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Drugs in Developement

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

Indication: Acute myeloid leukemia and other hematological cancers
Mode of Action: CXCR4 antagonism
Stage of development: Phase 2
Patent Status: Patents granted or pending worldwide.

BL-8040 Overview
BL-8040 is a short synthetic 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).
The main development program for BL-8040 relates to acute myeloid leukemia (AML). BL-8040 is currently undergoing a Phase 2a clinical trial for the treatment of relapsed or refractory AML. Positive data from the dose-escalation stage of the study, which was recently presented at the 2014 ASH (American Society of Hematology) Conference, has shown substantial mobilization of AML cancer cells from the bone marrow to the peripheral blood and robust apoptosis of these cells, as well as an excellent safety and tolerability profile. The dose-escalation stage of the study is expected to be completed in early 2015, while the full study results from both the dose- escalation and dose-expansion stages of the study are expected in the second half of 2015.
Targeting a second AML treatment line, a Phase 2b trial has recently commenced for BL-8040 as a consolidation treatment for AML patients who have responded to standard induction treatment. The trial is being conducted in collaboration with the German Study Alliance Leukemia Group. The trial aims to improve the response of AML patients to the second stage of AML treatment, termed consolidation therapy, by eliminating the minimal residual disease left in the bone marrow after the first stage of the standard treatment regimen, known as induction therapy.
BL-8040 will also target a third population of AML patients, and is scheduled to commence a Phase 2 trial, for the treatment of AML patients with the FLT3-ITD mutation in the near future. AML patients with the FLT3-ITD mutation exhibit poor response and high relapse rates to chemotherapy, and only transient response rates to FLT3 inhibitors. Preclinical data (presented at the European Hematology Association Conference in June 2014) show that by inhibiting the CXCR4 receptor, BL-8040 enhances the effect of FLT3 inhibition in killing FLT3-mutated leukemic cells. The Phase 2 trial, which will be conducted in collaboration with the MD Anderson Cancer Center, is aimed at improving the response of FLT3-ITD mutated AML patients to treatment with  a targeted FLT3 inhibitor. Patients testing positive for the FLT3-ITD mutation will receive several treatment cycles. The safety of the combination treatment, as well as the response rate to the treatment and the duration of the response will be evaluated.    
A second clinical development program planned for BL-8040 designates the drug for the treatment of hypoplastic myelodysplastic syndrome (hMDS) and aplastic anemia (AA). hMDS is a subtype of myelodysplastic syndrome, a collection of myeloid malignancies characterized by one or more peripheral blood cytopenias (deficiency in the number of blood cells). AA is a disease in which the bone marrow and the blood stem cells that reside in the marrow are depleted, resulting in a deficiency of all three blood cell types: red blood cells, white blood cells, and platelets. Both AA and hMDS are characterized by a T cell-driven autoimmune attack on the bone marrow that results in depletion of hematopoietic precursors, leading to anemia and low white blood cell counts. In this regard, high CXCR4 expression on pathogenic T cells has been suggested to facilitate infiltration of the bone marrow. BL-8040, a CXCR4 antagonist, is expected to inhibit migration of pathogenic T cells to the bone marrow, thereby mitigating the severe depletion of hematopoietic stem and progenitor cells. Treatment for these bone-marrow failure conditions consists of immunosuppressive therapy with hATG and cyclosporine; however, a sizable fraction of patients do not respond to this therapy. Preclinical data suggest that BL-8040 promotes stem cell proliferation and differentiation thereby allowing recovery of hematopoiesis (formation and development of blood cells). The data show that treatment of mice with BL-8040 contributes to bone marrow regeneration, and increases the number of progenitor cells and the mature components of the blood and immune systems. BioLineRx is planning to commence a Phase 2 trial, to assess the addition of BL-8040 to the standard immunosuppressive therapy in patients with hMDS or AA, in the fourth quarter of 2015. This trial will be conducted in collaboration with the MD Anderson Cancer Center.
A third clinical development program for the BL-8040 treatment platform involves assessing the drug as a novel monotherapy treatment for the mobilization of stem cells from the bone marrow to the peripheral blood circulation, where they can be harvested for transplantation supporting the treatment of hematological indications. Stem cell mobilization is increasingly used as a method of collecting hematopoietic stem cells for transplantation, as part of the treatment of certain types of hematological cancers, and for the treatment of severe anemia or immune deficiency disorders. 
A  Phase 1 study, exploring the safety, tolerability, pharmacodynamic and pharmacokinetic effects of ascending doses of BL-8040 in healthy subjects was recently completed. All safety and efficacy endpoints of this study were met, showing that treatment with BL-8040 as a single agent was safe and well tolerated at all doses and resulted in efficient stem cell mobilization and collection in all study participants. Importantly, the results support BL-8040 as one-day, single-dose collection regimen, which is a significant improvement upon the current standard of care. Robust stem cell mobilization was evident in all treated participants, across the different doses tested, supporting a novel approach to stem cell collection. After a single administration, BL-8040 enabled collection of a yield of stem cells that exceeds the number required to support a transplant in all treated participants, following only one collection procedure. The results of this study were presented in an oral presentation at the EHA conference in June 2015. 
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  in comparison to other CXCR4 antagonists revealed that, unlike other compounds from the same class, BL-8040 acts as an antagonist as well as an 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, and  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 1/2, 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 with a single administration resulting  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 all measurements taken over a 24 hour period.  BL-8040 also significantly increased stem cell mobilization and at 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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