FDA gives Astex cancer drug IND
Administration (FDA) has approved its Investigational New Drug
(IND) application for the clinical development of its cell cycle
inhibitor, AT7519, for the treatment of cancer.
The go-ahead by the regulatory body signals the start of research into a cell cycle inhibitor that targets key Cyclin Dependent Kinases (CDKs) resulting in tumour shrinkage.
CDKs are regulatory proteins of the eukaryotic cell cycle. They act, after association with a number of different cyclins throughout the progression of the cell cycle, as central mediators of cell division.
Inhibition of CDKs could allow disruption of the cell cycle, evoking an anti-proliferative effect that may be useful as an intervention in the treatment of cancer and other diseases characterised by the rapid proliferation of cells.
AT7519 was discovered and developed using Astex's fragment-based drug discovery platform, Pyramid, and progressed from first synthesis to regulatory approval in a period of 14 months. Astrex is in the process of initiating a multi-centre Phase I trial of AT7519 in patients with refractory solid tumours in the US and in the UK.
Despite its potential most pharmaceutical companies are reluctant or unable to attempt a fragment-based approach, as it requires a new methodology for the detection of fragments and their subsequent development into novel drug candidates.
Detection using traditional bioassay-based HTS is not usually possible due to the inherently low binding affinity of the fragments. X-ray crystallography has the ability to accurately define the binding mode of low-affinity fragments bound to a target protein.
The IND approval closely follows that of Astex's Clinical Trial Authorisation (CTA) application for AT7519 by the UK Medicines and Healthcare Products Regulatory Agency (MHRA).
"We are very pleased to have been given the go-ahead by the regulatory authorities both in the US and in the UK to advance AT7519 into clinical development."
"We are now putting the final preparations in place to begin the clinical trial of AT7519 in the coming weeks," said Dr Harren Jhoti, chief scientific officer of Astex.
Astex's Pyramid approach uses the structure of the target protein to guide chemical design and optimisation. Low affinity, but novel fragments are identified and transformed (using iterative rounds of chemical synthesis and crystallography) into tractable drug leads.
The high attrition of drug candidates in clinical development can be largely attributed to poor ADME profiles, due to the size of the compounds. Drug candidates identified using fragment-based discovery are expected to be of low molecular weight, and therefore should suffer lower attrition rates as they progress to market.
It offers an opportunity to find lead compounds for targets that have proved 'intractable' to conventional bioassay-based screening. It is an efficient way to screen chemical space and discover drug candidates with novel chemical structures.
Research-based pharmaceutical companies worldwide spent $30.5 billion on R&D in 2001, which represents a 15.5 per cent increase over expenditures in 2000, and more than triple the investment in 1990. Despite this, the tremendous development of many new technologies, and a 200-fold increase in the number of screening data points over the past decade, the number of drug candidates entering development remains relatively unchanged.
The core problem is the quality of lead compounds that are discovered and developed into drug candidates. It is clear that the industry needs new approaches to lead discovery that will generate small-molecule lead compounds with a higher rate of success in development.
