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Modulator therapies for cystic fibrosis
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Modulator therapies for cystic fibrosis
development and how these have impacted upon treatment outcomes and the lives of people with CF.
Keywords CFTR modulator; corrector; cystic fibrosis; gene editing; gene therapy; organoid; personalized medicine; potentiator; therapeutics
Iram J Haq Meena Chow Parameswaran Noreen Zainal Abidin
Introduction
Attaybenes Socas
There are around 10 000 children and adults living with cystic fibrosis (CF) in the United Kingdom (UK) making it the most common life-limiting genetic disorder. Worldwide approximately 80 000 people have CF, with prevalence varying according to ethnicity. CF was historically a disease of infancy and early childhood with a very limited prognosis. However, significant advances in the understanding of the pathophysiology of CF and the development of multidisciplinary clinical care have yielded incremental improvements in survival rates with a predicted median life expectancy of a child born with CF today of 56 years.
Andrea Gonzalez-Ciscar Aaron I Gardner Malcolm Brodlie
Abstract Cystic fibrosis (CF) is a life-limiting genetic disease that arises from defects in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and protein. This causes abnormal epithelial ion transport. CF is a multisystem condition but airway infection and inflammation carry the greatest treatment burden and are the predominant cause of morbidity and mortality. Novel therapeutic strategies have recently been developed to target specific molecular defects arising from CFTR mutations. These CFTR modulator therapies are designed to correct the underlying protein processing defect or to potentiate CFTR function to improve ion transport. Such advances have revolutionized CF treatment approaches, which have previously only addressed downstream effects, and hold significant promise for the future. This review will summarize recent advances in CFTR modulator
What causes CF? The genetic causes of CF are recessive mutations in the CF transmembrane conductance regulator (CFTR) gene located on the long arm of chromosome seven. CFTR encodes for a cAMPregulated chloride channel expressed on the apical surface of epithelial cells in the respiratory, gastrointestinal, pancreatic and reproductive tracts. Although this gives rise to multisystem pathology, progressive respiratory disease is the major cause of morbidity and mortality. Dysfunctional CFTR-mediated chloride and bicarbonate transport leads to disordered airway surface liquid homeostasis, reduced mucociliary clearance and susceptibility to airway infection, most notably with Staphylococcus aureus and Pseudomonas aeruginosa. Progressive neutrophilic inflammation occurs with the eventual development of bronchiectasis and respiratory failure. Approximately 2000 CFTR variants have been identified but a much smaller number are commonly recognized as diseasecausing clinically. By far the most common mutation is F508del, a deletion of phenylalanine at codon 508, with around 90% of people with CF having at least one affected allele. CFTR mutations have been classified into six main groups based on the mechanisms underlying aberrant CFTR synthesis, trafficking and function (Table 1). Disease phenotype is partly determined by the net effect of a mutation on CFTR quantity and function. Despite this classification, there is considerable phenotypic heterogeneity amongst individuals within the same mutation class, arising from environmental, microbiological and additional ‘nonCFTR’ genetic effects.
Iram J Haq MBBS MRes MRCPCH Paediatric Respiratory Grid Trainee, Great North Children’s Hospital, Newcastle Upon Tyne, UK. Conflict of interest: None declared. Meena Chow Parameswaran MBChB Paediatric Specialty Trainee, Freeman Hospital, Newcastle Upon Tyne, UK. Conflict of interest: None declared. Noreen Zainal Abidin MBBS MRCPCH Paediatric Speciality Trainee, James Cook University Hospital, Middlesbrough, UK. Conflict of interest: None declared. Attaybenes Socas BSc MRes Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK. Conflict of interest: None declared. Andrea Gonzalez-Ciscar BMedSci (Hons) MBChB Academic Foundation Doctor, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK. Conflicts of interest: None declared. Aaron I Gardner BSc MRes PhD Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK. Conflict of interest: None declared.
How is CF managed? Introduction of the UK CF Newborn Screening Programme in 2007 has facilitated early identification of infants with CF and implementation of optimal clinical management at a young age. Traditionally, medical treatments for CF have targeted downstream effects of CFTR dysfunction on target organs. These include intensive chest physiotherapy and inhaled drugs to facilitate mucus clearance, life-long antimicrobials to combat respiratory infections and pancreatic enzyme replacement therapy and fat-soluble vitamin supplements to reduce features of
Malcolm Brodlie BSc (Hons) MB ChB MRCPCH PhD MRC Clinician Scientist and Clinical Senior Lecturer, Institute of Cellular Medicine, Newcastle University, UK and Honorary Consultant in Paediatric Respiratory Medicine, Great North Children’s Hospital, Newcastle upon Tyne, UK. Conflicts of interest: MB has been CI on investigator-led research grants from Pfizer and Roche Diagnostics; speaker fees paid to Newcastle University from Novartis, Roche Diagnostics and TEVA; travel expenses to educational meetings from Boehringer Ingelheim and Vertex.
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Please cite this article as: Haq IJ et al., Modulator therapies for cystic fibrosis, Paediatrics and Child Health, https://doi.org/10.1016/ j.paed.2019.01.011
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CFTR mutation classes and functional effects Mutation class
Example mutation
Functional effect
Potential therapy (Approved?)
IA (VII)
c.1585-1G>A 1717-1G>A c.1624G>T p.Gly542X G542X c.1521_1523delCTT p.Phe508del F508del c.1652G>A p.Gly551Asp G551D c.350G>A p.Arg117His R117H c.1364C>A p.Ala455Glu A455E c.859A>T p.Asn287Tyr N287Y
No mRNA
Bypass therapy (No)
No protein
Read-through (No)
Improper trafficking
Corrector (No) Corrector þ potentiator (Yes)
Impaired gating
Potentiator (Yes)
Reduced conductance
Potentiator (No)
Less protein
Corrector, potentiator (No)
Increased turnover
Stabilizer (No)
IB (I)
II
III
IV
V
VI
CFTR mutation classes have been summarized with examples of mutations, resultant functional effect and potential therapeutic strategies for each mutation class.
Table 1
pancreatic malabsorption and maintain nutrition. Importantly the most effective care is delivered by skilled multidisciplinary teams in a coordinated, proactive and holistic manner. While these approaches have greatly improved survival, the burden of life-long treatment is substantial. Eventual progressive respiratory failure results in lung transplantation becoming the only life-sustaining treatment, which is not a feasible option for all patients. Over the last ten years, CF therapeutics has been revolutionized by improvements in our understanding of CFTR molecular abnormalities together with application of high throughput screening assays and advanced medicinal chemistry. This approach has facilitated the investigation and development of novel small molecule therapies that target the underlying defect by modulating CFTR function. In this review, we will summarize developments in this exciting area of precision medicine.
50% of CFTR function observed in non-CF cultures. Subsequent decreases in sodium absorption and restoration of airway surface volume were also sufficient to improve cilial function and mucociliary clearance. These findings were rapidly translated to clinical trials in adults and children where significant improvements in the primary outcome assessment of lung function were demonstrated. A pivotal phase III randomized controlled trial (RCT) of 161 patients with at least one G551D allele aged 12 years published in 2011 demonstrated a 10.4 percentage point increase in predicted forced expiratory volume in 1 second (% pred. FEV1) compared with placebo after 24 weeks ivacaftor treatment. Additional benefits in secondary outcome measures included a significant mean reduction in sweat chloride of 48.1 mmol/L, weight gain of 3.1 kg and a reduction in pulmonary exacerbations by 55% after 48 weeks of treatment. Ivacaftor was commissioned for use in this patient group in the UK in 2012, with subsequent extension to younger children (currently those over 2 years of age) and people with rarer class III mutations. This equates overall to around 5% of people with CF in the UK. In 2017, the US Food and Drug Administration extended ivacaftor’s application to 33 mutations based on preclinical in vitro data and is now applicable to 9% of the US CF population. Ivacaftor is generally well tolerated by patients with minimally reported adverse outcomes in clinical trials to date. Elevation of liver enzymes is the most frequently occurring complication, with levels returning to baseline after drug discontinuation. For this reason, prescription is limited to specialist accredited CF centres and involves surveillance of liver
Development of CFTR modulators Ivacaftor as an exemplar CFTR modulator for class III gating mutations Ivacaftor, also known as VX-770 or KalydecoÔ, is a CFTR potentiator identified by high-throughput screening of over 200 000 compounds and specifically developed to target class III CFTR mutations. It functions by binding to and stabilising mutant CFTR expressed at the cell surface, where it increases its open probability and subsequent chloride transport (Figure 1). In vitro ivacaftor treatment of primary human bronchial epithelial cell cultures expressing the G551D CFTR mutation resulted in a 10fold increase in chloride secretion that corresponded to around
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Figure 1 Classes of CFTR mutations and potential therapeutics. CFTR mutations are typically categorized into one of six classes, although more recently a subdivision of class I into class IA (VII) and class IB (I) has been proposed. Class IA mutations, such as c.1585-1G > A, result in a lack of mRNA whereas class IB, such as G542X, mutations result in lack of protein. Class II mutations, including the most common mutation F508del, are associated with impaired trafficking. Class III mutations such as G551D are associated with impaired gating and class IV mutations such as R117H with reduced conductance. Low levels of CFTR are found in class V mutations, such as A455E, which arise from splicing defects. Finally, class VI mutations, such as N287Y, are associated with increased CFTR turnover at the plasma membrane. The CFTR potentiator ivacaftor approved for use in those with class III mutations has demonstrated significant improvements in lung function. Correctors such as lumacaftor, and more recently tezacaftor, have been developed as part of a co-therapy with ivacaftor for those with class II mutations. Recent phase II trials have demonstrated improvements in FEV1 with triple therapy comprising of ivacaftor, tezacaftor and the ‘next generation’ small molecules e VX-152, VX-440, VX-445 and VX-659. Based on these studies phase III trials using triple therapy with VX-445 and VX-659 are underway. More fundamental therapies such as read-through agents, gene therapy, gene editing such as CRISPR-Cas9 and CFTR amplifiers may prove beneficial for a wider range of patients, however all remain in the early stages of development.* Ataluren failed to demonstrate clinical benefit in a phase III trial for CF. y A phase II trial using non-viral gene transfer demonstrated stabilisation in lung function decline.
function. Prescribers should also be mindful of potential drug interactions. European and North American observational post-approval data has shown sustained clinical benefit for several years after starting ivacaftor, with improved lung function, lower risk of death or lung transplantation and a lower prevalence of CFassociated respiratory pathogens. Additional extrapulmonary
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benefits in G551D patients described have included resolution of intestinal pH to healthy levels, improvements in glucose handling and bone physiology. In light of the relatively recent introduction of ivacaftor, true longer-term clinical outcomes are not yet known. However, there is wide agreement amongst CF clinicians that it has substantially benefited patients with class III mutations with a notable
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studied in an open-label phase III trial. The combination therapy in this cohort had generally similar safety profiles to that observed in the larger trials with older patients. At week 24, they reported significant reductions from baseline in sweat chloride levels of 24.8 mmol/L. A significant increase in BMI was also reported which was sustained at the week 26 follow up visit. However, this study was not powered to detect a significant change in FEV1. Nonetheless, the study demonstrated a significant improvement in lung clearance index (LCI) in a subset of patients, which could support LCI as a more sensitive marker to evaluate treatment effects in younger population with relatively well-preserved lung function. Subsequent in vitro studies of F508del homozygous bronchial epithelial cultures have identified that chronic exposure to lumacaftor and ivacaftor results in destabilization of rescued F508del protein at the cell surface, which may explain the modest improvement in lung function observed in the lumacaftorivacaftor combination therapy clinically. At the time of writing this review patients in several countries, including the US and Ireland, have access to lumacaftor-ivacaftor treatment. However, it has not been recommended by NICE for patients in the UK and access is only available through a compassionate use programme for people with severe lung disease. There is an ongoing campaign by stakeholders such as the Cystic Fibrosis Trust around this issue and negotiations between NHS England and the pharmaceutical company Vertex.
reduction in disease-associated morbidity and appears to be a disease-modifying transformative intervention. Ivacaftor has demonstrated some benefit in patients with residual function mutations, whereby there is partial functioning of CFTR at the cell surface, as exemplified by the R117H CFTR mutation. In 2012, phase III RCTs of patients with at least one R117H allele demonstrated a significant absolute increase in % predicted FEV1 of 5.0% together with improvements in reported respiratory symptoms. Perplexingly, treatment in R117H children aged 6e11 years showed a reduction in absolute % predicted FEV1 of 6.0%. Sweat chloride improvements were similar in both groups, with significant reductions of 21.9 mmol/L and 27.6 mmol/L in adults and children respectively. One potential explanation provided by the authors for these variations in lung function was relative stability of lung function evident in the paediatric participants. In 2017, the US FDA approved the use of ivacaftor for people with at least one of 23 residual function mutations based on in vitro and clinical data, however this is not available to patients with these mutations in the UK at present.
Strategies for the F508del CFTR mutation Biology of F508del-CFTR F508del is by far the most common CFTR mutation worldwide. It primarily results in defective CFTR processing (class II mutation). Despite correct synthesis the mutation leads to abnormal protein folding leading to the vast majority of mutant CFTR being degraded in the cell and not trafficked to the cell surface (Figure 1). Furthermore, if expressed at the apical membrane, F508del-CFTR exhibits gating and conductance defects, also operating as a class III mutation. Restoring chloride transport to F508del-CFTR therefore requires at least two steps: firstly correction of the processing and trafficking defect (with a CFTR corrector) and secondly potentiation to increase channel opening (with a CFTR potentiator). Hence, combination therapies involving small molecules with two or possibly three types of activity are likely required to improve the function of F508del-CFTR.
Tezacaftor and ivacaftor (SymdekoÔ) Tezacaftor is a second generation CFTR corrector similar to lumacaftor (Figure 1). A phase II study evaluated the efficacy and safety of tezacaftor monotherapy and tezacaftor-ivacaftor combination therapy in patients homozygous for F508del or heterozygous for F508del and G551D. This trial demonstrated a modest reduction in sweat chloride of 6.0 mmol/L and a 3.8 % increase in absolute % pred. FEV1 in the tezacaftor (100 mg daily)/ivacaftor (150 mg twice daily) combination group in patients homozygous for F508del. This led to a phase III RCT which evaluated the combination therapy of tezacaftor-ivacaftor in patients homozygous for F508del who were 12 years of age or older. This demonstrated a significant improvement in absolute % predicted FEV1 by 4.0 % and a 35% lower rate of pulmonary exacerbation in the treatment group. In contrast to the lumacaftor-ivacaftor combination, the tezacaftor-ivacaftor group did not experience a decline in the mean post-dose FEV1 at 2 or 4 hours after administration. The rate of respiratory side effects was also not reported to be higher in the tezacaftor-ivacaftor group which represents a potential advantage for patients with low baseline lung function. In a further RCT the tezacaftor-ivacaftor combination was shown to be efficacious in F508del heterozygous patients carrying a residual function CFTR mutation on the second allele. Whilst the study demonstrated a significant improvement in predicted FEV1 in both tezacaftor-ivacaftor and ivacaftor monotherapy, the difference was more significant in favour of the combination therapy in this cohort of patients. Some patients, for example in the US, now have access to tezacaftor-ivacaftor treatment but this is not currently the case in the UK.
Lumacaftor and ivacaftor dual combination therapy (OrkambiÔ) Conceptually, the combination of lumacaftor (a CFTR corrector) and ivacaftor offers a promising solution for F508del homozygous patients. Following initial in vitro work a complex phase II trial found a modest but statistically significant reduction in sweat chloride levels in the lumacaftor-ivacaftor treatment groups. Subsequently, two phase III RCTs (TRAFFIC and TRANSPORT) demonstrated a statistically significant improvement in absolute % pred. FEV1 in the lumacaftor-ivacaftor groups (3.3% for 600 mg once daily and 2.8% for 400mg twice daily respectively) In pooled analysis from both studies, there was a 30% and 39% reduction in pulmonary exacerbations in the lumacaftorivacaftor groups and approximately a 1% increment in body mass index. Seven patients in the treatment group experienced serious deranged liver function which normalized upon discontinuation of the treatment. Some patients experienced transient respiratory symptoms within the first two days of commencing treatment that resolved by week 2e3 of the trial. The use of the combination therapy in younger F508del homozygous patients aged between 6 and 11 years was later
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from people with CF demonstrate minimal or no swelling response. Organoids have also been shown to respond to CFTR modulator therapy and therefore represent a valuable platform for drug development and to assess individual responses, especially in the case of rare CFTR mutations. The culture of airway epithelial cells are another ex vivo model to study responses to CFTR modulator therapy. Lower airway epithelial cells must be sampled as part of a clinicallyindicated bronchoscopy however nasal epithelial cells are more readily accessible via nasal brushings. Historically differentiated cultures have then been grown at an air-liquid interface and then technically demanding electrophysiological experiments have been performed. More recently cells from nasal mucosal brushings have been cultured to form ‘spheroids’. Similar to rectal organoids, spheroids from healthy volunteers swell in response to CFTR activation whilst spheroids from patients with CF do not. Spheroids of F508del homozygous patients have been observed to swell with ivacaftor-lumcaftor treatment. Although still in its infancy, researchers are already providing evidence of bench to bedside pairing of nasal spheroid modulator response to improved clinical outcomes in patients. Organoids hence herald a novel method of higher throughput drug screening at an individual level that was not previously possible.
Triple therapy combinations The development of next-generation CFTR correctors that target different parts of the F508del-CFTR protein pathway is an ongoing and rapidly developing area of research. Most notably involving the corrector tezacaftor and potentiator ivacaftor in combination with an additional next-generation corrector, socalled ‘triple therapy’ (Figure 1). Safety and efficacy data of triple combination therapies from phase I and II studies of three different next-generation correctors (VX-440, VX-152 and VX-659) in combination with tezacaftor and ivacaftor have recently been presented. Phase II studies with VX-152 or VX-440 as an additional corrector in patients homozygous for F508del, who were already on tezacaftor-ivacaftor, showed an improvement in mean % pred. FEV1 of 7.3% and 9.5% respectively. Results of phase II trials involving VX-445 and VX-659 published recently showed increases in mean % pred. FEV1 of 11% and 9.7% respectively in F508del homozygous patients. These next generation compounds have also been investigated in patients heterozygous for F508del and one minimal function mutation. Phase II studies with triple therapy involving VX-152, VX-440, VX-445 and VX 650 have shown improvement of % pred. FEV1 of 9.7%, 12%, 13.8% and 8.7% respectively. All triple combination therapies have been reported as being generally well tolerated. With these initial data, Vertex have announced that VX-445 and VX-659 will move forward in to phase III RCTs which are due to complete next year. If the promising early phase results are reproduced in phase III then triple therapy combinations may represent a step-change in the efficacy of CFTR modulator approaches for F508del homozygous patients, and potentially heterozygous patients too, to a level similar to that observed with ivacaftor in patients with gating mutations.
Alternative approaches CFTR amplification Combination therapy with ivacaftor-lumacaftor has shown benefit for patients homozygous for F508del but not heterozygotes suggesting a major limiting factor is a reduced availability of mutant protein for modulators to act on. Recently novel mutation independent ‘amplifier’ compounds that increase immature CFTR protein expression by stabilising CFTR mRNA have been identified. These amplifiers effectively overcome any ‘substrate’ limitation and act synergistically with CFTR correctors and potentiators to augment therapeutic benefit. Amplifiers are in their infancy however do appear to be a step closer towards more inclusive modulator therapies in CF.
Personalized approaches to rare CFTR mutations More than 40% of people with CF are excluded from currently available CFTR modulator therapies due to their CFTR genotype. Clinical trials of CFTR modulators have shown that people with similar functional mutation types, and even those with identical CFTR genotypes, often do not respond in an identical way. This observation arguably reflects the complexity of CFTR function and the heterogeneity of the clinical phenotype in people with CF but also highlights the need for personalized approaches. This is particularly relevant for individuals with rare mutations where conventional clinical trials to demonstrate efficacy are not feasible. This has started to be recognized by the drug approval process in North America to allow expansion of eligibility based on results demonstrating efficacy in ex vivo patient-derived model systems.
Readthrough agents for class I mutations Nonsense mutations are one of the basic defects in class I mutations and give rise to in-frame ʻstop’ codons (PTCs). These cause premature termination of CFTR translation resulting in shortened, non-functional protein and a severe disease phenotype. Treatment in this group is challenged by the need to target therapies to the level of the gene itself. Therapeutic strategies in this group focus on read-through of PTCs. The most promising read-through agent ataluren did not demonstrate clinical efficacy in a phase III trial. Further read-through agents are in development but still confined to pre-clinical disease models (RCT101) and phase I trials (ELX-02).
Patient-derived organoids Specialized culture techniques have been developed whereby stem cell progenitors from gut biopsies produce 3-dimensional structures resembling ‘mini-guts’ or intestinal ‘organoids’. Cells from biopsy-derived rectal tissue can be cultured to produce organoids that express CFTR in the apical (luminal) epithelium. Using a potent CFTR activator, an organoid with fully functional CFTR swells in response to fluid secretion. Conversely, organoids
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Gene therapy Gene therapy is a comparatively slow-moving field, its continued development driven by hope for a cure for all patients with CF due to its mutation independence. The concept is deceptively simple e to replace or repair the defective CFTR gene; though its implementation is fraught with challenges. Current efforts in gene
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research in this area to develop more effective compounds and strategies that target mutation types not currently covered. It is important that longer-term outcomes continue to be recorded and evaluated however the example of ivacaftor suggests that the most clinically effective modulators likely represent a diseasemodifying intervention with major patient benefit. Equitable access to CFTR modulator therapy for all people with CF must be a priority. Alternative approaches will certainly be necessary for people with class I mutations and could also likely be used synergistically with modulators in the future. With newborn screening for CF in place there is also the obvious future potential to start modulator therapy at a young age with a preventative rationale. A
replacement focus on using viral and non-viral vectors to deliver CFTR complementary DNA to airway tissue. Although proven safe for human use, this approach has not consistently demonstrated clinical benefit. Hurdles include prolonging gene expression in treated cells and suppression of a host immune response. Repairing defective CFTR mRNA is alternative approach to restoring CFTR function. The inhaled drug QR-010, a bespoke oligonucleotide aimed at repairing F508del, is currently undergoing phase I trials. The developing pharmaceutical company (ProQR) are also looking to extend similar mRNA-based therapies to nonsense mutations in CF. Gene editing Gene editing technology such as ‘ZFN’, ‘TALEN’ and ‘CRISPRCas9’ have emerged in the last decade, all powerful tools allowing precise targeting of mutant DNA, subsequent splicing and replacement with a desired DNA sequence. In vitro work has demonstrated that through CRISPR CFTR correction is possible in CF intestinal organoids and lung epithelial cells generated from skin stem cells from a person who is homozygous for F508del.
FURTHER READING Bessonova L, Volkova N, Bengtsson L, et al. Data from the US and UK cystic fibrosis registries support disease modification by CFTR modulation with ivacaftor. Thorax 2018; 73: 731e40. Brodlie M, Haq IJ, Roberts K, Elborn JS. Targeted therapies to improve CFTR function in cystic fibrosis. Genome Med 2015; 7: 1e16. Bush A, Simmonds NJ. Hot off the breath: ‘I’ve a cost for’dthe 64 million dollar question. Thorax 2012; 67: 382e4. Davies JC, Moskowitz SM, Brown C, et al. VX-659eTezacaftor eIvacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles. N Engl J Med 2018; 379: 1599e611. Davies JC, Wainwright CE, Canny GJ, et al. Efficacy and safety of ivacaftor in patients aged 6 to 11 Years with cystic fibrosis with a G551D mutation. Am J Respir Crit Care Med 2013; 187: 1219e25. Dekkers JF, Berkers G, Kruisselbrink, et al. Characterizing responses to CFTR-modulating drugs using rectal organoids derived from subjects with cystic fibrosis. Sci Transl Med 2016; 8: 344ra84. Elborn JS. Cystic fibrosis. Lancet 2016; 388: 2519e31. Haq IJ, Gray MA, Garnett JP, Ward C, Brodlie M. Airway surface liquid homeostasis in cystic fibrosis: pathophysiology and therapeutic targets. Thorax 2016; 71: 284e7. Keating D, Marigowda G, Burr L, et al. VX-445eTezacaftoreIvacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles. N Engl J Med 2018; 379: 1612e20. NHS. Clinical commissioning policy: ivacaftor for cystic fibrosis. 2013, www.england.nhs.uk/wp-content/uploads/2013/04/a01-p-b.pdf. 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: 1663e72. Rowe SM, Daines C, Ringshausen FC, et al. Tezacaftor-ivacaftor in residual-function heterozygotes with cystic fibrosis. N Engl J Med 2017; 377: 2024e35. Taylor-Cousar JL, Munck A, McKone EF, et al. Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del. NEJM 2017; 377: 2013e23. Van Goor F, Hadida S, Grootenhuis PDJ, et al. Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc Natl Acad Sci Unit States Am 2009; 106: 18825e30. 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: 220e31. Zainal Abidin N, Haq IJ, Gardner AI, Brodlie M. Ataluren in cystic fibrosis: development, clinical studies and where are we now? Expert Opin Pharmocother 2017; 18: 1363e71.
Economic and ethical implications A huge body of work is underway to investigate and develop personalized therapies that will benefit all people with CF, regardless of their underlying genetic CFTR defect. Progress has been rapid over the last decade and clearly this is an exciting time for people with CF, and their families, and also for clinicians and researchers within this field. Nevertheless, CF is a relatively rare disease and there are significant associated economic implications in relation to the availability of such orphan drugs. Despite its clear benefits, the cost of ivacaftor treatment is high, with the current estimated cost per patient at around £14 000 per 28 days of treatment. Cost-effectiveness analyses are fraught with difficulties when predicting and balancing the impact of a disease-modifying drug against future savings in other healthcare associated expenses, wider societal benefits and possible reductions in the cost of the drug once off patent. Despite the approval of ivacaftor in the UK, there remains a global disparity in the access that people with CF have to other CFTR modulators, this is exemplified by lumacaftor-ivacaftor which is available in the US and Ireland, but only available in the UK to those with advanced disease solely on compassionate grounds. In the current economic climate, this issue of treatment cost is likely to escalate further as improvements in next generation modulators are refined. Clearly these disparities matter deeply to people with CF and have ethical implications, which have also been raised by CF clinicians and organisations such as the CF Trust. It is imperative that negotiations between healthcare providers and pharmaceutical companies are approached in a positive and constructive way with patient considerations at the forefront of all discussions.
Conclusions The exciting development of CFTR modulators has signalled a new era in CF therapeutics. The translation of laboratory-based science to phase III RCTs through to patient benefit has been rapid. CFTR modulators also represent one of the best examples of precision medicine to date. There continues to be active
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Acknowledgements
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Malcolm Brodlie is supported by an MRC Clinician Scientist Fellowship (MR/M008797/1). Iram Haq has been supported by a Wellcome Trust Clinical Training Fellowship. The research was supported by the National Institute for Health Research Newcastle Biomedical Research Centre based at Newcastle Hospitals NHS Foundation Trust and Newcastle University. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.
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Practice points C
Cystic fibrosis (CF) is a life-limiting genetic disease that arises from defects in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and protein.
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CFTR modulators have been developed as a targeted strategy to restore CFTR function in specific CFTR mutation types. Ivacaftor is a CFTR potentiator that improves channel opening and is commissioned in the UK for patients with gating mutations, most commonly G551D. Clinically significant improvements in lung function have been demonstrated in phase III randomized controlled trials and postapproval studies. Lumacaftor-ivacaftor, a combination of a CFTR corrector and potentiator has shown more modest improvements in patients homozygous for the most common CFTR F508del mutation. Although licensed in the UK, it has not been approved by NICE. Phase II clinical trials have recently shown significant benefits in lung function with novel triple combination therapies, which may hold significant promise for people with CF with F508del mutations. Research is currently underway to investigate alternative approaches, including gene therapy and editing techniques.
Ó 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: Haq IJ et al., Modulator therapies for cystic fibrosis, Paediatrics and Child Health, https://doi.org/10.1016/ j.paed.2019.01.011
Modulator therapies for cystic fibrosis
development and how these have impacted upon treatment outcomes and the lives of people with CF.
Keywords CFTR modulator; corrector; cystic fibrosis; gene editing; gene therapy; organoid; personalized medicine; potentiator; therapeutics
Iram J Haq Meena Chow Parameswaran Noreen Zainal Abidin
Introduction
Attaybenes Socas
There are around 10 000 children and adults living with cystic fibrosis (CF) in the United Kingdom (UK) making it the most common life-limiting genetic disorder. Worldwide approximately 80 000 people have CF, with prevalence varying according to ethnicity. CF was historically a disease of infancy and early childhood with a very limited prognosis. However, significant advances in the understanding of the pathophysiology of CF and the development of multidisciplinary clinical care have yielded incremental improvements in survival rates with a predicted median life expectancy of a child born with CF today of 56 years.
Andrea Gonzalez-Ciscar Aaron I Gardner Malcolm Brodlie
Abstract Cystic fibrosis (CF) is a life-limiting genetic disease that arises from defects in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and protein. This causes abnormal epithelial ion transport. CF is a multisystem condition but airway infection and inflammation carry the greatest treatment burden and are the predominant cause of morbidity and mortality. Novel therapeutic strategies have recently been developed to target specific molecular defects arising from CFTR mutations. These CFTR modulator therapies are designed to correct the underlying protein processing defect or to potentiate CFTR function to improve ion transport. Such advances have revolutionized CF treatment approaches, which have previously only addressed downstream effects, and hold significant promise for the future. This review will summarize recent advances in CFTR modulator
What causes CF? The genetic causes of CF are recessive mutations in the CF transmembrane conductance regulator (CFTR) gene located on the long arm of chromosome seven. CFTR encodes for a cAMPregulated chloride channel expressed on the apical surface of epithelial cells in the respiratory, gastrointestinal, pancreatic and reproductive tracts. Although this gives rise to multisystem pathology, progressive respiratory disease is the major cause of morbidity and mortality. Dysfunctional CFTR-mediated chloride and bicarbonate transport leads to disordered airway surface liquid homeostasis, reduced mucociliary clearance and susceptibility to airway infection, most notably with Staphylococcus aureus and Pseudomonas aeruginosa. Progressive neutrophilic inflammation occurs with the eventual development of bronchiectasis and respiratory failure. Approximately 2000 CFTR variants have been identified but a much smaller number are commonly recognized as diseasecausing clinically. By far the most common mutation is F508del, a deletion of phenylalanine at codon 508, with around 90% of people with CF having at least one affected allele. CFTR mutations have been classified into six main groups based on the mechanisms underlying aberrant CFTR synthesis, trafficking and function (Table 1). Disease phenotype is partly determined by the net effect of a mutation on CFTR quantity and function. Despite this classification, there is considerable phenotypic heterogeneity amongst individuals within the same mutation class, arising from environmental, microbiological and additional ‘nonCFTR’ genetic effects.
Iram J Haq MBBS MRes MRCPCH Paediatric Respiratory Grid Trainee, Great North Children’s Hospital, Newcastle Upon Tyne, UK. Conflict of interest: None declared. Meena Chow Parameswaran MBChB Paediatric Specialty Trainee, Freeman Hospital, Newcastle Upon Tyne, UK. Conflict of interest: None declared. Noreen Zainal Abidin MBBS MRCPCH Paediatric Speciality Trainee, James Cook University Hospital, Middlesbrough, UK. Conflict of interest: None declared. Attaybenes Socas BSc MRes Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK. Conflict of interest: None declared. Andrea Gonzalez-Ciscar BMedSci (Hons) MBChB Academic Foundation Doctor, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK. Conflicts of interest: None declared. Aaron I Gardner BSc MRes PhD Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK. Conflict of interest: None declared.
How is CF managed? Introduction of the UK CF Newborn Screening Programme in 2007 has facilitated early identification of infants with CF and implementation of optimal clinical management at a young age. Traditionally, medical treatments for CF have targeted downstream effects of CFTR dysfunction on target organs. These include intensive chest physiotherapy and inhaled drugs to facilitate mucus clearance, life-long antimicrobials to combat respiratory infections and pancreatic enzyme replacement therapy and fat-soluble vitamin supplements to reduce features of
Malcolm Brodlie BSc (Hons) MB ChB MRCPCH PhD MRC Clinician Scientist and Clinical Senior Lecturer, Institute of Cellular Medicine, Newcastle University, UK and Honorary Consultant in Paediatric Respiratory Medicine, Great North Children’s Hospital, Newcastle upon Tyne, UK. Conflicts of interest: MB has been CI on investigator-led research grants from Pfizer and Roche Diagnostics; speaker fees paid to Newcastle University from Novartis, Roche Diagnostics and TEVA; travel expenses to educational meetings from Boehringer Ingelheim and Vertex.
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CFTR mutation classes and functional effects Mutation class
Example mutation
Functional effect
Potential therapy (Approved?)
IA (VII)
c.1585-1G>A 1717-1G>A c.1624G>T p.Gly542X G542X c.1521_1523delCTT p.Phe508del F508del c.1652G>A p.Gly551Asp G551D c.350G>A p.Arg117His R117H c.1364C>A p.Ala455Glu A455E c.859A>T p.Asn287Tyr N287Y
No mRNA
Bypass therapy (No)
No protein
Read-through (No)
Improper trafficking
Corrector (No) Corrector þ potentiator (Yes)
Impaired gating
Potentiator (Yes)
Reduced conductance
Potentiator (No)
Less protein
Corrector, potentiator (No)
Increased turnover
Stabilizer (No)
IB (I)
II
III
IV
V
VI
CFTR mutation classes have been summarized with examples of mutations, resultant functional effect and potential therapeutic strategies for each mutation class.
Table 1
pancreatic malabsorption and maintain nutrition. Importantly the most effective care is delivered by skilled multidisciplinary teams in a coordinated, proactive and holistic manner. While these approaches have greatly improved survival, the burden of life-long treatment is substantial. Eventual progressive respiratory failure results in lung transplantation becoming the only life-sustaining treatment, which is not a feasible option for all patients. Over the last ten years, CF therapeutics has been revolutionized by improvements in our understanding of CFTR molecular abnormalities together with application of high throughput screening assays and advanced medicinal chemistry. This approach has facilitated the investigation and development of novel small molecule therapies that target the underlying defect by modulating CFTR function. In this review, we will summarize developments in this exciting area of precision medicine.
50% of CFTR function observed in non-CF cultures. Subsequent decreases in sodium absorption and restoration of airway surface volume were also sufficient to improve cilial function and mucociliary clearance. These findings were rapidly translated to clinical trials in adults and children where significant improvements in the primary outcome assessment of lung function were demonstrated. A pivotal phase III randomized controlled trial (RCT) of 161 patients with at least one G551D allele aged 12 years published in 2011 demonstrated a 10.4 percentage point increase in predicted forced expiratory volume in 1 second (% pred. FEV1) compared with placebo after 24 weeks ivacaftor treatment. Additional benefits in secondary outcome measures included a significant mean reduction in sweat chloride of 48.1 mmol/L, weight gain of 3.1 kg and a reduction in pulmonary exacerbations by 55% after 48 weeks of treatment. Ivacaftor was commissioned for use in this patient group in the UK in 2012, with subsequent extension to younger children (currently those over 2 years of age) and people with rarer class III mutations. This equates overall to around 5% of people with CF in the UK. In 2017, the US Food and Drug Administration extended ivacaftor’s application to 33 mutations based on preclinical in vitro data and is now applicable to 9% of the US CF population. Ivacaftor is generally well tolerated by patients with minimally reported adverse outcomes in clinical trials to date. Elevation of liver enzymes is the most frequently occurring complication, with levels returning to baseline after drug discontinuation. For this reason, prescription is limited to specialist accredited CF centres and involves surveillance of liver
Development of CFTR modulators Ivacaftor as an exemplar CFTR modulator for class III gating mutations Ivacaftor, also known as VX-770 or KalydecoÔ, is a CFTR potentiator identified by high-throughput screening of over 200 000 compounds and specifically developed to target class III CFTR mutations. It functions by binding to and stabilising mutant CFTR expressed at the cell surface, where it increases its open probability and subsequent chloride transport (Figure 1). In vitro ivacaftor treatment of primary human bronchial epithelial cell cultures expressing the G551D CFTR mutation resulted in a 10fold increase in chloride secretion that corresponded to around
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Figure 1 Classes of CFTR mutations and potential therapeutics. CFTR mutations are typically categorized into one of six classes, although more recently a subdivision of class I into class IA (VII) and class IB (I) has been proposed. Class IA mutations, such as c.1585-1G > A, result in a lack of mRNA whereas class IB, such as G542X, mutations result in lack of protein. Class II mutations, including the most common mutation F508del, are associated with impaired trafficking. Class III mutations such as G551D are associated with impaired gating and class IV mutations such as R117H with reduced conductance. Low levels of CFTR are found in class V mutations, such as A455E, which arise from splicing defects. Finally, class VI mutations, such as N287Y, are associated with increased CFTR turnover at the plasma membrane. The CFTR potentiator ivacaftor approved for use in those with class III mutations has demonstrated significant improvements in lung function. Correctors such as lumacaftor, and more recently tezacaftor, have been developed as part of a co-therapy with ivacaftor for those with class II mutations. Recent phase II trials have demonstrated improvements in FEV1 with triple therapy comprising of ivacaftor, tezacaftor and the ‘next generation’ small molecules e VX-152, VX-440, VX-445 and VX-659. Based on these studies phase III trials using triple therapy with VX-445 and VX-659 are underway. More fundamental therapies such as read-through agents, gene therapy, gene editing such as CRISPR-Cas9 and CFTR amplifiers may prove beneficial for a wider range of patients, however all remain in the early stages of development.* Ataluren failed to demonstrate clinical benefit in a phase III trial for CF. y A phase II trial using non-viral gene transfer demonstrated stabilisation in lung function decline.
function. Prescribers should also be mindful of potential drug interactions. European and North American observational post-approval data has shown sustained clinical benefit for several years after starting ivacaftor, with improved lung function, lower risk of death or lung transplantation and a lower prevalence of CFassociated respiratory pathogens. Additional extrapulmonary
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benefits in G551D patients described have included resolution of intestinal pH to healthy levels, improvements in glucose handling and bone physiology. In light of the relatively recent introduction of ivacaftor, true longer-term clinical outcomes are not yet known. However, there is wide agreement amongst CF clinicians that it has substantially benefited patients with class III mutations with a notable
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studied in an open-label phase III trial. The combination therapy in this cohort had generally similar safety profiles to that observed in the larger trials with older patients. At week 24, they reported significant reductions from baseline in sweat chloride levels of 24.8 mmol/L. A significant increase in BMI was also reported which was sustained at the week 26 follow up visit. However, this study was not powered to detect a significant change in FEV1. Nonetheless, the study demonstrated a significant improvement in lung clearance index (LCI) in a subset of patients, which could support LCI as a more sensitive marker to evaluate treatment effects in younger population with relatively well-preserved lung function. Subsequent in vitro studies of F508del homozygous bronchial epithelial cultures have identified that chronic exposure to lumacaftor and ivacaftor results in destabilization of rescued F508del protein at the cell surface, which may explain the modest improvement in lung function observed in the lumacaftorivacaftor combination therapy clinically. At the time of writing this review patients in several countries, including the US and Ireland, have access to lumacaftor-ivacaftor treatment. However, it has not been recommended by NICE for patients in the UK and access is only available through a compassionate use programme for people with severe lung disease. There is an ongoing campaign by stakeholders such as the Cystic Fibrosis Trust around this issue and negotiations between NHS England and the pharmaceutical company Vertex.
reduction in disease-associated morbidity and appears to be a disease-modifying transformative intervention. Ivacaftor has demonstrated some benefit in patients with residual function mutations, whereby there is partial functioning of CFTR at the cell surface, as exemplified by the R117H CFTR mutation. In 2012, phase III RCTs of patients with at least one R117H allele demonstrated a significant absolute increase in % predicted FEV1 of 5.0% together with improvements in reported respiratory symptoms. Perplexingly, treatment in R117H children aged 6e11 years showed a reduction in absolute % predicted FEV1 of 6.0%. Sweat chloride improvements were similar in both groups, with significant reductions of 21.9 mmol/L and 27.6 mmol/L in adults and children respectively. One potential explanation provided by the authors for these variations in lung function was relative stability of lung function evident in the paediatric participants. In 2017, the US FDA approved the use of ivacaftor for people with at least one of 23 residual function mutations based on in vitro and clinical data, however this is not available to patients with these mutations in the UK at present.
Strategies for the F508del CFTR mutation Biology of F508del-CFTR F508del is by far the most common CFTR mutation worldwide. It primarily results in defective CFTR processing (class II mutation). Despite correct synthesis the mutation leads to abnormal protein folding leading to the vast majority of mutant CFTR being degraded in the cell and not trafficked to the cell surface (Figure 1). Furthermore, if expressed at the apical membrane, F508del-CFTR exhibits gating and conductance defects, also operating as a class III mutation. Restoring chloride transport to F508del-CFTR therefore requires at least two steps: firstly correction of the processing and trafficking defect (with a CFTR corrector) and secondly potentiation to increase channel opening (with a CFTR potentiator). Hence, combination therapies involving small molecules with two or possibly three types of activity are likely required to improve the function of F508del-CFTR.
Tezacaftor and ivacaftor (SymdekoÔ) Tezacaftor is a second generation CFTR corrector similar to lumacaftor (Figure 1). A phase II study evaluated the efficacy and safety of tezacaftor monotherapy and tezacaftor-ivacaftor combination therapy in patients homozygous for F508del or heterozygous for F508del and G551D. This trial demonstrated a modest reduction in sweat chloride of 6.0 mmol/L and a 3.8 % increase in absolute % pred. FEV1 in the tezacaftor (100 mg daily)/ivacaftor (150 mg twice daily) combination group in patients homozygous for F508del. This led to a phase III RCT which evaluated the combination therapy of tezacaftor-ivacaftor in patients homozygous for F508del who were 12 years of age or older. This demonstrated a significant improvement in absolute % predicted FEV1 by 4.0 % and a 35% lower rate of pulmonary exacerbation in the treatment group. In contrast to the lumacaftor-ivacaftor combination, the tezacaftor-ivacaftor group did not experience a decline in the mean post-dose FEV1 at 2 or 4 hours after administration. The rate of respiratory side effects was also not reported to be higher in the tezacaftor-ivacaftor group which represents a potential advantage for patients with low baseline lung function. In a further RCT the tezacaftor-ivacaftor combination was shown to be efficacious in F508del heterozygous patients carrying a residual function CFTR mutation on the second allele. Whilst the study demonstrated a significant improvement in predicted FEV1 in both tezacaftor-ivacaftor and ivacaftor monotherapy, the difference was more significant in favour of the combination therapy in this cohort of patients. Some patients, for example in the US, now have access to tezacaftor-ivacaftor treatment but this is not currently the case in the UK.
Lumacaftor and ivacaftor dual combination therapy (OrkambiÔ) Conceptually, the combination of lumacaftor (a CFTR corrector) and ivacaftor offers a promising solution for F508del homozygous patients. Following initial in vitro work a complex phase II trial found a modest but statistically significant reduction in sweat chloride levels in the lumacaftor-ivacaftor treatment groups. Subsequently, two phase III RCTs (TRAFFIC and TRANSPORT) demonstrated a statistically significant improvement in absolute % pred. FEV1 in the lumacaftor-ivacaftor groups (3.3% for 600 mg once daily and 2.8% for 400mg twice daily respectively) In pooled analysis from both studies, there was a 30% and 39% reduction in pulmonary exacerbations in the lumacaftorivacaftor groups and approximately a 1% increment in body mass index. Seven patients in the treatment group experienced serious deranged liver function which normalized upon discontinuation of the treatment. Some patients experienced transient respiratory symptoms within the first two days of commencing treatment that resolved by week 2e3 of the trial. The use of the combination therapy in younger F508del homozygous patients aged between 6 and 11 years was later
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from people with CF demonstrate minimal or no swelling response. Organoids have also been shown to respond to CFTR modulator therapy and therefore represent a valuable platform for drug development and to assess individual responses, especially in the case of rare CFTR mutations. The culture of airway epithelial cells are another ex vivo model to study responses to CFTR modulator therapy. Lower airway epithelial cells must be sampled as part of a clinicallyindicated bronchoscopy however nasal epithelial cells are more readily accessible via nasal brushings. Historically differentiated cultures have then been grown at an air-liquid interface and then technically demanding electrophysiological experiments have been performed. More recently cells from nasal mucosal brushings have been cultured to form ‘spheroids’. Similar to rectal organoids, spheroids from healthy volunteers swell in response to CFTR activation whilst spheroids from patients with CF do not. Spheroids of F508del homozygous patients have been observed to swell with ivacaftor-lumcaftor treatment. Although still in its infancy, researchers are already providing evidence of bench to bedside pairing of nasal spheroid modulator response to improved clinical outcomes in patients. Organoids hence herald a novel method of higher throughput drug screening at an individual level that was not previously possible.
Triple therapy combinations The development of next-generation CFTR correctors that target different parts of the F508del-CFTR protein pathway is an ongoing and rapidly developing area of research. Most notably involving the corrector tezacaftor and potentiator ivacaftor in combination with an additional next-generation corrector, socalled ‘triple therapy’ (Figure 1). Safety and efficacy data of triple combination therapies from phase I and II studies of three different next-generation correctors (VX-440, VX-152 and VX-659) in combination with tezacaftor and ivacaftor have recently been presented. Phase II studies with VX-152 or VX-440 as an additional corrector in patients homozygous for F508del, who were already on tezacaftor-ivacaftor, showed an improvement in mean % pred. FEV1 of 7.3% and 9.5% respectively. Results of phase II trials involving VX-445 and VX-659 published recently showed increases in mean % pred. FEV1 of 11% and 9.7% respectively in F508del homozygous patients. These next generation compounds have also been investigated in patients heterozygous for F508del and one minimal function mutation. Phase II studies with triple therapy involving VX-152, VX-440, VX-445 and VX 650 have shown improvement of % pred. FEV1 of 9.7%, 12%, 13.8% and 8.7% respectively. All triple combination therapies have been reported as being generally well tolerated. With these initial data, Vertex have announced that VX-445 and VX-659 will move forward in to phase III RCTs which are due to complete next year. If the promising early phase results are reproduced in phase III then triple therapy combinations may represent a step-change in the efficacy of CFTR modulator approaches for F508del homozygous patients, and potentially heterozygous patients too, to a level similar to that observed with ivacaftor in patients with gating mutations.
Alternative approaches CFTR amplification Combination therapy with ivacaftor-lumacaftor has shown benefit for patients homozygous for F508del but not heterozygotes suggesting a major limiting factor is a reduced availability of mutant protein for modulators to act on. Recently novel mutation independent ‘amplifier’ compounds that increase immature CFTR protein expression by stabilising CFTR mRNA have been identified. These amplifiers effectively overcome any ‘substrate’ limitation and act synergistically with CFTR correctors and potentiators to augment therapeutic benefit. Amplifiers are in their infancy however do appear to be a step closer towards more inclusive modulator therapies in CF.
Personalized approaches to rare CFTR mutations More than 40% of people with CF are excluded from currently available CFTR modulator therapies due to their CFTR genotype. Clinical trials of CFTR modulators have shown that people with similar functional mutation types, and even those with identical CFTR genotypes, often do not respond in an identical way. This observation arguably reflects the complexity of CFTR function and the heterogeneity of the clinical phenotype in people with CF but also highlights the need for personalized approaches. This is particularly relevant for individuals with rare mutations where conventional clinical trials to demonstrate efficacy are not feasible. This has started to be recognized by the drug approval process in North America to allow expansion of eligibility based on results demonstrating efficacy in ex vivo patient-derived model systems.
Readthrough agents for class I mutations Nonsense mutations are one of the basic defects in class I mutations and give rise to in-frame ʻstop’ codons (PTCs). These cause premature termination of CFTR translation resulting in shortened, non-functional protein and a severe disease phenotype. Treatment in this group is challenged by the need to target therapies to the level of the gene itself. Therapeutic strategies in this group focus on read-through of PTCs. The most promising read-through agent ataluren did not demonstrate clinical efficacy in a phase III trial. Further read-through agents are in development but still confined to pre-clinical disease models (RCT101) and phase I trials (ELX-02).
Patient-derived organoids Specialized culture techniques have been developed whereby stem cell progenitors from gut biopsies produce 3-dimensional structures resembling ‘mini-guts’ or intestinal ‘organoids’. Cells from biopsy-derived rectal tissue can be cultured to produce organoids that express CFTR in the apical (luminal) epithelium. Using a potent CFTR activator, an organoid with fully functional CFTR swells in response to fluid secretion. Conversely, organoids
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Gene therapy Gene therapy is a comparatively slow-moving field, its continued development driven by hope for a cure for all patients with CF due to its mutation independence. The concept is deceptively simple e to replace or repair the defective CFTR gene; though its implementation is fraught with challenges. Current efforts in gene
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research in this area to develop more effective compounds and strategies that target mutation types not currently covered. It is important that longer-term outcomes continue to be recorded and evaluated however the example of ivacaftor suggests that the most clinically effective modulators likely represent a diseasemodifying intervention with major patient benefit. Equitable access to CFTR modulator therapy for all people with CF must be a priority. Alternative approaches will certainly be necessary for people with class I mutations and could also likely be used synergistically with modulators in the future. With newborn screening for CF in place there is also the obvious future potential to start modulator therapy at a young age with a preventative rationale. A
replacement focus on using viral and non-viral vectors to deliver CFTR complementary DNA to airway tissue. Although proven safe for human use, this approach has not consistently demonstrated clinical benefit. Hurdles include prolonging gene expression in treated cells and suppression of a host immune response. Repairing defective CFTR mRNA is alternative approach to restoring CFTR function. The inhaled drug QR-010, a bespoke oligonucleotide aimed at repairing F508del, is currently undergoing phase I trials. The developing pharmaceutical company (ProQR) are also looking to extend similar mRNA-based therapies to nonsense mutations in CF. Gene editing Gene editing technology such as ‘ZFN’, ‘TALEN’ and ‘CRISPRCas9’ have emerged in the last decade, all powerful tools allowing precise targeting of mutant DNA, subsequent splicing and replacement with a desired DNA sequence. In vitro work has demonstrated that through CRISPR CFTR correction is possible in CF intestinal organoids and lung epithelial cells generated from skin stem cells from a person who is homozygous for F508del.
FURTHER READING Bessonova L, Volkova N, Bengtsson L, et al. Data from the US and UK cystic fibrosis registries support disease modification by CFTR modulation with ivacaftor. Thorax 2018; 73: 731e40. Brodlie M, Haq IJ, Roberts K, Elborn JS. Targeted therapies to improve CFTR function in cystic fibrosis. Genome Med 2015; 7: 1e16. Bush A, Simmonds NJ. Hot off the breath: ‘I’ve a cost for’dthe 64 million dollar question. Thorax 2012; 67: 382e4. Davies JC, Moskowitz SM, Brown C, et al. VX-659eTezacaftor eIvacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles. N Engl J Med 2018; 379: 1599e611. Davies JC, Wainwright CE, Canny GJ, et al. Efficacy and safety of ivacaftor in patients aged 6 to 11 Years with cystic fibrosis with a G551D mutation. Am J Respir Crit Care Med 2013; 187: 1219e25. Dekkers JF, Berkers G, Kruisselbrink, et al. Characterizing responses to CFTR-modulating drugs using rectal organoids derived from subjects with cystic fibrosis. Sci Transl Med 2016; 8: 344ra84. Elborn JS. Cystic fibrosis. Lancet 2016; 388: 2519e31. Haq IJ, Gray MA, Garnett JP, Ward C, Brodlie M. Airway surface liquid homeostasis in cystic fibrosis: pathophysiology and therapeutic targets. Thorax 2016; 71: 284e7. Keating D, Marigowda G, Burr L, et al. VX-445eTezacaftoreIvacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles. N Engl J Med 2018; 379: 1612e20. NHS. Clinical commissioning policy: ivacaftor for cystic fibrosis. 2013, www.england.nhs.uk/wp-content/uploads/2013/04/a01-p-b.pdf. 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: 1663e72. Rowe SM, Daines C, Ringshausen FC, et al. Tezacaftor-ivacaftor in residual-function heterozygotes with cystic fibrosis. N Engl J Med 2017; 377: 2024e35. Taylor-Cousar JL, Munck A, McKone EF, et al. Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del. NEJM 2017; 377: 2013e23. Van Goor F, Hadida S, Grootenhuis PDJ, et al. Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc Natl Acad Sci Unit States Am 2009; 106: 18825e30. 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: 220e31. Zainal Abidin N, Haq IJ, Gardner AI, Brodlie M. Ataluren in cystic fibrosis: development, clinical studies and where are we now? Expert Opin Pharmocother 2017; 18: 1363e71.
Economic and ethical implications A huge body of work is underway to investigate and develop personalized therapies that will benefit all people with CF, regardless of their underlying genetic CFTR defect. Progress has been rapid over the last decade and clearly this is an exciting time for people with CF, and their families, and also for clinicians and researchers within this field. Nevertheless, CF is a relatively rare disease and there are significant associated economic implications in relation to the availability of such orphan drugs. Despite its clear benefits, the cost of ivacaftor treatment is high, with the current estimated cost per patient at around £14 000 per 28 days of treatment. Cost-effectiveness analyses are fraught with difficulties when predicting and balancing the impact of a disease-modifying drug against future savings in other healthcare associated expenses, wider societal benefits and possible reductions in the cost of the drug once off patent. Despite the approval of ivacaftor in the UK, there remains a global disparity in the access that people with CF have to other CFTR modulators, this is exemplified by lumacaftor-ivacaftor which is available in the US and Ireland, but only available in the UK to those with advanced disease solely on compassionate grounds. In the current economic climate, this issue of treatment cost is likely to escalate further as improvements in next generation modulators are refined. Clearly these disparities matter deeply to people with CF and have ethical implications, which have also been raised by CF clinicians and organisations such as the CF Trust. It is imperative that negotiations between healthcare providers and pharmaceutical companies are approached in a positive and constructive way with patient considerations at the forefront of all discussions.
Conclusions The exciting development of CFTR modulators has signalled a new era in CF therapeutics. The translation of laboratory-based science to phase III RCTs through to patient benefit has been rapid. CFTR modulators also represent one of the best examples of precision medicine to date. There continues to be active
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Acknowledgements
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Malcolm Brodlie is supported by an MRC Clinician Scientist Fellowship (MR/M008797/1). Iram Haq has been supported by a Wellcome Trust Clinical Training Fellowship. The research was supported by the National Institute for Health Research Newcastle Biomedical Research Centre based at Newcastle Hospitals NHS Foundation Trust and Newcastle University. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.
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Practice points C
Cystic fibrosis (CF) is a life-limiting genetic disease that arises from defects in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and protein.
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CFTR modulators have been developed as a targeted strategy to restore CFTR function in specific CFTR mutation types. Ivacaftor is a CFTR potentiator that improves channel opening and is commissioned in the UK for patients with gating mutations, most commonly G551D. Clinically significant improvements in lung function have been demonstrated in phase III randomized controlled trials and postapproval studies. Lumacaftor-ivacaftor, a combination of a CFTR corrector and potentiator has shown more modest improvements in patients homozygous for the most common CFTR F508del mutation. Although licensed in the UK, it has not been approved by NICE. Phase II clinical trials have recently shown significant benefits in lung function with novel triple combination therapies, which may hold significant promise for people with CF with F508del mutations. Research is currently underway to investigate alternative approaches, including gene therapy and editing techniques.
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