VIEWS & REVIEWS

Accelerated drug development delivers results

-Kate Palmer-

Time is most certainly money in the field of drug discovery and development. It takes an average of 10 years to get a drug from the test tube to the market. Therefore, any company that can refine its processes to increase the speed and efficiency uf drug deveiupmeni. is iiiu:i) tu lIIaxilllist: tilt: Idulll uil ib invt:stmt:iit. Appwaches to accelerating the drug development process were discussed at a I-day seminar organised by the Drug Information Association entitled 'Taking a Drug Discovery into Pre-Clinical Development' [Melbourne, Australill; October 1998].

The rapid advances in technology and scientific knowledge that have occurred in the last 30 years have opened up new opportunities for drug discovery within the pharmaceutical industry. However, these advances have brought with them a unique problem. Research scientists are overwhelmed with information. As a result, 3 key issues in drug development have become how to quickly and efficiently identify a therapeutic area in which to invest research resources, how to identify a therapeutic/molecular target within the chosen area, and how to choose a lead compound from the thousands that are identified as interacting with the target.

Choosing a therapeutic area

Some criteria that may be used in choosing a therapeutic area were outlined by Dr Jonathan Coates, the head of drug discovery at AMRAD Operations, Australia. These include:

• identifying an unmet medical need, i.e. a disease that is either currently untreated or for which there is the potential to improve on existing therapies (e.g. drugs to overcome HIV drug resistance or which can be used as part of a poly therapy regimen)

• ensuring there is a good market potential • determining that a potential drug will compete well

with existing therapies. An additional focus of drug research should be on

providing therapies that improve outcomes within specific therapeutic areas. For example, increasing a patient's quality of life, and reducing the cost or use of healthcare resources, said Dr Tony Causey from Covance Inc., Harrogate, UK.

Honing in on targets

The most important issues in choosing an appropriate therapeutic target were highlighted by Dr Coates. Initially, the validity of the target has to be determined - will interaction with the target have the desired clinical effect? Some targets are already well defined, such as reverse transcriptase in HIV or protease in herpesvirus. However, novelty is the ultimate aim, said Dr Coates. This means choosing a target that will dilleliulaie lhe Ji~ed~e uut wltil.,J. has not been the focus of succcssful research previously.

Defining both the selectivity of the agent for the target and the drug's mechanism (inhibitor, antagonist or agonist) at that target are also important. Other considerations are whether there is a high likelihood that a drug will be able to access the target and whether there is a predisposition to resistance within the target. This is a very important issue in the development of drugs for treating bacterial and viral infections.

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Lead compounds A 'lead' compound is 'a compound with the

required type of biological activity in a mlidated assay or assays', said Dr Coates. Such compounds can come from a variety of sources, including a research idea, rational drug design, knowledge of competitor compounds and random screening of synthetic and natural products. Potential lead compounds can be screened in a number of ways, including high throughput screening and 'smart cells' [see boxed text].

Smart cells

Recombinant DNA technology is used to express the target enzyme and a substrate in either a eukaryot ic , bacteria or yeast cell. When the enzyme acts on the substrate , a product is produced which has a lethal effect, resulting in the system dying. If a compound is added to the system that can penetrate the cell wall and can inhibit the enzyme, the toxic product will not be produced and so the cells will survive. This is a '3 in l ' assay, demonstrating that a compound can inhibit the target enzyme, is non-toxic to the whole cell and that it is bioavailable.

Medicinal chemists can then optimise the activity of compounds to achieve the best lead using the principle of structural-activity relationships.

In addition to identifying a lead compound, Dr Causey highlighted the need to develop back-up compounds. These can be used for patent protection and to give viable alternatives if the lead compound fails to clear hurdles later in the development process. The concurrent development of back-up compounds will save time and money if the lead compound falls by the wayside, said Dr Causey.

'Developability' ... In order for a lead compound to move along the

development path successfully it must have certain properties. The desired combination of these properties was termed 'developability' by Dr Causey. These features include: • an appropriate ievei of potency and seiecriviry • a low tox.icity profile • oral bioavailability • an optimal metabolic profile • an appropriate duration of action • chemical stability • a relatively easy manufacturing process • a patentable structure.

Although all these properties are important, often no single compound will possess them all. In this case,

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4 VIEWS & REVIEWS

there will need to be some trade-offs, as there is no point in taking a very selective and potent compound into development if it takes 50 steps to synthesise it and it is insoluble, said Dr Causey .

. . . and optimisation It is the optimisation of pharmaceutical properties

that defines a 'drug candidate' and differentiates it from a mere 'compound', said Dr Bill Charman from the Victorian College of Pharmacy at Monash Cniversity. Melbourne, Australia.

Rapid drug development can only occur if potential problems with compounds are recognised and over­come as early as possible in the discovery process. said Dr John Flack, the director of pharmaceutical research and development at AMRAD. There should be 'no surprises' later in the development process. he added. To achieve this, it is critical that pharmaceutical companies have an effective interface between drug discovery and drug development departments. Consequently, members of each department should have a thorough understanding of the requirements of the other.

Ten steps to happiness Dr Flack also presented what he saw as the

10 essential steps for achieving accelerated drug development [see boxed text]. Several companies have been committed to accelerated drug development for some time and it has already borne fruit.

Ten steps to achieve accelerated drug development

1. Organise to do it - focus on the discoveryl development interface. 2. Recognise new technology as a means to an end not as an end in itself. 3. Start early and take calculated risks. 4. Appoint champions and form empowered teams; set milestones and plan. 5. Only generate essential data. 6. Minimise bureaucracy and the decision making process. 7. Rethink each process and make it more efficient. 8. Ensure internal and external resources are available. 9. If external resources are to be used, ensure that the facilities are available and that the necessary experience, expertise and commitment is present. 10. Adopt a proactive approach to discussion with regulatory authorities.

Glaxo-Wellcome used this system during the development of ranitidine and were able to reduce the duration of the development phase from around 9-12 years to 5-7 years. It can be hoped that imple­menting the principles of accelerated drug discovery will lead to faster availability of future drugs for the treatment of currently untreatable or poorly treated diseases.

Inpharma3 19 Dec 1998 No. 1168 1173-8324/98/1168-0004/S01.00" Adis International Limited 1998. All rights reserved