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).