All Hands on Deck Alice McDowell explores the need for collaborative drug discovery programmes
Drugs have been a fundamental component of medicine for most of human history — traditional knowledge of plant extracts, passed down for many centuries, is the origin of around a quarter of all modern medicinal drugs. Opium, for instance, has been used for pain relief for 5,000 years and willow bark was used to reduce fevers for at least 3,000 years before the chemical structure of its active component was discovered, synthesised, and marketed as aspirin. For those of us fortunate enough to have access to them, the drugs available today protect and prolong our lives in innumerable ways. With anaesthetics to facilitate surgical interventions, antibiotics to protect us from deadly infections, and hormones that enable us to manage conditions such as diabetes, it can be easy to take modern medicine for granted. When disaster strikes, it is the absence of drugs for diseases like cancer, multiple sclerosis, dementia, and (at the time of writing) COVID-19, of which we are most acutely aware. So the question becomes: what do we do when we need new drugs? At present, the drug development pipeline is lengthy, expensive, and inefficient. Drug discovery often begins with screening large libraries of small-molecule compounds against biological targets. These targets are usually proteins which can potentially be manipulated for therapeutic benefit. Hits from these screens then undergo further validation in cultured cells and animal models of human disease. A long process of preclinical testing and improvement follows, in which a number of pharmacological properties of the drug candidate are determined. If a candidate is successful up to this point, several rounds of human clinical trials can begin to further gauge safety, dose, and efficacy of the drug. If the drug passes all of these trials and gains approval by regulatory bodies, only then can the structure of the final product be patented, and the drug manufactured, marketed, and distributed. This system requires massive financial investment, because so much work goes into drug candidates that eventually fail and produce no financial return. Despite 24
All Hands on Deck
improvements like the use of artificial intelligence for target identification, bringing a new drug to market takes an average of 10 years and £1 billion. Financing is a natural stumbling block to drug development, but fundraising becomes nearly impossible if the drug in question must be provided at low cost, or to a relatively small number of rare disease sufferers. The financial motives of pharmaceutical companies inevitably cause progress on less profitable drugs to stagnate. Research on partially-developed drugs that are not profitable enough to take further is locked away. For drugs that do make it to market, researching alternative applications to potentially extend their benefits is almost impossible until their patents expire. Even then, accessing the original research can be difficult and expensive. In contrast, when pharmaceutical companies do agree to share data, significant discoveries can be made. For example, AstraZeneca has provided anti-cancer antibody-drug conjugates (ADCs) to researchers wishing to repurpose them as a treatment for African sleeping sickness, an often fatal parasitic disease caused by African trypanosomes. Existing drugs for this disease are not always fully effective and often have severe side effects, which means that new drugs are desperately needed. Recent experiments by Dr Paula MacGregor (University of Cambridge) and her collaborators have shown that changing the antibody in an ADC to one that targets trypanosomes can produce an anti-trypanosomal therapy that is effective in mice. Since ADCs have been trialled extensively for their safety already, bringing them to market may prove cheaper and faster than would be possible for a completely novel drug. The success of projects like this is contingent on the cooperation of large pharmaceutical companies which often lack the incentives to provide it — but what if sharing data and materials that might advance medicine was the
Michaelmas 2020
