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STAT3 Inhibitors

The drugs we are developing target abnormal STAT3 pathway regulation, and we are focused on combining our STAT3 compounds with Standard -of- Care chemotherapeutics to form Precision Oncology super-treatments. STAT3 is normally used during development where it mediates the expression of a variety of genes in response to cell stimuli, and plays a key role in many cellular processes such as cell survival, growth, division, pluripotency and apoptosis as well as immune system evasion. The rationale for focusing on STAT3 is that a large number of cancer types and subtypes, as well as refractory cancers of other types/subtypes, are driven by and dependent on STAT3 misregulation.  As such, STAT3 represents an “Achilles Heel”, rendering them vulnerable to new STAT3 inhibitors.

For example, with the three areas we are focused on in the near term – Breast Cancer, Ovarian Cancer and Glioma – the phosphorylated STAT3 gene product is nearly 100% upregulated in specific genomically identified subtypes, and directly related to rapid, uncontrolled cell proliferation and metastasis in cancer cells. 

We have found that our compounds, both the New Chemical Entities (52 new compounds) and the Re-purposed compounds (11 STAT3 inhibitor compounds identified from a pool of marketed drugs) all perturb cancer cell growth, division and survival and REVERSE acquired drug resistance to anticancer drugs and radiation.

Though the STAT3 pathway has long been coveted as an anti-cancer target, very few inhibitors exist on the market.  This is because most chemicals found to inhibit STAT3 pathway do so by interfering with cell signaling proteins at the head of this pathway, and because these are used by multiple pathways, their effects are “pleiotropic” or interfere with a large number of pathways used by normal cells too.  This makes them toxic to patients and results in clinical trial failure.  In contrast, GLG’s STAT3 inhibitors specifically interfere with STAT3 phosphorylation or DNA binding by disrupting the function of specific parts of the STAT3 protein such as the SH2 or DNA binding domain.  Our focus on repurposed compounds means they are already approved for other indications with safe toxicity profiles from clinical trials already conducted.

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Repurposed Compounds

Our compound library is presently composed of 52 New Chemical Entities (NCEs) and 11 re-purposed compounds (STAT3 inhibitor compounds identified from a pool of marketed drugs). 

Focus on repurposed drugs offers many advantages.  One is pathway specificity, as ensured by their both known and benign safety profiles.  This specificity lowers risk during clinical trails aimed at reformulating/branding them as cancer therapies.

How can repurposed drugs constitute new products?  Any repurposed compound for treatment of cancer must be justified by unique data, in unique patient sets compared to those corresponding to the original indication the compound was approved for, and thus will represent a reformulation and constitute a novel, separate product. 

For example, we have reformulated our lead compound, GLG-801 into a stable salt, GLG-805. GLG-801 is an oral compound while GLG-805 is both an oral and an IV compound and as such, each will be used for different indications.  We are also targeting generic anticancer compounds through acquisition, and will be  nanoforumulating and converted these into super generics that are considered new reforumulated drugs. A good example is paclitaxel, an old chemotherapeutic reformulated and now sold as a reformulated compound by Celgene as ABRAXANE®. Paclitaxel was discovered by the NCI in 1962. BMS that was selected to market the drug in 1989, obtained the trademark Taxol in 1990 and FDA approval in 1992.   Celgene reformulated this natural, plant derived alkaloid as ABRAXANE®; sales reached nearly $1 billion in 2016.

Orphan Indications

We target orphan (e.g. rare) indications and we use state-of-the-art integrative genomics methods to target intransigent and/or orphan-like molecular subtypes of more  prevalent indications such as STAT3 related cancers.  With orphan indications, competition is low, Patent landscape is favorable, needs are great and favorable regulatory environments allow for compressed trial timelines. 

 

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