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Drugs in Developement

BL-8040 - Multiple cancer and hematology indications
AGI-134 - Solid tumors
BL-8040

Indication: Solid tumors, malignant and non-malignant hematological indications
Mode of action: CXCR4 antagonism
Stage of development: Phase 2
Patent status: Over 10 patent families cover the BL-8040 composition and methods of use thereof

BL-8040 Overview

BL-8040 is a short peptide for the treatment of acute myeloid leukemia, solid tumors, and certain hematological indications. It functions as a high-affinity antagonist for 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 expression often correlates with disease severity. In a number of clinical and pre-clinical studies, BL-8040 has shown robust mobilization of cancer cells from the bone marrow, thereby sensitizing these cells to chemo- and bio-based anti-cancer therapy, as well as a direct anti-cancer effect by inducing apoptosis. In addition, BL-8040 has also demonstrated robust stem-cell mobilization, including the mobilization of colony-forming cells, and T, B and NK cells. BL-8040 was licensed by BioLineRx from Biokine Therapeutics and was previously developed under the name BKT-140.

In the first quarter of 2016, BioLineRx completed a Phase 2a trial for the treatment of relapsed or refractory acute myeloid leukemia (r/r AML) which was conducted at six world-leading cancer research centers in the U.S. and at five premier sites in Israel. In March 2016, BioLineRx announced positive top-line results from this study and in September 2016 BioLineRx presented detailed results of the study at the Society of Hematologic Oncology (SOHO) Annual Meeting in Houston, Texas. In December 2016, BioLineRx presented additional positive correlative data from the study, as well as detailed mechanism-of-action data, at the 58th American Society of Hematology (ASH) Annual Meeting and Exhibition in San Diego, California.

BL-8040 is also being investigated as a consolidation treatment together with cytarabine (the current standard of care) for AML patients who have responded to standard induction treatment and are in complete remission. In this regard, BioLineRx is currently running a significant Phase 2b trial in Germany, in collaboration with the German Study Alliance Leukemia Group. The Phase 2b trial is a double-blind, placebo-controlled, randomized, multi-center study aimed at assessing the efficacy of BL-8040 in addition to standard consolidation therapy in AML patients. Up to 194 patients will be enrolled in the trial. The primary endpoint of the study is to compare the relapse-free survival (RFS) time in AML subjects in their first remission during a minimum follow-up time of 18 months after randomization. BioLineRx is considering performing an interim analysis on this study in 2018, with top-line results expected in 2019.

In March 2015, BioLineRx reported successful top-line safety and efficacy results from a Phase 1 safety and efficacy trial for the use of BL-8040 as a novel treatment for stem cell mobilization at Hadassah Medical Center in Jerusalem. In March 2016, BioLineRx announced the initiation of a Phase 2 trial for BL-8040 for allogeneic stem-cell transplantation, conducted in collaboration with the Washington University School of Medicine, Division of Oncology and Hematology. Positive interim results from this study were announced in the first quarter of 2017, and topline results are expected by the end of 2017.

In January 2016, BioLineRx entered into a collaboration with MSD, known as Merck in the U.S. and Canada, in the field of cancer immunotherapy. In this regard, in September 2016 BioLineRx initiated a Phase 2a study, known as the COMBAT study, focusing on evaluating the safety and efficacy of BL-8040 in combination with KEYTRUDA® (pembrolizumab), MSD’s anti-PD-1 therapy, in up to 30 patients with metastatic pancreatic adenocarcinoma. The study is an open-label, multicenter, single-arm trial designed to evaluate the clinical response, safety and tolerability of the combination of these therapies as well as multiple pharmacodynamic parameters, including the ability to improve infiltration of T cells into the tumor and their reactivity. 

In August 2016, BioLineRx entered into an additional collaboration for the investigation of BL-8040 in combination with KEYTRUDA in pancreatic cancer – this time with MD Anderson Cancer Center. The study will be conducted as an investigator-sponsored study, as part of a strategic clinical research collaboration between Merck and MD Anderson Cancer Center aimed at evaluating KEYTRUDA in combination with various treatments and novel drugs, including BL-8040. The open-label, single center, single-arm Phase 2 study will focus on the mechanism of action by which both drugs might synergize. In addition to assessing clinical response, the study will include multiple assessments to evaluate the biological anti-tumor effects induced by the combination. BioLineRx will supply BL-8040 for the study, which commenced in January 2017.

In September, 2016, BioLineRx entered into a collaboration with Genentech, Inc., a member of the Roche Group, to support several Phase 1b studies investigating BL-8040 in combination with Atezolizumab, Genentech’s anti-PDL1 cancer immunotherapy, in multiple cancer indications. The Phase 1b studies, which are all expected to commence in 2017, will evaluate the clinical response, safety and tolerability of the combination of these therapies, as well as multiple pharmacodynamic parameters, in hematologic malignancies and solid tumors.

In addition to the above, BioLineRx is currently conducting, or planning to conduct, a number of investigator-initiated, open-label studies in a variety of indications, to support the interest of the scientific and medical communities in exploring additional uses for BL-8040. These studies serve to further elucidate the mechanism of action for BL-8040.

In September 2013, the FDA granted an Orphan Drug Designation to BL-8040 as a therapeutic for the treatment of AML; and in January 2014, the FDA granted an Orphan Drug Designation to BL-8040 as a treatment for stem cell mobilization. In January 2015, the FDA modified this Orphan Drug Designation for BL-8040 for use either as a single agent or in combination with G-CSF.

Pre-Clinical Data

In vitro and in vivo data show that BL-8040 binds to CXCR4 at the low nanomolar range (1-10nM) 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, BCL-2 inhibitor ABT-199 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. 

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 under a worldwide, exclusive license from Biokine Therapeutics.

For more information: info@BioLineRx.com