By Sabrina Hossain, University of Birmingham
The progression of drug discovery and development over the last 50 years has been rather exciting for scientists and the community to follow. The drastic improvements of the techniques used to understand the molecular basis of diseases, alongside more competent machinery for a faster drug production line, has led to significant benefits for global health. However, in what should theoretically be the peak of excellence for modern-day drug discovery, the biopharmaceutical industry is faced with a ‘productivity problem’ or ‘reproducibility crisis’.
Despite seemingly having everything in its favour, modern-day drug discovery and development has been slowing down in production, with Research and Development (R&D) expenditure constantly increasing per year, and drug pipelines drying up faster.
The productivity problem is essentially that that the annual flux of drugs being brought successfully into market (meaning that the chemical compound of interest has passed all stages of human clinical trials and has been approved of for distribution by regulating bodies such as the US FDA or the UK MHRA) has remained at a constant rate of around 20-30 chemical compounds. Even though the end of the 2017 saw one of the highest drug approval rates in over 20 years, of 46 drugs being approved by the US FDA, this came at the expense of the costliest Research and Development year for the major pharmaceutical companies, and lower financial returns overall.
How do we refine modern day drug discovery?
“The most fruitful basis of the discovery of a new drug is to start with an old drug” – James Black.
As Nobel prize winning pharmacologist, James Black, said the best way for drug discovery is to start with an already established drug, and this is the basis of drug redeployment.
Drug redeployment or repositioning, is the application of an already synthesised drug (approved of or not) from its original indication, into a new indication. There are several advantages of using drug redeployment as opposed to de novo drug synthesis, in which drugs are discovered and developed from scratch. The two major benefits being time and costs. On average, a novel drug synthesised from de novo synthesis takes between 10 – 17 years, costing an average of $2.6 billion (USD), whereas with drug redeployment this process takes between 3 – 12 years and costing between $8.4 – $41.3 million (USD).
So why does drug redeployment take less time and why is it significantly cheaper? This is because a lot of information exists about drugs which have already been discovered and developed, for example, pharmacodynamics (the biological effect of the drug inside the body) and pharmacokinetics (the way the drug behaves inside the body). For these reasons, pharmaceutical companies can often skip laborious initial screening processes and in some cases even skip Phase I human clinical trials due to known toxicity or doses from prior trials. Also, in a lot of cases, established and previously approved drugs have years of Phase IV clinical trial information available about their safety and side effect profiles, which can be extremely useful when assessing if a drug can be used for treating a different disease or problem from the one it was originally approved to target.
Has this form of drug discovery ever been done before?
Drug redeployment has been applied into the drug discovery process for many decades, just indirectly. A famous case of a redeployed drug includes the tragic drug thalidomide, originally used to treat morning sickness in expectant mothers. The drug was discontinued after 4 years of production for causing severe birth defects in newborns with over 10,000 cases reported across a spread of 46 countries. Following on from this, thalidomide was prescribed to a male patient suffering a rare form of leprosy known as erythema nodosum leprosum (ENL), for its sedative purposes, to relieve the patient from the painful boils that prevented him from sleeping. The following morning, the doctor was shocked to discover that not only had the patient slept well, but the drug had also somehow managed to treat the symptoms of ENL. Thalidomide later became one of the first drugs used to treat ENL and a starting point for the development of even better drugs to treat this rare condition.
Asides from serendipity, drug redeployment can be achieved more systematically. For example, the drug bromocriptine was launched by pharma company Sandoz in 1965, marketed as a drug to treat Parkinson’s disease. In 2009, the drug was redeployed and approved of for usage in order to treat type II diabetes through design of a ‘quick-release’ formulation. Bromocriptine ability as a D2-dopamine agonist allows for its usage in both indications.
There certainly is a deficit in the market for drugs that needs addressing, especially medicines in relation to rare disease and the 300 million people affected by them, and also diseases niche to lower income countries. Drug redeployment has been recognised as a growing field of importance with more scientists and businesses keen to learn how to implement this new turn of drug discovery and development, with events such as the Drug Repositioning, Rescuing and Repurposing conference held annually in Chicago.
Currently, the field is in its infancy and with the right recognition and funding, the movement can be propelled leading to faster and cheaper drug discovery.
- Chong, C.R. and Sullivan, D. J. (2007) New uses for old drugs. Nature, 448(7154), pp. 645-646.
- Gordon, J. N. and Goggin, P. M. Thalidomide and its derivatives: emerging from the wilderness. Postgrad Med J. 2003 Mar;79(929):127-32.
- Mehndiratta, M.M., Wadhai, S.A., Tyagi, B.K., Gulati, N.S. and Sinha, M. (2016) ‘Drug repositioning’, International Journal of Epilepsy, 3(2), pp. 91-94.
- Scannell, J.W. and Bosley, J. (2016) When Quality Beats Quantity: Decision Theory, Drug Discovery, and the Reproducibility Crisis, PLOS ONE, 11(2), pp. e0147215.
- Thor, K.B. and Ashburn, T.T. (2004) Drug repositioning: identifying and developing new uses for existing drugs. Nature Reviews Drug Discovery, 3(8), pp. 673-683.
I am 3rd year undergraduate student studying Biochemistry at the University of Birmingham, United Kingdom. I am also available on Twitter @beaniehos.