1 LIBTAYO® (cemiplimab) and standard-of-care chemotherapy in first-line metastatic pancreatic ductal adenocarcinoma (PDAC). The study will initially enroll 10-12 PDAC patients and will be expanded to a total of 40 patients following an evaluation of the initial 10-12 patients based on pre-defined criteria.