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Published: April 2017
Report Code: LS10812
Category : Pharmaceuticals
Phosphatidylinositol 3-kinases (PI3K) are lipid kinases that play a vital role in cell regulation, including cell survival, proliferation and differentiation. They act as intermediate molecules in PI3K/AKT/mTOR signaling pathway by sending chemical messengers from cell surface to cytoplasm. These signals activate multiple effector kinase pathways, including protein kinase B, bruton's tyrosine kinase and protein kinase C pathway, which result in survival and growth of normal cells. Recent cancer studies have shown that PI3K pathway is mostly targeted either by germline mutation or somatic mutation in human cancers, thus making it one of the most promising targets for therapeutics in cancer.
The activity of PI3K is strictly regulated by PTEN (phosphatase and tensin homolog deleted from chromosome 10) in normal cells. Abnormal activation of PI3K or dysregulated PI3K signaling pathway is mainly observed in tumor angiogenesis and carcinogenesis. Other genetic factors that target PI3K pathway in cancer development include loss of PTEN regulation, gene amplification in PI3Ks and receptor tyrosine kinases (RTKs) mutation activation. Due to all these factors, PI3K has emerged as an attractive target among researchers for novel cancer therapeutics.
Factors such as emerging combination therapies and biomarker identification are driving the growth of the PI3K inhibitors pipeline. Combination therapies are being used to stop further cancer growth and kill the cancerous cells. Also, combining novel drugs against different signaling pathways as well as combination of drugs with biological and biochemical agents may further enhance the treatment quality.
Companies are developing various biomarkers through next-generation sequencing with a single agent strategy at an early stage of development, which can help in avoiding recurrence of cancers. This approach can be applied as combination therapies or as single agent therapies.
Some of the key barriers hindering the growth of the PI3K inhibitors pipeline analysis are complex mechanism of action and alternative targets. The complex mechanism of action of PI3K creates problem in identifying the exact disease etiology. In cancer, mutation in receptor tyrosine kinase activate both PI3K and Raf-mitogen-activated protein kinase pathway that cause cross-inhibitory effect. This leads to the blocking effect on PI3K pathway.
For alternative targets, researchers identified that PI3K pathway is linked to many physiological processes, which results in hampering the clinical outcomes. This has led the researchers to think about several other targets that are associated with the PI3K/mTOR network, that can be successful as anti-cancer therapeutics.
As of March 2017, the PI3K inhibitors pipeline comprises approximately 37 active drug candidates, of which eight drug candidates are in Phase III stage, 10 drug candidates are in Phase II stage, nine drug candidates are in Phase I stage, eight drug candidates are in Pre-Clinical stage and two drug candidates are in Discovery stage.
Based on target, it was found that around 59.0% drug candidates target PI3K, 19.0% target PI3K delta, 8.0% target PI3K alpha, and 14.0% target others, including, but not limited to, PI3K beta and PI3K gamma.
Pharmaceutical companies such as Bayer AG, Verastem, Inc., F. Hoffmann-La Roche AG, Gilead Sciences, Inc. and SignalRx Pharmaceuticals, Inc., TG Therapeutics, Inc. are developing TGR-1202, a Phase III PI3K inhibitors drug candidate for the treatment of chronic lymphocytic Leukemia. TGR-1202 is evaluated in combination with the anti-CD30 antibody drug conjugate, brentuximab vedotin, in patients with relapsed or refractory hodgkin’s lymphoma; in combination with the bruton's tyrosine kinase inhibitor, ibrutinib, in patients with chronic lymphocytic Leukemia; and in combination with the janus kinase inhibitor, ruxolitinib, in patients with myelofibrosis or polycythemia vera.
TGR-1202 is a promising drug candidate and has been awarded orphan drug designation by the United States Food and Drug Administration (USFDA) in August 2016, for the treatment of patients of chronic lymphocytic Leukemia.
The major players for PI3K inhibitors pipeline include, but are not limited to, Novartis AG, Genentech, Inc., SignalRX Pharmaceuticals Inc., Verastem, Inc., GlaxoSmithKline plc, Takeda Pharmaceutical Limited, Bayer AG and PIQUR Therapeutics AG.
Novartis AG, Genentech, Inc., Verastem, Inc. and Bayer AG have their drug candidates in the Phase III stage of development. Novartis AG has two drug candidates in Phase III stage of development. SignalRx Pharmaceuticals, Inc. is developing six drug candidates, of which one is in Phase II stage, three are in Pre-Clinical stage and two drug candidates are in Discovery stage. SignalRx Pharmaceuticals, Inc. is using Control Resulting from Inhibiting Multiple Pathways (CRIMP) technology platform for developing its six drug candidates for PI3K. PIQUR Therapeutics AG is developing three drug candidates for PI3K, of which PQR309 are in Phase II stage of development, and PQR 530 and PQR 514 are in Pre-Clinical stage of development. GlaxoSmithKline has its drug candidates in Phase II stage of development. Takeda Pharmaceutical Limited has one product in Phase II stage.
Some of the key players developing PI3K inhibitors include Novartis Pharmaceuticals, F. Hoffmann-La Roche AG, Gilead Sciences, Inc., TG Therapeutics, Inc., Verastem, Inc., Bayer AG, GlaxoSmithKline plc, SignalRX Pharmaceuticals Inc., Eli Lilly and Company, PIQUR Therapeutics AG, Takeda Pharmaceutical Limited and Pfizer, Inc.
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