Discovery and development of drugs

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Chapter 3 Discovery and development of drugs

Patrick Vallance

Synopsis

• Preclinical drug development. Discovery of new drugs in the laboratory is an exercise in prediction. Selecting the target for a drug is probably the key decision.

• Techniques of discovery. Several approaches, including using small molecules, large proteins and nucleic-based approaches, broaden what we think of as a medicine.

• Studies in animals. Some are required by regulation (for safety), others give insight into the effect of the drug in the whole body, but none replaces the need for clinical testing.

• Experimental medicine. Getting the medicine into the clinic to test its properties and its effects on biological systems is a key step.

• Ethical issues.

• Need for animal testing.

• Prediction. Failures of prediction occur and a drug may be abandoned at any stage, including after marketing. New drug development is a colossally expensive and commercially driven activity.

• Orphan drugs and diseases.

Making a new medicine

Discovering and developing a new medicine requires combining the skills of biology, chemistry, clinical medicine and, of course, pharmacology. There are three key decision points along the way:

1. Selecting the molecular target you want the drug to act on to produce the desired effect.

2. Choosing the right chemical as the drug candidate. All the promise and all the faults become fixed at this point.

3. Designing the right clinical experiment to show that the medicine will really do what you want it to do.

Medicinal therapeutics rests on the two great supporting pillars of pharmacology:

1. Selectivity – the desired effect alone is obtained: ‘We must learn to aim, learn to aim with chemical substances’ (Paul Ehrlich).1

2. Dose – ‘The dose alone decides that something is no poison’ (Paracelsus).2

Once a target has been selected the process of finding the right chemical to act as an antagonist, agonist, inhibitor, activator or modulator of the protein function depends on a process of screening. For decades, the rational discovery of new medicines depended on modifications of the structures of natural chemical mediators. This may still be the route to find the drug, but more often now large libraries of compounds are screened against the target in robotic high throughput screens. However, it is worth remembering that the exact molecular basis of drug action may remain unknown, and this book contains frequent examples of old drugs whose mechanism of action remains mysterious. The evolution of molecular medicine (including recombinant DNA technology) in the past 30 years has led to identification of many thousands of potential drug targets, but the function of many of these genes remains unknown. The hope was that the identification of targets identified by genetics coupled with high throughout screening would lead to a great increase in the productivity of drug discovery. This has turned out not to be the case since it is clearly important to understand both the function of the target and the nature of the interaction of the chemical drug with the target in order to make a selective and safe medicine. The skills of quantitative pharmacology are key.

The chances of discovering a truly novel medicine, i.e. one that does something valuable for patients that had previously not been possible (or that does safely what could previously have been achieved only with substantial risk), are increased when the discovery and development programme is founded on precise knowledge of the biological processes it is desired to change. The commercial rewards of a successful product are potentially enormous and provide a great incentive for developers to invest and risk huge sums of money. Most projects in drug discovery and development fail. Indeed the chances of making it through from target selection to having a medicine on the market are under 1 in 100.

The huge increase in understanding of molecular signalling – both between cells and within cells – has opened many new opportunities to develop medicines that can target discrete steps in the body’s elaborate pathways of chemical reactions.3 The challenge, of course, is to do so in a way that produces benefit without harm. The more fundamental the pathway targeted the more likely there is to be a big effect, whether beneficial, harmful or both. No benefit comes without some risk.

The molecular, industrialised and automated approach to drug discovery that followed sequencing of the genome and application of high throughput chemical approaches led to two consequences:

1. More potential drugs and therapeutic targets were identified that could be experimentally validated in animals and humans. This ‘production line’ approach also led to a loss of integration of the established specialities (chemistry, biochemistry, pharmacology) and to an overall lack of understanding of how physiological and pathophysiological processes contribute to the interaction of drug and disease.

2. Theoretically, new drugs could be targeted at selected groups of patients based on their genetic make-up. This concept of ‘the right medicine for the right patient’ is the basis of pharmacogenetics (see p. 106), the genetically determined variability in drug response.

Pharmacogenetics has gained momentum from recent advances in molecular genetics and genome sequencing, due to:

• rapid screening for gene variants

• knowledge of the genetic sequences of target genes such as those coding for enzymes, ion channels, and other receptor types involved in drug response.

Expectations of pharmacogenetics and its progeny, pharmacoproteomics (understanding of and drug effects on protein variants) remain high, but the applicability will not be universal. They include the following:

• The identification of subgroups of patients with a disease or syndrome based on their genotype. The most extreme of obvious examples of this are diseases caused by single gene defects. The ability accurately to subclassify based on common genetic variation is less clear.

• Targeting of specific drugs for patients with specific gene variants. This is most advanced in the field of cancer (usually targeting somatic changes in cancers) and increasingly in the field of the pharmacogenetics of safety (i.e. unwanted drug effects).

Consequences of these expectations include: smaller clinical trial programmes with well-defined patient groups (based on phenotypic and genotypic characterisation), better understanding of the pharmacokinetics and dynamics according to genetic variation, and improved monitoring of adverse events after marketing.

New drug development proceeds thus:

• Idea or hypothesis. ‘This protein causes this disease/these effects which I could stop by affecting protein function.’

• Design and synthesis of substances. ‘This molecule produces the wanted effect on protein function and has the physico-chemical characteristics that make it a potential medicine.’

• Studies on tissues and whole animal (preclinical studies). ‘When I test it in appropriate models it does what I expect and that allows me to believe it would do the same in humans.’

• Studies in humans (clinical studies) (see Ch. 4). ‘Initially I want to know whether the molecule has drug-like properties in terms of its kinetics. I then want to know that it does what I need it to do in terms of the effect on disease.’

• Granting of an official licence to make therapeutic claims and to sell (see Ch. 6). ‘Is my medicine better than than placebo? Does it do more than existing medicines and is it well tolerated.’

• Post-licensing (marketing) studies of safety and comparisons with other medicines. ‘Now many thousands of patients have taken it, am I still sure that it is safe.’

The (critical) phase of progress from the laboratory to humans is often termed translational science or experimental medicine. It was defined as ‘the application of biomedical research (pre-clinical and clinical), conducted to support drug development, which aids in the identification of the appropriate patient for treatment (patient selection), the correct dose and schedule to be tested in the clinic (dosing regimen) and the best disease in which to test a potential agent’.4

It will be obvious from the account that follows that drug development is an extremely arduous, highly technical and enormously expensive operation. Successful developments (1% of compounds that proceed to full test eventually become licensed medicines) must carry the cost of the failures (99%).5 It is also obvious that such programmes are likely to be carried to completion only when the organisations and the individuals within them are motivated overall by the challenge to succeed and to serve society, as well as to make money. A previous edition of this chapter included a quote from a paper I wrote from my time in academia and I leave it here:

Let us get one thing straight: the drug industry works within a system that demands it makes a profit to satisfy shareholders. Indeed, it has a fiduciary6 duty to do so. The best way to make a lot of money is to invent a drug that produces a dramatically beneficial clinical effect, is far more effective than existing options, and has few unwanted effects. Unfortunately most drugs fall short of this ideal.7

Techniques of discovery

(See Fig. 3.1)

image

Fig. 3.1 Drug discovery sources in context. Different types of chemical compounds (top left) are tested against bioassays that are relevant to therapeutic targets, which are derived from several possible sources of information (right). The initial lead compounds discovered by the screening process are optimised by analogue synthesis and tested for appropriate pharmacokinetic properties. The candidate compounds then enter the development process involving regulatory toxicology studies and clinical trials.

The newer technologies, the impact of which has yet to be fully felt, include the following:

Molecular modelling and structural biology

aided by three-dimensional computer graphics (including virtual reality) allows the design of structures based on new and known molecules to enhance their desired, and to eliminate their undesired, properties to create highly selective targeted compounds. In principle all molecular structures capable of binding to a single high-affinity site can be modelled.

High throughput screening

allows the screening of millions of compounds against a single target or a cell-based screen to determine activity against the target. Traditionally these are large robotic screens but newer technologies, including use of small molecules using coding tags, allow miniaturisation of the process. The quality of the ‘hit’ which is the starting point for medicinal chemistry ‘lead optimisation’, depends on the quality of the molecules in the compound collection and the nature of the biochemical target used for the screen.

Fragments

If the crystal structure of the protein target is known it is possible to screen small fragments of potential drugs to find those that bind and where they bind. It is then possible to construct a drug by adding fragments.

Proteins as medicines: biotechnology

The targets of most drugs are proteins (cell receptors, enzymes) and it is only lack of technology that has hitherto prevented the exploitation of proteins (and peptides) as medicines. This technology is now available and some of the most successful new medicines of the last few years have been biological – antibodies or petides. The practical limitations are that (1) they need to be injected, as they are digested when swallowed and (2) they target soluble factors and targets on the cell membrane but are generally unable to target intracellular proteins. However, these limitations are offset by their high degree of specificity, their often very long half-life (for antibodies) that means that the medicine may be given by monthly injections, and the more predictable toxicity when compared to the rather unpredictable effect of classical small molecule drugs (the usual ‘white pills’). Biotechnology involves the use of recombinant DNA technology/genetic engineering to clone and express human genes, for example in microbial (Escherichia coli or yeast) cells so that they manufacture proteins. Such techniques can deliver hormones and autacoids in commercial amounts (such as insulin and growth hormone, erythropoietins, cell growth factors and plasminogen activators, interferons, vaccines and – probably most important – antibodies).

Transgenic animals (that breed true for the gene) are also used as models for human disease as well as for production of medicines.

Antisense approaches
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