Products Overview
Astex has established a broad pipeline of small molecule, molecularly targeted drugs using its drug discovery engine, Pyramid™. Astex’s own product development has been primarily focussed in oncology though collaborations with partners have used Pyramid™ to address targets in a number of therapy areas.
Astex’s five clinical candidates, on which brief details are set out below, have all been derived from the Pyramid™ platform.
AT9283
AT9283 is a small molecule targeted inhibitor of several protein kinases associated with cancer. Initial clinical trials have demonstrated early signals of efficacy in both solid tumour patients, and patients with haematological malignancies. Additionally, we have developed a comprehensive preclinical data package showing clear evidence of mechanism-based efficacy in multiple xenograft models at doses which are well tolerated.
AT9283 is a potent inhibitor of Aurora kinases A and B, both of which are over-expressed in certain solid and haematological tumour types, and of JAK2 kinase, including the V617F mutant form associated with the pathogenesis of certain myeloproliferative diseases such as polycythemia vera, essential thrombocythemia and myelofibrosis. Aurora kinases are involved in mitotic control during cell division, having central roles in centrosome function, chromatid separation, and cytokinesis. Dysregulation of the Aurora kinases is thought to contribute to chromosomal instability and tumour progression. Over-expression of Aurora A has been shown to induce oncogenic transformation, and is observed in a high proportion of colorectal, breast, and gastric tumours, as well as in ovarian and pancreatic tumours. Aurora B over-expression has been observed in colorectal tumours. AT9283 is expected to be useful in the treatment of a range of solid tumours and 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.
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 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.
We expect AT7519 to have potential to treat patients with chronic leukaemias and to treat a range of solid tumours.
Novartis has an option to acquire a licence for AT7519 under our collaboration and licence agreement dated December 2005. Pending exercise of this option, we are responsible for designing and implementing the clinical development of this product.
AT13387
AT13387 is a small molecule inhibitor of Hsp90, an enzyme 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 so-called 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. Patient dosing has commenced.
Dependent upon the results of this initial Phase I study, we expect to conduct additional Phase II studies in patients with defined tumour types.
AT9311
This programme is exclusively licensed to Novartis. AT9311 is a potent orally active small molecule targeted 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 certain AGC kinases, including 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 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 has potential as monotherapy and in combination therapy for 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.
We are currently exploring options for third party funding to complete pre-clinical and initial clinical development of AT13148. 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.
Additional pipeline programmes
In addition to the products described above, we have a number of programmes in earlier stages of research and development. These additional programmes aim to identify inhibitors of certain other targets implicated in the progression of various diseases.
- BACE inhibitor programme. Alzheimer's disease is the most common form of dementia and the fourth leading cause of death in adults after heart disease, cancer and stroke. This progressive neurodegenerative disorder is characterised by cerebral deposits of amyloid b peptide (Ab), a protein-breakdown product of amyloid precursor protein (APP), which accumulates in the brain as aggregated amyloid plaques. The aspartic protease, beta-site amyloid precursor protein cleaving enzyme (BACE), also known as memapsin 2 or b-secretase is involved, together with γ-secretases, in the sequential cleavage of APP to form the Aβ peptide. BACE activity appears to be the rate-limiting step in Ab production. BACE was first described, and the sequence published, in 1999 and it is now a major therapeutic target for Alzheimer's disease.
We have determined a novel crystal structure of BACE and have used this three-dimensional structural information to design specific inhibitors targeting the enzyme. In March 2003, we partnered the BACE programme in a collaboration with AstraZeneca. As part of the collaboration we have provided an initial series of small molecule inhibitors and have applied our Pyramid™ approach to identify additional novel lead series. Selected compounds are being optimised by AstraZeneca for subsequent clinical development.
- Fibroblast growth factor receptor (FGFR) inhibitor programme. FGFR over-expression has recently been associated with the progression of a number of different tumour types. For example, over-expression of FGFR3 is associated with a chromosomal translocation which defines a group of patients with multiple myeloma who have a poor prognosis; FGFR1 amplification is seen in over 40 per cent of patients with lobular breast carcinomas; FGFR4 over-expression is associated with poor prognosis in patients with prostate and thyroid cancers, and an FGFR4 polymorphsim is associated with increased incidence of prostate, colon, lung and breast cancers; activating mutations of FGFR3 are associated with over 51 per cent. of bladder cancers. Selective inhibitors of FGFR therefore have potential in the treatment of a broad range of commonly occurring cancers. We have used PyramidTM to identify several novel lead series which specifically target FGFR.
- Akt/PKB inhibitor programme. In addition to our development of AT13148, described above, we have a collaboration and licensing agreement with AstraZeneca which continues to target selective inhibitors of the enzyme Akt (also known as Protein Kinase B or PKB). This programme is currently in the lead optimisation stage. Inhibitors identified under this programme are expected to have potential in the treatment of a broad range of cancers.
- Cell cycle inhibitor programme. In December 2005, we established a discovery programme targeting a specific enzyme involved in cell cycle control as part of our partnership with Novartis. The discovery programme is using the PyramidTM platform to identify novel inhibitors of this new enzyme. Drug candidates identified under this programme are expected to have potential utility to treat a broad range of solid tumours and haematological malignancies.
- B-raf inhibitor programme. The B-raf gene has been found to be mutated in about 70 per cent. of malignant melanomas, 10 per cent. of colorectal cancers and a smaller proportion of other cancer types. B-raf acts as a component of a chain of protein switches that control the growth and division of cells. The mutation renders B-raf constitutively active so it is no longer responsive to control signals. As a consequence, the mutated cells multiply unchecked, leading to cancer. Inhibitors of B-raf are expected to reverse this, allowing control of mutated and unresponsive cells.In February 2004, we established a collaborative programme with the Wellcome Trust, the Institute of Cancer Research and Cancer Research Technology Ltd, which was aimed at identifying selective inhibitors of B-raf. We used the PyramidTM platform to identify novel chemical series which are being further developed by the Institute of Cancer Research.
- Type 2 methionine aminopeptidase (MetAP2) inhibitor programme. We have established a PyramidTM programme to identify novel inhibitors of MetAP2, an enzyme involved in endothelial cell proliferation, and implicated in the processes leading to angiogenesis (formation of new blood vessels). Solid tumours cannot grow without the formation of new blood vessels, so inhibition of processes involved in angiogenesis represents an attractive target for new molecularly targeted cancer drugs. Our MetAP2 programme is currently in the lead discovery stage.
- Anti-viral: enzyme inhibitor programmes. We are seeking the opportunity to apply our fragment-based drug discovery platform in additional areas of high unmet need outside of oncology. The anti-viral area is one of several in which there are challenging drug targets that could benefit from novel drug molecules arising from our approach. We have established early exploratory programs looking at several key anti-viral targets to investigate the utility of the fragment based approach.