Pipeline
Astex has established a broad pipeline of small molecule, molecularly-targeted drugs using its drug discovery engine, Pyramid™.
Brief details on the status of Astex’s five development candidates are set out below.
AT9283
AT9283 is a small molecule inhibitor of kinases including aurora A and B, JAK2 and BCR-abl. Initial clinical trials have demonstrated early signals of efficacy in patients with haematological malignancies.
Solid tumours
AT9283 is being 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 are investigating two different dosing regimens to assess the safety and tolerability of AT9283 in patients with advanced solid malignancies.
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 two centres in the USA. Our current plans are to explore the potential of AT9283 to treat patients with acute myeloid leukaemia and possibly other haematological malignancies including myelofibrosis, chronic myeloid leukaemia, and high risk myelodysplastic syndromes. We are also investigating the possibility of using an oral formulation. 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.
Our clinical development plan has been formulated to investigate each of these anti-tumour actions of AT7519. AT7519 has potential in the treatment of patients with certain types of leukaemia as well as in the treatment of patients with a broad range of solid tumours.
AT7519 has been under investigation as monotherapy in two Phase I trials at multiple sites in the UK, USA and Canada in patients with advanced solid tumours. Each of these trials was designed to investigate different dosing regimens. Examples of patients showing both partial response and prolonged disease stabilisation have been observed.
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.
An IND for AT13387 was approved in January 2008 for an initial "oligo-specific" Phase I study in patients with a limited range of tumour types. This study is being conducted at three 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.
Dependent upon the results of this initial Phase I study, we expect to conduct additional Phase II studies in patients with defined tumour types.
To learn more about the development status of this compound, please see the most recent Astex presentations.
AT9311
AT9311 is a potent orally active small molecule inhibitor of certain cyclin-dependent kinases (CDKs). We have conducted an extensive preclinical programme on AT9311. Subject to regulatory approval and to satisfactory completion of pre-clinical toxicology work we plan to conduct an initial Phase I dose escalation clinical trial to assess the safety and tolerability of AT9311 in patients with advanced solid tumours.
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.
AT13148 is currently in early pre-clinical development. 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.
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.