International Journal of Pharma Research & Review, Apr 2016;5(4):29-33 ISSN:2278-6074 W David Strain et.al, IJPRR2016;5(4) 29 Case Report Case study in drug discovery and development: When it doesn't go to plan Denufosol for the treatment of cystic fibrosis Christine Smith 1 and W David Strain 2* 1. Novo Nordisk UK Ltd, UK. 2. Diabetes and Vascular Medicine, University of Exeter Medical School, UK. ABSTRACT In current healthcare provision there is an ever growing focus on acquisition cost of pharmacological interventions, and whether they represent value for money. It is often forgotten that for every “breakthrough” drug that makes it onto our formularies, approximately 1000 never get beyond phase 1 clinical trials. Even once this hurdle is passed, there are many more obstacles that stand in the way of a new medication ever being prescribed. The cost of the development of these failed medications is incorporated into the cost of every new product that is brought to market, therefore, every effort is made to ensure, once a product gets to the final stages of development it is used in the most appropriate population using the most appropriate outcomes in order to demonstrate its maximal efficiency. Keywords: Pharmacological interventions, formularies Received 1 Mar 2016 Received in revised form 27 Apr 2016 Accepted 30 Apr 2016 * Address for correspondence W David Strain, Diabetes and Vascular Medicine, University of Exeter Medical School, Barrack Road, Exeter EX2 5AX, UK. E-mail: d.strain@exeter.ac.uk CASE STUDY We present the case of denufosol, a drug that was developed for the treatment of cystic fibrosis. Despite promising results in phase 1 and 2 studies, it failed to achieve clinically meaningful results in final phases of development and thus the potential benefits were never realised. We discuss the potential pitfalls in the trial design and the choice of outcomes used to highlight some considerations for potential investigators, and people considering clinical trial designs Cystic Fibrosis, also known as mucoviscidosis, is an autosomal recessive disorder caused by an abnormality in both copies of the gene that regulates the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Approximately 1 in 25 adults in the UK carry the faulty gene, however in the heterozygous state there are almost no visible effects. The homozygous recessive state occurs in 1:3,000 live-births in those of Northern European ancestry, although with much less frequency in those of Asian or Black African Origin. The absence of a functioning gene causes a failure of the chloride ion channel in part responsible for creating secretions, such as sweat, digestive fluids and mucus to become too thick. The channel comprises of two domains Trans membrane domains, each containing 6 alpha helices and capable of hydrolyzing (i.e. deriving energy from) ATP. It is regulated by phosphorylation, predominantly by cAMP- dependent protein kinase, and is anchored to the cellular cytoskeleton at the carboxyl terminal. The channel is primarily responsible for the movement of water and halogens, predominantly chlorine, out of, and in the case of sweat glands into, the cell. In the sweat glands this results in excess amounts of chlorine and thiocyanate (another substrate of the channel) remaining in the gland. The negative charge of the chlorine is neutralized by the cation, sodium, resulting in excessive salt in the sweat, which forms the basis of the Sweat Test for the diagnosis of cystic fibrosis. In other tissues, the principle pathology is caused by a lack of flow of water into the extracellular space. This causes hyperviscosity of the secretions. In the airways this also leads to a deficiency of the Airway Surface Liquid (ASL), in which the cilia operate. In the absence of this ASL, the cilia cannot effectively clear the thick mucus, resulting in blockage of the small airways. Further, the thick nutrient-rich