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Drugs in Developement

BL-8040 Acute myeloid leukemia & other hematological cancers
BL-7010 Celiac Disease
BL-1040 AMI
BL-5010 Skin lesions
BL-7040 Inflammatory Bowel Disease
BL-8020 Hepatitis C (HCV)

Indication: Acute myeloid leukemia & other hematological cancers
Mode of Action: CXCR4 antagonism
Stage of development: Phase II
Patent Status: Patents granted or pending worldwide.

BL-8040 Overview
BL-8040 is a short peptide that functions as a high-affinity antagonist of CXCR4, a chemokine receptor that is directly involved in tumor progression, angiogenesis, metastasis, and cell survival. CXCR4 is over-expressed in more than 70% of human cancers and its overexpression often correlates with poor prognosis. BL-8040 binds to CXCR4 on tumor cells and blocks its availability to the ligand CXCL12 leading to the release of tumor cells from the protective microenvironment of the bone marrow resulting in heightened sensitivity  to chemo- and bio-based anti-cancer therapy. Upon binding BL-8040 also exhibits a CXCR4-dependent preferential anti-tumor effect against malignant cells inducing their cell death (apoptosis).

BL-8040 is undergoing a Phase II multicenter, open-label study under an IND, designed to evaluate the safety and efficacy profile of repeated escalating doses of BL-8040 in adult subjects with relapsed or refractory acute myeloid leukemia (AML). The primary endpoints of the study are the safety and tolerability of BL-8040. Secondary endpoints include the pharmacokinetic profile of the drug and an efficacy evaluation, as assessed by various parameters, such as the response rate by bone marrow biopsy. The study is also designed in a way that will enable the investigators to evaluate the capabilities of BL-8040 in mobilizing cancer cells from the bone marrow to the peripheral blood, and in inducing their cell death. Up to 50 patients are expected to be enrolled in the study, which is currently being conducted at 8 sites in the U.S. and Israel.

Initial results from this Phase II clinical trial show that BL-8040 in combination with high-dose Cytarabine (Ara-C), is safe at all doses tested to date, and triggers substantial mobilization of cancer cells from the bone marrow to the peripheral blood, thereby increasing the vulnerability of the cells to chemotherapy treatment. In addition, signs of robust apoptosis (cell death) of cancer cells were observed following administration of the higher doses tested to date. The study has not yet reached the highest planned doses, suggesting that a strengthening of BL-8040’s effects may be observed in future dosing cohorts.

In addition, BioLineRx has received the necessary regulatory approvals to commence a Phase I trial for BL-8040, for the mobilization of stem cells from the bone marrow to the peripheral blood circulation.  The study is planned to be conducted in the Hadassah Medical Center in Jerusalem, and the study is expected to commence during the second half of 2014. 

The Phase 1 study will be divided into two parts. Part 1 is a randomized, double-blind, placebo-controlled dose escalation study exploring the safety and tolerability of escalating repeated doses of BL-8040 in healthy volunteers. Secondary objectives include assessment of the efficacy of BL-8040 in mobilizing stem cells as a stand-alone therapy, as well as monitoring the pharmacokinetic profile of the drug. This part will be performed in up to 4 cohorts, with 8 healthy volunteers in each cohort. Part 1 of the study will serve to select the optimal safe and efficacious dose of BL-8040 to be used as a stand-alone therapy in Part 2 of the study. Part 2 is an open-label study designed to assess BL-8040’s stem cell mobilization capacity, as well as the yield of cells collected by leukapheresis. Secondary endpoints of the study include evaluation of the viability and biological activity of cells mobilized by BL-8040 and collected by leukapheresis. This part will be performed in a single cohort of 8 healthy volunteers who will receive the selected dose regimen of BL-8040 based on the data from Part 1.

Pre-Clinical Data
In vitro and in vivo data show that BL-8040 binds to CXCR4 at the low nanomolar range (1-2.5nM) and occupies it for prolonged periods of time (>24h). Characterization of the CXCR4 antagonism action of BL-8040 with comparison to other CXCR4 antagonists revealed that, unlike other compounds from the same class, BL-8040 act as an antagonist and inverse agonist. This activity leads to decreased autonomous signaling of CXCR4 and suggests activity against constitutively active variants.

BL-8040 inhibits the growth of various tumor types including multiple myeloma, non-Hodgkin's lymphoma, leukemia, non-small cell lung carcinoma, neuroblastoma and melanoma. BL-8040 significantly and preferentially stimulated apoptotic cell death of malignant cells (multiple myeloma, non-Hodgkin's lymphoma and leukemias). Significant synergistic and/or additive tumor cell killing activity has been observed in-vitro and in-vivo when tumor cells were treated with BL-8040 together with Rituximab, Bortezomib, Imatinib, Cytarbine and the FLT-3 inhibitor AC-220 (in NHL, MM, CML, AML, AML-FLT3-ITD models; respectively). BL-8040 also mobilizes cancer cells as well as neutrophils and progenitor cells from the bone marrow to the peripheral blood. BL-8040 is efficient, both alone and in combination with the anti-cancer drug Rituximab, in reducing bone marrow metastasis of lymphoma cells and stimulating lymphoma cell death.

Additional Clinical Data
In a Phase I/II, open-label, dose escalation, safety and efficacy clinical trial in 18 multiple myeloma (MM) patients, BL-8040 demonstrated an excellent safety profile and was well tolerated at all doses tested. BL-8040 was administered to MM patients who underwent stem cell mobilization and collection for autologous stem cell transplantation. BL-8040 was highly efficacious as a single administration resulted in a dose dependent elevation of CD34+ cell levels in blood. BL-8040 had a long PD effect, CD34+ cell levels in blood remained high for the duration of measurements (24hrs). BL-8040 also significantly increased stem cells mobilization and in the high doses (0.3-0.9 mg/kg) reduced the number of apheresis sessions required for transplantation to one.

The U.S. Food & Drug Administration (FDA) has granted an Orphan Drug Designation to BL-8040 as a therapeutic for the treatment of AML as well as for stem cell mobilization

BL-8040 is being developed by BioLineRx Ltd. under a worldwide exclusive license from Biokine Therapeutics.

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