IBL-202 is a first-in-class oral kinase inhibitor rationally designed to uniquely combine pan-PIM kinase and pan-PI3K inhibition in a single agent. IBL-202 is a product of the company’s dual mechanism kinase inhibitor program.
Scientific Rationale of IBL-202 by Inflection Bioscience's Chief Scientific Officer Dr. Shaun McNulty.
In-vivo profiling to determine IBL-202’s oral bioavailability and preliminary tox profile (non-GLP) in mice and rats has been completed. IBL-202 has been synthesised to gram quantities and data to support its ‘drug like’ properties have been generated.
Initial in vitro efficacy with IBL-202 in a panel of cell lines was carried out showing it to be superior to PI3K or PIM kinase inhibition alone. In collaboration with our research partners, pre-clinical efficacy with IBL-202 has been demonstrated in chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), acute myeloid leukemia (AML) and multiple myeloma.
B-cell malignancies (BCM) are a type of cancer that forms in B-cells and includes non-Hodgkin lymphomas (NHL) and chronic lymphocytic leukemia (CLL), with over 700,000 new cases per annum reported. Poor response and high relapse rates have been identified as very significant problems for BCM, with no cures and over 250,000 deaths globally each year. Drug resistance remains a major issue. PI3K inhibitors have been approved in BCM in the past 6 years and shown to be effective in BCM, although relapse is inevitable. PIM kinase has been shown to be over-expressed in BCM and associated with resistance, relapse and poor outcomes. As PIM is specifically identified as a cause of resistance to PI3K inhibition, dual PIM and PI3K inhibition in BCM should reduce resistance and improve survival.
IBL-202 in CLL
Chronic Lymphocytic Leukaemia (CLL) most commonly affects older adults. Average 5 year survival rates are >80% (<70% for those over 75 years). There has been considerable progress in the treatment of CLL over the past ten years. Targeted therapeutics which interfere with the disease biology of CLL have been approved including the B-cell receptor inhibitors (eg. BTK inhibitor Imbruvica®, PI3K inhibitors) and Bcl-2 inhibitors (eg Venclexta®). These advances have provided new and improved options across first, second and third line. Critically, however, a key feature of CLL is the emergence of treatment resistance, meaning there are still no curative medicines and most patients ultimately relapse.
Rationale for dual PIM and PI3K inhibition in the treatment of CLL
The efficacy of PI3K inhibition in CLL, in particular targeting the PI3K delta and gamma isoforms, has already been established (Zydelig®, Copiktra®)
PIM kinase is over expressed in CLL cells (Koskinen, et al 2014)
PIM kinase enhances Bcl-2 activity, a key survival pathway in CLL (Koskinen, et al 2004)
PIM kinases are essential for CLL cell survival and for regulation of CXCR4 receptor - a hallmark of CLL (Decker, et al 2014)
Therefore, a strong rationale exists to target both CLL driving signalling pathways (B-cell receptor and Bcl-2) by targeting both PI3K and PIM kinase.
Dr Giles Best, Kolling Institute Sydney, discusses the potential of IBL-202 in CLL.
IBL-202’s potential in CLL was confirmed through anti-proliferative profiling in a range of CLL lines and patient samples. Its further potential in the treatment of resistant CLL was more recently demonstrated in assays which mimic the hypoxic microenvironment of the bone marrow, where CLL cells can shelter from many standard therapeutics. IBL-202 was shown to have a significant impact on CD49d and CXCR4 gene expression and on the migration, cycling and proliferation of CLL cells, suggesting that IBL-202 may significantly impair the migratory and proliferative capacity of the CLL cells to penetrate the difficult to treat areas of the bone marrow and lymph nodes. Synergistic complementarity with Venclexta® in the treatment of CLL was also demonstrated.
The data supporting the potential of IBL-202 in CLL was recently published in the peer-reviewed British Journal of Hematology in 2018 (see Peer Review Publications and Poster Presentation in Publications page). Taken together, the current data for IBL-202 support its onward development into the clinic.
IBL-202 Indication Expansion
Beyond CLL, there is potential for IBL-202 in other B-cell malignancies (MCL, DLBCL, FL, SLL) as well as in AML and multiple myeloma.