A new era in cystic fibrosis therapy
Shanker Krishna, Respiratory Account Director, Touch Medical Media, UK
Insights into ivacaftor as a game-changing therapy for cystic fibrosis, discussed at the ATS Annual Meeting, Washington DC, May 19–24, 2017
Cystic fibrosis (CF) is an inherited condition caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. This prevents chloride transport in epithelial cells and leads to the accumulation of thick, viscous mucus in the respiratory, digestive and reproductive systems. This mucus is particularly problematic in the lungs since it accumulates and blocks the airways, leading to breathing difficulties.1 The incidence of CF in Europe and the US is 1 in every 2000–3000 live births,2 making it one of the most widespread life-shortening genetic diseases.
Until recently, the only therapeutic options for CF involved removing mucus from the lungs and treating lung infections. However, in the last decade, the treatment landscape for CF has been transformed, adding years to the lives of people with CF.3 Today the median predicted survival age is close to 40, a dramatic improvement from the 1950s, when children with CF rarely lived into their teens.3
This dramatic improvement in survival has been largely due to discovery of the CFTR gene in 1989. Around 2,000 mutations in this gene have been identified, 242 of which have been found to cause CF. Despite this diversity, 85–90% of white people with CF have at least one copy of the F508del mutation.4 Genotyping of people with CF is now routine procedure.
A number of small molecules are able to treat the underlying cause of CF by targeting the defect in the CFTR protein. Chief among them is ivacaftor (Kalydeco®, Vertex Pharma), which was approved by the FDA in January 2012 for the treatment of CF in adults and children age 6 and older with specific gating mutations (one of 10) in the CF gene. Approval was based on a phase III clinical trial in which, compared with placebo, ivacaftor showed improvements in lung function at 2 weeks that were sustained at 48 weeks.5 Since then, its use has been expanded; in May 2017, another 23 mutations were added to those treatable in patients aged 2 and above.6 Approval was based partly on data from test results in laboratory-grown cells with rare CF-causing mutations. This use of precision medicine is a landmark development in the approval process, since many rare CF mutations have such small patient populations that clinical trial studies are not feasible. Vertex and the FDA are now discussing the possible approval of additional mutations.
A combined therapy including ivacaftor and another agent targeting CFTR, lumacaftor (Orkambi®, Vertex Pharma), has also been approved for people with CF with two copies of F508del (around half of those with the condition).7 However, high discontinuation rates due to respiratory problems8 and the cost of treatment have limited the uptake of this drug.
Other therapies targeting the F508del mutation are currently in clinical development. Vertex recently announced positive data from two phase III trials investigating the combination of tezacaftor (VX-661) and ivacaftor.9 Tezacaftor has a more favorable pharmacokinetic profile than lumacaftor, allowing once-daily dosing.10
However, not all agents targeting the F508del mutation have proved successful. Ataluren (TranslarnaTM, PTC Therapeutics) appeared promising in early studies but its development was halted in March this year following its failure to meet the endpoint of a phase III clinical trial.11 However, new therapies may be on the horizon. A triple therapy involving next-generation CFTR therapies VX-152 and VX-440 with tezacaftor and ivacaftor is being investigated.10
Other CFTR modulators currently in clinical development include agents that can directly and indirectly modulate the nitric oxide pathway, including the phosphodiesterase-5 inhibitor sildenafil; the guanylate cyclase stimulator riociguat; and a new class of small molecule inhibitors of S-nitrosoglutathione reductase, of which N1115 is being investigated.12
At the preclinical stage, thymosin alpha 1 (Tα1), a synthetic version of a natural polypeptide, has generated considerable interest owing to its ability to simultaneously reduce the inflammation typical of CF and improve the activity, maturation, and stability of CFTR.13
The cloning of the CFTR gene led to the hope that gene replacement therapy might be effective in CF; however, the thickened secretions and airflow obstruction in the lungs of people with CF make the delivery of a gene vector extremely challenging.14 Current research is focused on nanoparticles and intranasal delivery of liposomal gene carriers.
Because of the rarity of many CF mutations, there is an urgent need for innovative CFTR biomarkers and study designs. Many preclinical studies are using primary bronchial epithelial cell lines and airway epithelial cells obtained from stem cells to evaluate responses to CFTR modulator therapy.12 A number of questions also remain around the optimal use of ivacaftor. Firstly, while we now know that ivacaftor is safe and effective in children aged 2 years and above, further study is required to determine whether this can be extended to the new born period. We also need more long-term data on the benefits and safety of ivacaftor, both alone and in combination.
In summary, the approval of ivacaftor represents a landmark in CF therapy, heralding a new era of optimism for patients with CF and their care providers.
References1. NIH, Cystic Fibrosis Fact Sheet, Available at: https://report.nih.gov/NIHfactsheets/ViewFactSheet.aspx?csid=36 (accessed June 7, 2017).
2. WHO, Genes and human disease, Available at: www.who.int/genomics/public/geneticdiseases/en/index2.html (accessed June 7, 2017).
3. Smyth AR, Bell SC, Bojcin S, et al., European Cystic Fibrosis Society Standards of Care: Best Practice Guidelines, J Cyst Fibros, 2014;13 Suppl 1:S23–42.
4. Bobadilla JL, Macek M, Jr., Fine JP, et al., Cystic fibrosis: a worldwide analysis of CFTR mutations – correlation with incidence data and application to screening, Hum Mutat, 2002;19:575–606.
5. Ramsey BW, Davies J, McElvaney NG, et al., A CFTR potentiator in patients with cystic fibrosis and the G551D mutation, N Engl J Med, 2011;365:1663–72.
6. FDA, FDA expands approved use of Kalydeco to treat additional mutations of cystic fibrosis, Available at: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm559212.htm (accessed June 7, 2017).
7. Wainwright CE, Elborn JS, Ramsey BW, et al., Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR, N Engl J Med, 2015;373:220–31.
8. Hubert D, Chiron R, Camara B, et al., Real-life initiation of lumacaftor/ivacaftor combination in adults with cystic fibrosis homozygous for the Phe508del CFTR mutation and severe lung disease, J Cyst Fibros, 2017;16:388–91.
9. Vertex, Two Phase 3 Studies of the Tezacaftor/Ivacaftor Combination Treatment Met Primary Endpoints with Statistically Significant Improvements in Lung Function (FEV1) in People with Cystic Fibrosis, Available at: http://investors.vrtx.com/releasedetail.cfm?ReleaseID=1019156 (accessed June 7, 2017).
10. Cystic Fibrosis News Today, Tezacaftor (VX-661) for Cystic Fibrosis, Available at: https://cysticfibrosisnewstoday.com/tezacaftor-vx-661-for-cystic-fibrosis (accessed June 7, 2017).
11. Genetic Engineering & Biotechnology News, PTC Halts Translarna Development in Cystic Fibrosis after Phase III Failure, Available at: www.genengnews.com/gen-news-highlights/ptc-halts-translarna-development-in-cystic-fibrosis-after-phase-iii-failure/81253964 (accessed June 7, 2017).
12. Quon BS, Rowe SM, New and emerging targeted therapies for cystic fibrosis, BMJ, 2016;352:i859.
13. Romani L, Oikonomou V, Moretti S, et al., Thymosin alpha1 represents a potential potent single-molecule-based therapy for cystic fibrosis, Nat Med, 2017;23:590–600.
14. Armstrong DK, Cunningham S, Davies JC, et al., Gene therapy in cystic fibrosis, Arch Dis Child, 2014;99:465–8.