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)

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

Microenvironment modifier

Blockade of CXCR4 on immuno-suppressor cells reduces their attraction & infiltration into the tumor, relieving immunosuppression and possibly acting synergistically with checkpoint inhibitor agents

Solid tumors

In January 2016, we entered into a collaboration with MSD, known as Merck in the U.S. and Canada, in the field of cancer immunotherapy. Based on this collaboration, in September 2016 we initiated a Phase 2a study, known as the COMBAT study, focusing on evaluation of the safety and efficacy of motixafortide in combination with KEYTRUDA® (pembrolizumab), MSD’s anti-PD-1 therapy, in patients with metastatic pancreatic adenocarcinoma. Partial results were presented at the 2018 ASCO Gastrointestinal Cancers Symposium (ASCO GI) and ASCO-SITC in January 2018. In July 2018, we announced the expansion of the COMBAT/KEYNOTE-202 study under the collaboration to include a triple combination arm investigating the safety, tolerability and efficacy of motixafortide, KEYTRUDA and chemotherapy. We initiated this arm of the trial in December 2018. Preliminary results from the new triple combination arm of the study were presented at ESMO IO in Geneva (Dec 2019); Final results announced in December 2020 showed substantial improvement across all study endpoints, including OS, PFS, and ORR, in the most challenging PDAC patients. Data are 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

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. 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.