IBL-202

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.

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.

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 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 below). Taken together, the current data for IBL-202 support its onward development into the clinic.

IBL-202 Indication Expansion

Beyond potential lead target indication in CLL, there is potential for IBL-202 in other B-cell lymphomas (MCL, DLBCL, FLL, SLL) as well as in AML and multiple myeloma (see Peer Review Publications and Poster Presentation below).

Peer Review Publications:

"The dual inhibitor of the phosphoinositol‐3 and PIM kinases, IBL‐202, is effective against chronic lymphocytic leukaemia cells under conditions that mimic the hypoxic tumour microenvironment"

O. Giles Best, British Journal of Haematology, 5 July 2018. Link here.

Poster Presentations:

"The Dual PI3/PIM-Kinase Inhibitor, IBL-202, Is Highly Synergistic with Venetoclax Against CLL Cells, and TP53-Knock-out Cells, and Under Conditions That Mimic the Tumor Microenvironment"

2018 ASH Annual Conference, December 1-4, 2018, San Diego. Link to abstract here.

“Dual inhibition of PIM and PI3-kinase by IBL-202 is effective against CLL cells cultured under conditions that mimic the hypoxic tumour microenvironment” 

International Workshop on Chronic Lymphocytic Leukaemia 2015, September 7-9, 2015 in Sydney, Australia. Link to interview with Dr. Giles Best here.

“Cotargeting of PIM, PI3K and Mtor in Mantle Cell Lymphoma (MCL)”

57th ASH Annual Meeting, Orlando, December 5-8, 2015. Link to abstract here

"Initial Evaluation of Novel Dual PIM/PI3K and Triple PIM/PI3K/MTOR inhibitors in multiple myeloma"

20th Congress of the European Hematology Association (EHA) June 11 – 14, 2015, Vienna. Link to abstract here.

“Dual Inhibition of PIM and PI3-Kinase by IBL-202 is Highly Synergistic Compared to Mono-Molecular Inhibition and Represents a Novel Treatment Strategy for Chronic Lymphocytic Leukemia”

56th Annual Meeting of the American Society for Haematology (ASH), December 6-9, 2014 San Francisco, California. Link to abstract here

“Combined inhibition of PIM and PI3 kinases shows an enhanced efficacy in a number of solid tumour cell lines”

American Association for Cancer Research (AACR) Annual Meeting 2014, April 5-9, San Diego, California. Link to abstract here

“Co-targeting PIM and PI3K/mTOR pathways with a single molecule: Novel orally available combined PIM/PI3K and PIM/PI3K/mTOR kinases inhibitors”

2013 AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics Conference, Boston, USA. Link to abstract here.

To request a copy of the corresponding poster please email the company at bd@inflectionbio.com

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