Details on the status of the Astex pipeline follow.
Guadecitabine (SGI-110) – DNMT inhibitor (Hematologic Malignancies)+/-
Guadecitabine (SGI-110)—DNMT inhibitor (AML, MDS)
Guadacitabine (SGI-110) is a small molecule, next generation DNA-hypomethylating agent that targets and reverses aberrant DNA hypermethylation, an epigenetic change characteristic of many cancer cells, restoring the expression of silenced tumor suppressor genes and cancer testis antigens. Guadecitabine-mediated demethylation of DNA upregulates tumor-associated antigens, and may sensitize tumor cells to other anticancer agents, including immunotherapeutics, as well as resensitizing resistant cancer cells to chemotherapeutics. Guadecitabine was rationally designed to prolong the exposure of tumor cells to the active moiety, decitabine, ensuring greater uptake of decitabine into the DNA of rapidly dividing cancer cells.
Astex has conducted a large (400 patient) Phase 1-2 study of guadecitabine in patients with acute myelogenous leukemia (AML) or myelodysplastic syndromes (MDS), and has initiated an 800-patient, global, randomized Phase 3 study, ASTRAL-1 (www.clinicaltrials.gov identifier NCT02348489), in treatment naïve AML patients who are unfit to receive, or not considered candidates for, intensive induction chemotherapy.
Guadecitabine is also being tested in clinical trials for the treatment of solid tumors, including studies investigating combination with carboplatin in the treatment of platinum-resistant ovarian cancer, in hepatocellular (liver) cancer following failure of Nexavar® (sorafenib), and in combination with irinotecan in the treatment of colorectal cancer.
Guadecitabine is wholly owned by Astex
For more information about the ASTRAL-1 study, please email ASTRALemail@example.com
Onalespib (AT13387) – HSP90 inhibitor (Lung & Melanoma)+/-
Onalespib (AT13387)—Hsp90 inhibitor (Lung & Melanoma)
Onalespib (AT13387) is a small molecule inhibitor of Hsp90, a so called “Heat Shock” protein. Heat shock proteins are hypothesised to support the growth and proliferation of many cancer cells. Hsp90 acts as a “molecular chaperone” stabilizing and preventing the breakdown of key cancer-forming (oncogenic) proteins. These client proteins, and their association with different tumor types, include HER2 (the target for Herceptin® in breast cancer), ALK (the target for Xalori® in gastrointestinal tumors) and B-Raf (the target for Zelbora® and Tafinlar® in the treatment of non small cell lung cancers).
As a targeted inhibitor of Hsp90, onalespib has the potential to control the proliferation of multiple solid tumors and hematological malignancies where uncontrolled cell growth is dependent on the interaction between Hsp90 and its client proteins. These include tumor types that have become resistant to initial therapy. Astex is pursuing an approach based on the observation that addition of onalespib to a molecularly targeted agent may delay the emergence of resistance to the agent, and hence prolong the window of therapeutic benefit.
Onalespib is currently being evaluated in a Phase 2 clinical study in combination with Xalkori® (crizotinib) in the treatment of ALK +ve non-small cell lung cancer, and via a CRADA with the US National Cancer Institute (NCI) in combination with Tafinlar® (dabrafenib) and Mekinist® (trametinib) in the treatment of B-Raf melanoma.
Onalespib (AT13387) is wholly owned by Astex.
AT7519 – CDK inhibitor (MM)+/-
AT7519—CDK inhibitor (MM)
AT7519 is a small molecule targeted inhibitor of several cyclin-dependent kinases that regulate two important disease processes: the cell replication cycle and gene expression. The normal regulation of the cell cycle is disrupted in all cancers allowing the uncontrolled tissue growth characteristic of the disease. CDKs 1 and 2 act as key controls of the cell cycle, and the inhibition of these enzymes both prevents cell proliferation and initiates cell death. AT7519 is an inhibitor of both CDK1 and 2 and in preclinical testing induces tumor shrinkage in multiple animal models of cancer.
In addition to its direct effects on the cell cycle, AT7519 is also a potent inhibitor of RNA polymerase Ⅱ–dependent transcription. This activity results from inhibition by AT7519 of another cyclin-dependent kinase, CDK9. The survival of several tumor types is very dependent on the cellular levels of certain anti-apoptotic proteins (eg, Mcl-1), which require RNA polymerase II activity for their generation. This is true for hematological malignancies in particular (eg, CLL and AML) and AT7519 has been found to induce rapid cell death in leukemia cell lines and tumor shrinkage in relevant animal models.
Astex has investigated AT7519 in two phase 1 clinical trials, evaluating different dosing regimens of AT7519 as monotherapy in patients with advanced solid tumors. These studies were conducted at multiple sites in the UK, USA and Canada. Evidence of clinical activity was observed in these trials. A phase 2 study of AT7519 in combination with bortezomib in patients with multiple myeloma has been conducted at multiple centers in the US with funding support from the Multiple Myeloma Research Foundation. In addition two phase 2 trials of AT7519 to treat patients with chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) are starting, sponsored by the NCIC Clinical Trials Group in Canada.
Novartis has an option to develop and commercialize AT7519.
AT13148 – ROCK inhibitor (solid tumours)+/-
AT13148 – AGC kinase inhibitor
AT13148 is an orally active small molecule inhibitor of Rho activated kinases (ROCK) 1 and 2 and of protein kinase (PK) A and is currently in phase 1 clinical studies. Translational research carried out in collaboration with the Institute of Cancer Research (ICR) and supported by the CRUK Drug Development Office (DDO) has highlighted that ROCK inhibition is a potential target in Ras dependent cancers. Prof Julian Downward (published in Cell. 2012 149(3):642-55) has demonstrated that ROCK activity is an important enabling event in supporting ras transformation in lung cancer. Specifically, the work demonstrates that combining ROCK inhibition with proteasome inhibition is able to block growth of mutant ras lung cancer. Patients with such tumours are poorly served by current standard of care therapies. In addition, recently published studies have identified that ~50% of patients suffering from Cushing’s syndrome have a point mutation in PKA leading to its constitutive activation (Science 344, 913 (2014) DOI: 10.1126/science). In these adrenal tumours, this molecular change results in the increased secretion of cortisol that is associated with the disease. AT13148 has the potential to be the first agent used to treat patients with these molecular defects.
Astex is developing AT13148 under Cancer Research UK’s Clinical Development Program (CDP). AT13148 is currently being tested in a phase 1 clinical trial in patients with advanced solid tumors.
AT13148 is wholly owned by Astex.
ASTX727 – Oral HMA (MDS)+/-
ASTX727 - Oral HMA (MDS)
ASTX727 is a fixed dose oral combination product consisting of decitabine and E7727, a novel cytidine deaminase inhibitor (CDAi). ASTX727 is designed to allow for efficient oral delivery of decitabine at low doses.
Cytidine deaminase (CDA) is an enzyme that is responsible for the degradation of nucleosides, including decitabine and azacitidine. High levels of CDA in the gastrointestinal tract and liver rapidly degrade these nucleosides and prohibit or limit their oral bioavailability. E7727 is a proprietary and patented New Molecular Entity (NME) with a very wide therapeutic margin that inhibits CDA activity.
Decitabine can be delivered orally and efficiently absorbed in the gut when it is combined with E7727 due to the inhibition of CDA by E7727. ASTX727 entered clinical development in 2014.
ASTX727 is wholly owned by Astex.