I’ve had a little bit of experience in drug discovery. During my (chemistry) undergraduate, I completed a year’s industrial placement in a big pharma company working in lead optimisation. I made analogues of a target compound for SAR (structural activity relationship) studies. I churned out variations of a particular molecule identified by biologists from high throughput screening and then passed them on to a pharmacology team for assessment. The medicinal chemistry section I was part of had little input into either of the preceding or following processes.
The confusion (assuming it’s not just me of course) could be a remnant of the ‘old’ ways of drug discovery. Traditionally each step, and indeed each contributing discipline, was quite separate. Biologists worked in the early stages on target identification and validation, medicinal chemists worked on lead discovery and optimisation and toxicologists and pharmacologists worked on safety and drug metabolism. This is before the involvement of clinicians in the clinical trials stages. Each team of scientists worked quite separately on their individual section of the chain.
However, the pharmaceutical landscape has undergone considerable change since I was part of it six years ago. Once dominated by big multinational pharma companies, an ecosystem of collaborative research partners has now emerged. This encompasses small and large pharma, SMEs, academia, health charities and the NHS with each contributing complementary skills and expertise. As such, interdisciplinarity and researcher mobility across the academic-industry divide (another common separator) are becoming increasingly important.
So, in the spirit of interdisciplinarity, here’s a bit of a ‘beginner’s guide’ to the drug discovery pipeline. (Note: many variations of the steps in the pipeline exist – the below is my interpretation and is intended only as a guide).
It all begins with Target Identification. A thorough understanding of the disease mechanisms and the role of enzymes, receptors and/or proteins is vital. Identifying the biological origin of a disease leads to the discovery of potential targets for intervention.
Next up is Target Validation; the step often cited as one of the most challenging and a common reason for the later failure of drug discovery projects. It’s been estimated that around 75% of failures in phase II trials result from ineffective initial validation. In general terms, most drugs are inhibitors that block the action of a particular target protein. However, the only way to be completely certain that a protein is instrumental in a given disease is to test the idea in humans. Obviously such clinical trials cannot be used for initial drug discovery, which means that a potential target must undergo a validation process; its role in disease must be clearly defined before drugs are sought that act against it. Not an easy task!
The process continues with Lead Identification. Finding chemical starting points for drug discovery projects often involves the screening of large chemical ‘libraries’ of small molecules in an automated manner (often known as an HTS, a high throughput screen). Alternatively knowledge of the target (or closely related targets) can be used to design inhibitors in silico or select focused sets of compounds displaying complimentary shapes and properties for screening. Verification of active compounds identified through any screening approach is an important part of the drug discovery process. Through a rigorous evaluation of potential hits the most promising compounds are selected to progress from ‘hit’ to ‘lead’.
Once a lead compound has been identified, the process of Lead Optimisation begins. The goal of this stage is to identify compounds suitable for testing in a clinical setting. In order to achieve this, structural features of the lead compound are modified in order to achieve an optimised profile in terms of a variety of parameters including; action at the desired target, toxicity, oral absorption, metabolic clearance and activity in an animal model of the disease.
Once an active compound has been identified (the ‘drug’), it must undergo thorough testing of its biological and physicochemical properties. The absorption, distribution, metabolism, excretion and toxicity of the drug (ADMET) are probed. Or in other words, what the body does to the drug rather than what the drug does to the body.
It can take many years (and millions of pounds) to reach the Pre-clinical stage. This precedes the initiation of clinical trials and is when important feasibility, iterative testing and drug safety data is collected. The main goals of pre-clinical studies are to determine a product’s ultimate safety profile.
When the drug discovery process reaches the stage when people are involved, the pipeline has reached the clinical trial steps. The earlier phases look at whether a drug is safe and the side effects it can cause (Phase I into Phase II). Initial research is performed on human tissue before volunteers (who may or may not have a health problem) are enlisted to assess the effects and safety of a new treatment. Later phases aim to test whether a new treatment is better than existing treatments and are performed on volunteers with a particular health problem (Phase II into Phase III). A drug will usually be tested against another treatment; this will either be a substance containing no medication (a placebo) or a standard treatment that is already in use. These trials can often last a year or more and involve several thousand patients.
The final stage in the drug discovery process is Approval – it takes on average 10-15 years to reach this stage and only a very small percentage of drug candidates ever make it. The drug must meet a number of stringent criteria and be granted the appropriate licences before it reaches the market. These differ depending on the country where the drug will be marketed; for example American and European approval processes can be quite different.
With that my brief tour along the drug discovery pipeline is complete. However, it should be pointed out that biologic drugs have grown increasingly dominant in the research and development efforts of pharmaceutical companies in the past decade — a marked shift from the industry’s strong focus on small-molecule drugs in the 1990s. Biologic products, which include monoclonal antibodies, vaccines and cell therapies, made up 8% of total pharmaceutical sales in 2002 but 17% in 2012, according to a recent report by the Tufts Center for the Study of Drug Development in Boston, Massachusetts.
However, no matter what future changes the drug discovery industry in the UK may undergo, the principals of interdisciplinary working and researcher mobility and permeability look set to stay.
Hopefully, like me, you’re now a little less confused by the drug discovery process!