Introduction
When considering the success and cost of taking a molecule from the laboratory to an approved drug, the statistics are sobering. Of 1,000 candidate therapeutics being considered during the pre-clinical phase, only one will go on to clinical trials(1). Of the candidate drugs that enter testing in humans, only 10% will go on to be approved by the FDA(2). The average cost of developing one drug approved by the FDA is $2.6B with another $300M in post-marketing costs(3). Not only is drug development expensive, it is also time consuming. It typically takes 12-15 years for a drug to go from preclinical testing to approval(4). These statistics account for the pharmaceutical industry mantra, “An early kill is a good kill”. The sooner an industry sponsor can eliminate a candidate drug from its portfolio that will ultimately fail, the smaller the financial loss. It is within this backdrop that patients, healthcare providers, and biomedical researchers must operate. These realities often make developing drugs for orphan diseases like cystic fibrosis (CF) difficult. Large pharmaceutical sponsors often focus on diseases that have been shown to respond to treatment or that affect millions of people, where risk of failure is lower and the potential return-on-investment is much greater. Smaller biotechnology firms are often willing to take a chance on orphan diseases where the competition is less but frequently lack the capital to carry drug development to its completion. These smaller firms become dependent on outside support, such as angel funding and venture philanthropy to continue to move drug development forward. Despite these realities, the vision of the CF Foundation, particularly in its development of the Therapeutics Development Network in 1998(5), has led to an astounding number of new therapies being approved for people with CF considering the status of CF as an orphan disease. More industry sponsors are willing to consider developing new drugs for CF because the financial support of the CF Foundation has mitigated some of the risks associated with drug development and helped smaller firms bridge the gap between angel funding and venture capitalism.
In 1993, the FDA approved dornase alfa, the first drug developed specifically for CF(6). Since that time, multiple drugs have been approved to treat a variety of aspects of CF, including the abnormal cystic fibrosis transmembrane conductance regulator (CFTR) protein, mucus obstruction, bacterial infection, and gastrointestinal and nutritional disease (Figure 1). Many other candidate drugs are currently in clinical trials or preclinical evaluation, including potential therapies that can repair/replace abnormal RNA or DNA (https://www.cff.org/Trials/Pipeline. Accessed June 20, 2020). The development of modulator therapy to address the primary defect in the CFTR protein began in the late 1990s when high-throughput screening was first used to identify small molecules that could potentiate or correct CFTR dysfunction. This culminated with the 2019 approval of elexacaftor/tezacaftor/ivacaftor which provides highly-effective modulator therapy for approximately 90% of people with CF 12 years of age and older(7). Drug development for CF has become increasingly complex over the last 20 years, and clinical trial endpoints are changing because traditional endpoints are becoming less common events. In this manuscript, we will provide an overview of how a molecule goes from a drug candidate in the laboratory to an approved drug therapy for a patient (Figure 2).