Cystic fibrosis (CF) is an autosomal recessive disorder affecting thousands of people worldwide. When this genetic disease was first discovered in the first half of the 20th century, the median survival was approximately 5 years of age. Since then, median survival for patients with CF has steadily improved. Today, it is 47.4 years based on Cystic Fibrosis Foundation registry data from 2018. Patients with CF are living longer and staying healthier; the discussion to follow is how patients, researchers, and the CF Foundation reached this point.
Dr. James David Finklea Jr.
In 1938, pediatrician and pathologist Dorothy Anderson observed on the autopsies of children thought to have celiac disease pancreatic lesions she termed “cystic fibrosis of the pancreas.” In addition to the abnormal pancreas, she noted abnormal lungs filled with mucus that obstructed the airways.
Paul Di Sant’Agnese recognized during a heatwave in late 1948 that children with CF were routinely being diagnosed with heatstroke and dehydration. This helped lead to the discovery that these children had elevated salt content in their sweat, paving the way for the development of the sweat chloride test in 1959 by Gibson and Cooke. Not only did Dr. Di Sant’Agnese recognize excess salt in the sweat of patients with CF, but with the help of several concerned parents of children with CF, he established the Cystic Fibrosis Foundation in 1955. The Foundation helped organize the care center model over the next decades, increasing from 30 care centers in 1962 to over 100 in 1978. The care center model also developed a patient registry to track patient care longitudinally.
In June 1989, Francis Collins and Lap-Chee Tsui discovered the location of the CF transmembrane conductance regulator (CFTR) protein using a novel technique called chromosome jumping (Rommens JM, et al. Science. 1989;245[4922]1059). The discovery was a breakthrough in basic science research, but it would take 3 more decades before this discovery could be translated into a medication that could be used by most patients for everyday care.
In the early 1990s, when median survival for patients with CF was 29 years of age, the CF Foundation and Genentech, Inc., coordinated a 24-week multicenter double-blind randomized control trial (RCT) for a new inhaled medication that digested the extracellular DNA from the neutrophils that accumulated in the airways of patients with CF. Inhaled recombinant human DNase in these patients reduced the risk of pulmonary exacerbations and also had a small improvement in pulmonary function in the group compared with the placebo group (Fuchs H, et al. N Engl J Med. 1994;331:637). Five years later, another double-blind RCT demonstrated that inhaled tobramycin in patients with CF whose disease was colonized with Pseudomonas aeruginosa improved pulmonary function and reduced the risk of hospitalizations (Ramsey B, et al. N Engl J Med. 1999;340:23). In 2006, the use of hypertonic saline solution in patients with CF decreased the overall pulmonary exacerbation rate (Elkins MR, et al. N Engl J Med. 2006;354:229). The combination of these inhaled medications, along with inhaled aztreonam, formed the backbone of inhalation therapy for CF care today.
In 1998, even with the ongoing development and approval of new CF medications by the pharmaceutical industry, Robert Beall, CEO of the CF Foundation, realized that he needed to challenge the current drug development paradigm. Instead of trying to convince companies to develop CF medications, he started a concept called venture philanthropy. This concept entailed the CF Foundation financially investing in pharmaceutical companies’ development of new medications. The Foundation first invested in a small company named Aurora Biosciences (known today as Vertex Pharmaceuticals) in 2000. Aurora Biosciences specialized in high throughput screening. This process uses a unique technology allowing one to test the therapeutic reaction of airway cells to thousands of chemical compounds in a single day, instead of using the traditional process of tediously pipetting compounds one by one. Today, the CF Foundation has invested millions of dollars into bioscience research to advance CF care.
In 2011, the results of a study were published in which a small molecule altered defective CFTR protein in patients with CF with the CFTR mutation G551D, thus improving chloride transport at the airway surface. In the original study, after 24 weeks of therapy receiving the medication known as ivacaftor, predicted FEV1 in patients with CF improved 10.6%, and the patients were 55% less likely to have a pulmonary exacerbation compared with those receiving a placebo. This breakthrough provided patients with CF the first medication that could correct the CFTR at the source of the problem (Ramsey BW, et al. N Engl J Med. 2011;365:1663). Ivacaftor was approved by the US FDA in 2012.
Ivacaftor provided proof of concept that using small molecules could improve CFTR function. Ivacaftor was only beneficial to a small percentage of patients and was not effective in patients with CF who had either 1 or 2 F508del CFTR mutations. In 2015, patients with CF with F508del homozygous treated with a combination therapy of lumacaftor/ivacaftor had predicted FEV1% improved 2.6% to 4.0%. More importantly, there was a significant reduction in the number of pulmonary exacerbations per year compared with placebo. Unexpectedly, some of the patients experienced bronchoconstriction while receiving lumacaftor/ivacaftor (Wainwright CE, et al. N Engl J Med. 2015; 373:220). The problem was recognized, and a new small molecule to improve the processing and trafficking of CFTR called tezacaftor was developed. The combination of tezacaftor/ivacaftor in patients with CF who were F508del homozygous demonstrated a similar reduction in pulmonary exacerbations, an absolute improvement of predicted FEV1 of 4%, and no increased respiratory symptoms compared with the placebo arm (Taylor-Cousar JL, et al. N Engl J Med. 2017;377[21]2013).
CFTR modulators were a major breakthrough for patients with CF, but the efficacy of these therapies was dependent on the patients’ genotype and ranged from mildly to moderately effective. Unfortunately, these therapies were ineffective for the patients who were delta 508 heterozygotes. Starting in the summer of 2018, VX 445-tezacaftor-ivacaftor (ETI) was compared with placebo in patients with CF who were 1 copy of F508del and a second CFTR mutation that has minimal function. The study found an absolute improvement in predicted FEV1 of 14.3% and a 63% reduction in exacerbations at 24 weeks compared with placebo (Middleton PG, et al. N Engl J Med. 2019;381:1809). In late 2019, based on these data, ETI was approved by the FDA for all patients with CF who were F508del heterozygous. This innovation provided effective therapy to 90% of the CF population.
With the discovery of many highly effective therapies beneficial in most patients, the CF Foundation started a program called Path to a Cure to find therapies for the 10% of patients with CF who were not candidates for ETI or other CFTR modulators. This program looks to develop novel methods to restore CFTR protein function and repair or replace the CFTR protein via gene editing or gene transfer. This process creates many challenges that are quite complex, but patients, researchers, physicians, and CF Foundation will not stop working until CF stands for CURE FOUND.
Today, patients with CF are living longer, and many are eligible or have already started ETI therapy. This medication and the many others being developed will hopefully lead to patients with CF living a normal lifespan in the near future.
Dr. Finklea is Assistant Professor of Medicine, Division of Pulmonary and Critical Care, University of Texas Southwestern, Dallas, Texas. Dr. Finklea receives grant support from the Cystic Fibrosis Foundation.