Pipeline
Astex has established a broad pipeline of small molecule, molecularly-targeted drugs using its drug discovery engine, Pyramid™.
Astex Pipeline
Partnered Pipeline
Brief details on the status of Astex’s development candidates are set out below.
AT9283
AT9283 is a small molecule inhibitor of kinases including aurora A and B, JAK2 and Abl. Initial clinical trials have demonstrated early signals of efficacy in patients with haematological malignancies.
Solid tumours
AT9283 has been investigated as monotherapy in patients with advanced solid tumours in two Phase I, open label, dose escalation trials at centres in the UK, USA and Canada. The two trials confirmed AT9283 is safe and well tolerated in patients with advanced solid malignancies. Oral bioavailability of AT9283 in humans has also been demonstrated. In conjunction with Cancer Research UK, Astex is also investigating the activity of single agent AT9283 in paediatric patients in a trial being conducted at multiple sites in the UK.
Haematological malignancies
AT9283 is also being investigated in a Phase I/II open label, dose escalation trial to assess the safety, tolerability and preliminary efficacy of AT9283 as monotherapy in patients with acute leukaemias. The trial is being conducted at centres in the USA. AT9283 is also being investigated in a Phase II setting in a chemotherapy refractory, multiple myeloma patient population in a trial being sponsored by the NCIC Clinical Trials Group in Canada. An additional paediatric leukemia trial being sponsored by Cancer Research UK is due to begin during 2010. To learn more about the development status of this compound, please see the most recent Astex presentations.
AT7519
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 pre-clinical models induces tumour shrinkage in several animal models of cancer.
In addition to its direct effects on the cell cycle, AT7519 is also a potent inhibitor of a key enzyme involved in gene expression, RNA Polymerase II. This activity results from inhibition by AT7519 of another cyclin-dependent kinase, CDK9. The survival of several tumour types is very dependent on the cellular levels of certain anti-apoptotic proteins (e.g. Mcl-1) which require RNA polymerase II activity for their generation. This is true for haematological malignancies in particular (e.g. CLL and AML) and AT7519 has been found to induce rapid cell death in leukaemia cell lines and tumour shrinkage in relevant animal models.
Astex is completing two Phase I clinical trials, investigating different dosing regimens of AT7519 as monotherapy in patients with advanced solid tumours at multiple sites in the UK, USA and Canada. Evidence of clinical activity was observed in these trials. A Phase II combination Study of AT7519 with Bortezimib in patients with multiple myeloma will commence during 2010 at centres in the US with funding support from the Multiple Myeloma Research Foundation. In addition two Phase II trials in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) will begin during 2010, sponsored by the NCIC Clinical Trials Group in Canada.
To learn more about the development status of this compound, please see the most recent Astex presentations.
AT13387
AT13387 is a small molecule inhibitor of Hsp90, a so called "Heat Shock" protein believed to be responsible for supporting many tumour cells becoming cancerous. Hsp90 acts as a "molecular chaperone" stabilising and preventing the breakdown of key cancer forming (oncogenic) proteins. These client proteins and their association with different tumour types include HER2 (the target for Herceptin® in breast cancer), the androgen receptor (the target for hormone therapy in prostate cancer), mutant B-raf (melanoma), c-kit (the target for Gleevec® in gastro-intestinal tumours) and mutant EGFr (the target for Tarceva® and Iressa® in the treatment of non small cell lung cancers).
Although AT13387 is a targeted inhibitor of Hsp90, the functional role of Hsp90 means the product has the potential to control the proliferation of multiple solid tumours and haematological malignancies where uncontrolled cell growth is dependent on the interaction between Hsp90 and its client proteins. These include tumour types which have become resistant to initial therapy.
In vitro, AT13387 is an extremely potent inhibitor of Hsp90, and inhibits the growth and survival of a broad range of cell lines derived from different human tumours. We have also demonstrated that AT13387 suppresses the levels of key oncogenic proteins such as the androgen receptor, erbB2, EGFr and BRaf in cell lines derived from patients with some of our targeted indications. We have also shown that AT13387 inhibits tumour growth in multiple xenograft models and confirmed mechanism-based efficacy via suppression of key oncogenic proteins in these models. The preclinical toxicology programme has shown AT13387 to be well tolerated. Although designed for intravenous delivery, AT13387 has also demonstrated oral bioavailability.
AT13387 is currently being investigated in an initial "oligo-specific" Phase I study in patients with a limited range of tumour types. This study, which is investigating two different dosing schedules is being conducted at multiple sites in the USA. The study is designed to assess the safety and tolerability of AT13387 in patients with advanced refractory solid tumours, and via the selection of patients who are more likely to respond to Hsp90 inhibitor therapy. The study is also intended to provide early evidence of clinical efficacy.
Based upon the results of this initial Phase I study, Astex is planning to conduct an Phase II study in patients with TKI refractory Gastro-Intestinal Stromal Tumours (GIST).
In November 2009, Astex entered into a CRADA with the US National Cancer Institute (NCI) to support the further clinical development of AT13387 over the next 5 years with a number of single agent and combination Phase I/IIa and Phase II studies planned.
To learn more about the development status of this compound, please see the most recent Astex presentations.
AT13148
AT13148 is an orally active multi-targeted small molecule inhibitor of PKB/Akt, a key enzyme in the PI3K/PKB/mTOR tumour cell survival pathway. More than 50 per cent of all tumours have an abnormality in this pathway leading to increased Akt activity and enhanced potential for tumour cell survival. In addition, clinical trials have highlighted that activation of this survival pathway is a common resistance mechanism for some cytotoxics (e.g. platinum agents) and targeted therapies (e.g. EGFr inhibitors). Therefore, PKB inhibitors such as AT13148 have potential for use as both single agents and in combination with cytotoxics and other molecularly-targeted agents in the treatment of a range of solid tumours.
The product inhibits proliferation and promotes apoptosis in a range of tumour cell lines, and biomarker studies have confirmed the predicted mechanism-based effects of the product. AT13148 has favourable pharmacokinetics, including good oral bioavailability. In xenograft models, oral administration of AT13148 results in inhibition of tumour growth, and in these xenograft models the anti-tumour effects occur in parallel with inhibition of the activity of the PI3K/PKB/mTOR pathway. This has been demonstrated by the dose and time dependent inhibition of the phosphorylation of several pharmacodynamic biomarkers of PKB and pathway activity in tumours taken from treated animals. Preliminary toxicology work has indicated that AT13148 is suitable for further development.
In September 2008 Astex announced a partnership with Cancer Research UK and Cancer Research Technology (CRT) to take AT13148 into development under the charity’s Clinical Development Partnerships (CDP) programme. Under the terms of this agreement, Cancer Research UK's Drug Development Office will carry out further development work on the agent, some of which will be undertaken by The Institute of Cancer Research and, if successful, AT13148 will be taken into Phase I clinical trials at the Royal Marsden Hospital in the UK. Astex retains all commercial rights in the compound.
AT13148 is currently completing pre-clinical development. The initial Phase I trial is expected to be a single agent dose escalation study to assess safety and tolerability and preliminary efficacy in patients with advanced solid tumours. We are also considering undertaking additional Phase I studies to assess the safety, tolerability and preliminary efficacy of combinations of AT13148 with anti-cancer drugs for which the major mechanism of drug, and hence tumour resistance arises from activation of the PI3K/PKB/mTOR pathway.