No gambling on the future

Cyprotex is developing a new way of determining a drug's ADME properties, although it hit the headlines in the UK earlier this year for different reasons. Graham Lampard visited the company to find out what the future holds

Cyprotex. You're probably thinking you know the name, but where from? In February of this year, the company was floated on the Alternative Investments Markets, and hit the headlines as the name at the centre of, although not involved in, a spread betting scandal. 'If we do well, it will act as a talking point, people know the name and it will help us along,' said a phlegmatic David Leahy, the company's founder. 'The great thing is that it has not affected our relationship with customers.'

The company was established in April 1999, as a division of Medeval, a CRO company that carries out Phase I clinical trials; in January 2001 there was a management buyout led by Leahy, who is also the cso. Cyprotex is a pharmacokinetic technology and information business, and was set up to investigate drug pharmacokinetics.

biologically active

Pharmacokinetics are influenced by the rate at which a drug is adsorbed, distributed, metabolised and eliminated from the body following administration. These ADME properties of a potential drug are critical and must be optimised for it to be successful. Leahy said: 'The first thing is that the drug must be biologically active. In fact that is relatively easy to do. There are something like 10m new compounds synthesised, and HTS means it's almost automatic that if you've got a biological target, you can find something to interact with it.

'But many fail because you can't get the pharmacokinetics right, which is crucial for the in vivo/in vitro relationship.'

Cyprotex is trying to change the way in which the drug discovery process is carried out. Figure 1 shows the current, linear, low efficiency 10-15 year process. With this process the cost of developing new drugs seems to be inversely proportional to the number of new drugs coming onto the market. 'That is the figure that underlines the failure of the pharmaceutical industry.'

Figure 2 highlights the fact that the major cause of late stage drug failure is pharmacokinetic problems. 'The big part of failure is the in vivo/in vitro relationship, and yet the first time the pharmacokinetics are investigated is at the Phase I clinical trial stage' [red line in figure 1]. The company's technology and information allow evaluation of human pharmacokinetics across the entire discovery process [green line in figure 1]. 'Since there are 10m possible new drugs to be investigated, they can't all be tested on humans, so we have developed in silico methods of investigating nces.'

Figure 3 shows the problem that companies have when deciding which target molecules to choose. There are three distinct areas in which in silico technology can impact:

• With lead identification there could be hundreds of thousands of molecules, which come from different chemical series and the question is: "Which chemical series do I build my drug discovery project around?"

• With lead optimisation, the question becomes: "Which analogues should I optimise for development?"

• And finally, the 5-25 candidates that emerge from the above processes need to be tested further, but which does the company test on man?

'We narrow the thousands of compounds produced down to a few candidates by a combination of experimental and predictive - in silico - work.' Leahy said. 'The in silico methods work best when there is experimental data from similar compounds, so it is an iterative process of test, create the database, define the model, do the predictions, find new compound, test etc. etc.' Obviously, the success of this method depends on the data, and with 40-80,000 compounds being added each year the company is building a database that will produce better and better models with time.

'Another important feature of pharmacokinetics is that we are talking about the property of the compound not of the disease. If we characterise areas of chemistry, it doesn't matter whether it is being used to treat liver disease, cancer, or even in agrochemistry: all we are saying is that we can predict its ADME properties.'

The use of the in silico algorithms to simulate in vivo pharmacokinetics is at the heart of what the company does. 'If you like, we are developing a virtual human. We have a simulation model for a human or a mammal, which consists of a set of mathematical equations that look at 14 major organs in the body, such as the lungs, muscle, and skin, and the maths describe the flow of blood and drug pharmacokinetics in these organs,' Leahy explained.

'There are then 114 physiological parameters, such as blood flow and tissue volume, and the result is a virtual simulation model for a human. Also, if you alter the parameters you can simulate individual humans, depending on whether they are obese, have renal failure, or are old. It is also possible to simulate different racial groups.'

higher quality

The ability to combine ADME, experimental science, screening automation and systems and information management, is a competitive advantage as the company's science and technology will speed the discovery of higher quality new drugs, increase the quality of candidates delivered to development, and reduce the cost of delivering new drugs to the market. Figure 4 shows the drug discovery process as Leahy believes it could look with these new technologies fully implemented.

For its market, Cyprotex is focused on pharmaceutical and biotechnology drug discovery companies. It currently has a pipeline of more than 30 companies, and considering it has been a separate company only since 2001, it has achieved a lot, including clearing all debts and having cash in the bank. The US subsidiary is also up and running. Labsystems software has been developed and prototype commercial software released, and a strong business pipeline is being created.

The money gained from the AIM flotation, about £6.5m (US$10m), meant that by June this year Cyprotex had established a high throughput screening (HTS) facility that Leahy believes is unique in the industry. 'When people talk about HTS ADME, they usually talk about 100 compounds a week. Here, we are at more than 2,000 compounds a week.'

The company has also increased the number of employees from 17 to 38, launched a commercial software product from the mathematical models Cyprotex had developed, and established facilities in both the US and the UK. 'We particularly wanted to launch commercial global operations,' said Leahy. 'Probably two thirds of our market is in the US, so a base there was very important - and we have contacts in Japan, for the Far East markets.

'The important message is that we are not a conventional biotech company, running for five years at a burn rate, and raising additional funds every couple of years to do that; we do AIM to be a profitable business as soon as we can,' Leahy emphasised.