JCF-01160; No of Pages 2

Journal of Cystic Fibrosis xx (2015) xxx – xxx www.elsevier.com/locate/jcf

Case Report

Ivacaftor as salvage therapy in a patient with cystic fibrosis genotype F508del/R117H/IVS8-5T S. Carter, S. Kelly, E. Caples, B. Grogan, J. Doyle, C.G. Gallagher, E.F. McKone ⁎ National Referral Centre for Adult Cystic Fibrosis, St. Vincent's University Hospital, Elm Park, Dublin 4, Ireland Received 12 January 2015; revised 23 January 2015; accepted 23 January 2015

Abstract Ivacaftor is a novel CFTR potentiator that increases CFTR activity and improves clinical outcomes in cystic fibrosis (CF) patients with at least one copy of CFTR-G551D. Clinical trials have shown an improvement in lung function, weight and CF pulmonary exacerbation in adults with CFTR-G551D leading to the approval of ivacaftor as a novel CF therapy [1]. In vitro studies of ivacaftor have also shown significant improvements in CFTR chloride channel opening time in other non-G551D CFTR mutations suggesting that ivacaftor may be of benefit to patients with mutations other than gating mutations [2]. R117H-CFTR is a relatively common CFTR mutation that demonstrates an in-vitro response to ivacaftor [2,3]. A clinical trial has suggested that there may be a role for ivacaftor in older patients with R117H-CFTR although this trial did not include patients with very severe CF lung disease [4]. In 2014, ivacaftor was approved in the United States as a treatment for CF subjects aged greater than 6 years old with a copy of R117H-CFTR. We present a case demonstrating a substantial therapeutic effect of ivacaftor in a CF patient with genotype F508del/R117H and advanced lung disease. © 2015 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. Keywords: Pharmacogenetics; CFTR genotype; CFTR corrector therapy

1. Clinical Case MC, a 45 year old male with CF (F508del/R117H/IVS8-5T/ 9T), was diagnosed at the age of 16 years old. His CF is complicated by advanced lung disease (FEV1 = 31% predicted, SaO2 = 95% on 1 l O2 at rest), chronic infection with Burkholderia multivorans and pancreatic insufficiency (faecal elastase = 135 mcg/g (normal N 200 mcg/g)). Two years prior to February 2014, he had severe chronic pulmonary infection with multiple exacerbations (N 6/year) and persistently elevated C-reactive protein between 23 and 80 mmol/l. Due to his very frequent exacerbations, he was commenced on continuous outpatient IV and oral antibiotics with a resulting reduction in his exacerbation frequency. Owing to his advanced lung disease and multiple exacerbations, he had been assessed for lung transplantation and was on the active lung transplant list since January 2013. In February 2014, as part of the Vertex ⁎ Corresponding author.

Pharmaceuticals named patient program, he was approved to commence ivacaftor. At that time, immediately prior to starting ivacaftor, his FEV1 was 1.14 l (31% predicted) with a weight of 63 kg. Pre-treatment sweat chloride was 85 mmol/l. Lung function and weight were repeated after 2 weeks of ivacaftor treatment and every month thereafter. Sweat chloride and faecal elastase were repeated 3 months after starting ivacaftor. Since commencing ivacaftor therapy there has been a substantial clinical improvement (Fig. 1). After 5 months of treatment, his weight is up by 4.3 kg with an increase in FEV1 to 1.50 l (42% predicted). Immediate improvements in FEV1 were seen at 2 weeks and continued up to a peak at day 75. Our patient also reports improved sputum volume and colour although is still growing B. multivorans in his sputum. Exercise capacity is much improved with an improvement in 6-minute walk test distance and decreased oxygen requirements at rest and with exercise. CRP levels have reduced to between 14 and 28 mmol/l, the lowest seen in 12 months. Faecal elastase is now in the normal range (355 mcg/g; repeat 1 month later 492 mcg/g).

http://dx.doi.org/10.1016/j.jcf.2015.01.010 1569-1993/© 2015 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. Please cite this article as: Carter S, et al, Ivacaftor as salvage therapy in a patient with cystic fibrosis genotype F508del/R117H/IVS8-5T, J Cyst Fibros (2015), http://dx.doi.org/10.1016/j.jcf.2015.01.010

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S. Carter et al. / Journal of Cystic Fibrosis xx (2015) xxx–xxx

Fig. 1. FEV1 and 6MWT distance before and after commencing ivacaftor.

Sweat chloride on ivacaftor has reduced to 46 mmol/l. As a result, his continuous iv antibiotics have now been stopped and on 28th March he was taken off the active lung transplant list. To date, he continues to do well and is being followed closely by his CF team in conjunction with the lung transplant team. 2. Discussion R117H-CFTR is a CFTR mutation that is found in between 2% and 14% of CF patients worldwide. It is a missense mutation resulting in an Arginine to Histadine substitution in position 117 of CFTR exon 4. R117H-CFTR results in impaired CFTR conductance with some preservation of CFTR function. As a result, R117H-CFTR, when occurring on the opposite chromosome (in-trans) to a severe CFTR mutation, is associated with a milder CF phenotype with later age at diagnosis, older onset of pancreatic insufficiency and less severe lung disease than those with 2 severe CFTR mutations [5,6]. The R117H-CFTR phenotype is quite variable with some of this variability explained by the presence of additional CFTR polymorphisms. In particular, a polythymidine (Poly-T) repeat polymorphism in CFTR Intron 8 (IVS8) on the same chromosome (in-cis) influences the amount of CFTR expressed in the cell surface through altered CFTR exon 9 splicing [7]. An IVS8-5T repeat variant in-cis with R117H-CFTR is associated with a more reduced CFTR activity and a more severe phenotype compared to the patients who have R117H-CFTR in-cis with either the 7T or 9T variant [8,9]. The perception that R117H-CFTR only causes a mild phenotype has led to R117H-CFTR being reconsidered for inclusion in CF newborn screening programs [10]. In countries where R117H-CFTR occurs predominantly on a background of IVS8-5T, such as the UK [11] and Ireland (Dr David Barton, personal communication), CF patients can have very severe disease as seen in this case. These patients also may have a greater therapeutic benefit with drugs like ivacaftor as their CFTR expression is both reduced in function due to the impaired conductance seen with R117H-CFTR as well as reduced in

quantity as a result of the IVS8-5T splicing variant. These cases, as in this patient, have sufficiently reduced CFTR activity to develop significant disease but also have sufficient quantities expressed on the cell surface to benefit from monotherapy with ivacaftor. This is supported by the recent clinical trial results that show a benefit of ivacaftor in adult R117H patients with more severe disease who are more likely to have the R117H-IVS5T variants. We hypothesize that this mechanism results in the benefits seen on our patient highlighting the complex pharmacogenetics of CFTR potentiator therapy. References [1] 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(18):1663–72. [2] Van Goor F, Yu H, Burton B, Hoffman BJ. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros 2014;13(1):29–36. [3] Zolin A, McKone EF, van Rens J, et al. ECFS Patient Registry Annual Data Report 2010; 2012. [4] Moss RB, Flume PA, Elborn JS, et al. Ivacaftor treatment in patients with cystic fibrosis who have an R117H-CFTR mutation, the KONDUCT study. J Cyst Fibros 2014;13(S2):44. [5] McKone EF, Emerson SS, Edwards KL, Aitken ML. Effect of genotype on phenotype and mortality in cystic fibrosis: a retrospective cohort study. Lancet 2003;361(9370):1671–6. [6] http://www.cftr2.org/. (accessed July 2014). [7] Kiesewetter S, Macek Jr M, Davis C, et al. A mutation in CFTR produces different phenotypes depending on chromosomal background. Nat Genet 1993;5(3):274–8. [8] Noone PG, Pue CA, Zhou Z, et al. Lung disease associated with the IVS8 5T allele of the CFTR gene. Am J Respir Crit Care Med 2000;162(5): 1919–24. [9] Massie RJ, Poplawski N, Wilcken B, Goldblatt J, Byrnes C, Robertson C. Intron-8 polythymidine sequence in Australasian individuals with CF mutations R117H and R117C. Eur Respir J 2001;17(6):1195–200. [10] Thauvin-Robinet C, Munck A, Huet F, et al. The very low penetrance of cystic fibrosis for the R117H mutation: a reappraisal for genetic counselling and newborn screening. J Med Genet 2009;46(11):752–8. [11] Comer DM, Ennis M, McDowell C, et al. Clinical phenotype of cystic fibrosis patients with the G551D mutation. QJM 2009;102(11):793–8.

Please cite this article as: Carter S, et al, Ivacaftor as salvage therapy in a patient with cystic fibrosis genotype F508del/R117H/IVS8-5T, J Cyst Fibros (2015), http://dx.doi.org/10.1016/j.jcf.2015.01.010