Michael Collis
Editor, Physiological News

https://doi.org/10.36866/pn.92.23

Modern drugs have revolutionised our lives and our health. The pharmaceutical and biotechnology companies responsible for these drugs invest large sums to discover and develop new therapies. The risks of failure are, however, very high. A new drug with a mechanism of action that has not been previously evaluated in man has about a 1% chance of reaching the market. Even drugs that are improvements on clinically proven therapies only have about a 10% chance of success. The failure of mechanistically novel drugs is usually due to a lack of sufficient efficacy in treating the target disease (i.e. the original hypothesis on which the new drug was based turns out to be wrong or only partially correct). Problems with absorption/metabolism or unexpected side-effects in man are further pitfalls that can afflict both novel and clinically precedented drugs stopping their development. It is hardly surprising that the pharmaceutical industry is continually investigating more efficient ways to operate and better ways to predict which new drug approaches have the best chance of being both efficacious and safe. Despite this, the industry is going through a major consolidation with many mergers and takeovers with the unfortunate result that overall research capacity is reducing. The process of discovering and developing new drugs is continually evolving. In this article I will describe the process using small molecule pharmaceuticals as the example (Fig. 1). Potential biological treatments – antibodies, therapeutic proteins and genetic therapies – go through similar development processes, although the earlier research stages of selecting and optimising the best candidate drug will have specific tests based on the characteristics of the biological agent that is sought.

The initial idea that a chemical compound interacting with a particular biological protein (drug target) may be useful in the treatment of an important disease usually arises from a synthesis of published academic research, disease knowledge (including genetic information) and in-house research in the pharmaceutical or biotechnology company. Certain drug targets with discrete high affinity binding sites are amenable to interaction with low molecular weight (<500) compounds, e.g. ion channels, G-protein coupled receptors and certain classes of enzyme. Protein targets with diffuse low affinity binding sites are more likely to interact with large biological molecules than with low molecular weight chemicals. Once the idea for a new drug approach has been formulated and reviewed in a company, a research team is formed to evaluate the potential for this mechanistic approach to have efficacy in the disease of interest and to be safe. This early target validation stage (Fig. 2) utilises published knowledge on the drug target and wherever possible involves experiments to evaluate the effects of interacting with it. To do this the project team need a compound with some affinity for the target, or an anti-sense or transgenic approach to allow them to investigate the effects of stimulating or inhibiting/deleting the target in vivo. Having an ‘animal model’ of the relevant disease with predictive power regarding efficacy in man is extremely valuable at this stage. In some disease areas, such as mental health disorders, the lack of animal models that mimic some of the symptoms of disease and that have predictive power is a major impediment that prevents many companies from seeking new drugs for these complex and important disorders. As well as evaluating the potential efficacy of a new therapeutic approach, the project team will investigate what side-effects are likely to be associated with its mechanism of action and whether these would be acceptable to patients.

The next stage is to develop biological assays (screens) to identify compounds that interact with the drug target (screen development, Fig. 2). These assays (typically enzyme inhibition or receptor/channel binding) invariably use the human protein (target) of interest and are operated in vitro at very high throughput (many thousands of compounds a day) using robotics and minute reaction volumes (Fig. 3). The nanotechnology used in high-throughput drug screening is highly specialised as are the scientists who develop and run these assays. New chemical compounds and those already stored in the company collection are screened with the aim of identifying compounds referred to as ‘hits’ that bind to the drug target with micromolar affinity (Fig. 2). The synthetic chemists in the company subsequently modify the hits, usually aided by structural information on the drug target, to develop compounds known as ‘leads’ that bind with nanomolar affinity. Leads are further modified to optimise their affinity for the drug target and to reduce affinity for closely related members of the target protein family. Drugs need to have high affinity for the target, but they also need to be selective for that target. If they also bind to other enzymes, receptors or ion channels related to the target they are likely to cause unwanted side-effects. Further testing of leads in cell-based assays is then used to ensure that they have the desired effect in intact cells as well as in the test tube.
A chemical compound that has high affinity and selectivity for a drug target in in vitro assays is not a candidate drug. Drugs need to be absorbed by an acceptable route into the patient’s body and to maintain an effective concentration in the biological effect compartment for an appropriate period – usually 12–24 hours. There is often a fine balancing act to be mastered by the medicinal chemist between optimising the desirable properties of high affinity, selectivity and good absorption and slow metabolism in vivo for a candidate drug. The resulting candidate drug is usually a compromise between these properties. Once a candidate drug has been identified, it will undergo safety evaluation (safety pharmacology) to identify any unexpected adverse effects on major body systems such as the cardiovascular and nervous system.

An important activity during the early stages of the drug discovery process is identification of a biomarker of drug activity that can be used in man. Amazing as it may seem, in the past many drugs were given to patients without a clear idea of what dose was needed to have the desired biological effect. This meant that a negative result in a clinical trial provided no useful information, as it was impossible to determine whether lack of effect was because the mechanistic approach was wrong or because the dose was wrong. Nowadays companies want to identify a biological marker that can demonstrate in man that the drug is having the expected biological effect, before tests in patients are started to evaluate whether this effect is beneficial in treating the disease. If, for example, the drug inhibits an enzyme, then a biomarker might be the accumulation of the substrate for this enzyme. Only when the biomarker shows the new drug is having its expected biological action in human volunteers will the company go into clinical trials in patients.

But before the drug can be given to healthy or ill humans, toxicology studies must be performed (Fig. 1). These are designed to identify the dose (or in vivo concentration) of a new drug that causes detectable toxic effects. To do this, doses of the potential drug are increased stepwise in two species of experimental animals. Once the minimum toxic dose is known, it can be compared with the predicted therapeutic dose to decide whether the drug has a sufficient margin of safety to be given to humans. All drugs have adverse effects at some dose, but there is no fixed safety margin that must be achieved. The acceptable safety margin (therapeutic index) for a new drug depends on the medical scenario in which it will be used – a narrow safety window may be acceptable for an acute treatment for a life-threatening disorder for which there is no current therapy, a much greater safety window will be required for less serious diseases and those where there are already treatments available.

Once the candidate drug has been shown to have an acceptable therapeutic index it can be administered to man for the first time in Phase I volunteer studies (Fig. 1). These studies in normal individuals involve administration of very low doses to assess the absorption and metabolism of the compound, ensuring that it can reach the effective concentration by an appropriate route and persist for long enough to allow an acceptable dosing regimen. This is where a biomarker of the drug’s activity is so important as it will allow the scientist to define the relationship between the dose of drug, its plasma concentration and its biological effect and will define the dose to be used in the first patient studies. Phase I volunteer studies can also reveal subtle side-effects that could not be observed in safety pharmacology or toxicology studies in animals. Occasionally this reveals a potentially very useful unexpected effect of the drug. Remember that Viagra was designed for heart disease (by increasing cyclic GMP levels causing coronary vasodilatation and inhibiting platelet aggregation), but its interesting and important effects on male erectile function were identified in Phase I volunteer studies. (Further volunteer studies involved the use of instruments such as the ‘rigiscan’ and ‘top shelf’ visual stimulation – but that is another story!)

The next stage in the development process sees the new drug being given to patients in Phase II clinical trials. These clinical studies are designed and powered to answer the question, does this new drug benefit the patient? Phase II studies are usually conducted at a small number of specialist clinical centres using carefully selected patients to provide a relatively homogeneous group to allow efficacy to be evaluated using small groups (circa 100 per treatment group). If the new drug shows significant activity in the phase II trials (clinical proof of concept), then the decision will be made whether this is sufficient to progress into phase III clinical studies.

Phase III clinical trials tend to be worldwide and can involve from 3000 to 5000 patients. They are very expensive and pharmaceutical and biotechnology companies are very careful when deciding which potential new drugs are progressed to this stage. If a drug fails in phase III, perhaps because of a side-effect not seen in the smaller phase II studies, it is extremely bad news for the sponsoring company, which will have spent a great deal of money on it by this stage. Phase III clinical trials build a large database of evidence for efficacy and safety for a new drug. They also allow evaluation in different patient groups and different ethnicities and comparison with existing ‘best care’ therapy. If a new drug doesn’t have a clear advantage over the existing therapies, then it isn’t going to be successful and isn’t worth progressing.

Accumulating an enormous amount of pre-clinical and clinical information about a new drug isn’t the end of the discovery and development process. All of this data has to be submitted to the government regulatory authorities, e.g. the FDA, who approve the marketing of new drugs. The regulators scrutinise all the data the company have submitted and often ask for further studies to be performed. The path of drug discovery and development isn’t linear; there is much potential for having to repeat steps and initiate new studies or even ditch the original compound and progress a different one. After a period of review and evaluation by the regulatory bodies (which can take up to two years) the sponsoring company may finally get approval to market the new drug for a particular disease and at a specified dose range. Over 10 years will have passed from the initiation of the programme – drug discoverers need a lot of patience. If an industrial scientist is involved with one drug in his/her lifetime that goes through the whole discovery and development process and reaches the market, he or she has done well. The costs of drug discovery and development are huge, in the region of $1 billion for each drug reaching the market. The patience, the hard work and the financial investment are justified if patients benefit from a new drug that gives them a better quality and/or length of life. If the company that discovered and developed the drug makes sufficient income from its sales, it can re-invest it in new drug discovery programmes.