Ivacaftor-induced Cataracts in Patients with Cystic Fibrosis

From EyeWiki

Cystic fibrosis (CF) is a life-shortening, autosomal recessive disease that is characterized by recurrent lung infections and pancreatic insufficiency. It is caused by defects in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, a chloride channel of exocrine glands that plays an important role in airway mucocilliary clearance and pancreatic enzyme secretion [1]. There are over 200 known disease-causing mutations of the CFTR protein, which can range from having no CFTR protein at all to having less stable CFTR protein channels. Ivacaftor, one of the first commercially available therapies to directly target CFTR function, was initially developed to treat CF caused by gating mutations like G551D, the third most common mutation. When combined with other CFTR modulators, ivacaftor can be used to restore CFTR function in patients with additional mutations. For example, Trikafta (tezacaftor/ivacaftor/elexacaftor) has been shown to restore CFTR function in patients with at least one F508del mutation, a pathologic variant that affects 90% of the CF population [2]. Given Trikafta’s success in treating patients with the F508del mutation, it is highly likely that the majority of patients with CF will be on this medication in the future. However, one notable side effect of ivacaftor is its potential to cause noncongenital cataracts in children [3]. In this article, we will review the mechanism of action of ivacaftor, its involvement in the development of pediatric cataracts, and current recommendations for patients on ivacaftor therapy.

Mechanism of Action

Ivacaftor increases CFTR-mediated chloride transport by increasing the probability of CFTR channel opening [3]. In vitro studies with bronchial epithelial cells from patients with CF demonstrated that by increasing abnormal CFTR-mediated ion transport, ivacaftor increases the air-surface fluid level and ciliary beat frequency [4].


Ivacaftor-associated cataracts

Non-congenital cataract formation with ivacaftor treatment has been reported in preclinical rat studies, as well as in children and adolescents receiving both ivacaftor monotherapy and ivacaftor combined with other CFTR modulators like lumacaftor [5]. Although there are known differences in the ocular development of rats versus humans, the exact pathophysiology of ivacaftor-associated cataracts still remains unclear[6].. A study conducted by Vertex Pharmaceuticals Incorporated, the developer of the major CFTR modulators, found that 1/24 (4.17%) CF patients between 2 and 6 years old developed cortical cataracts within 84 weeks of starting ivacaftor [7]. Another Vertex study on lumacaftor combined with ivacaftor found that 1/176 (0.57%) CF patients 12 years and older developed subcapsular cataracts within 96 weeks of starting treatment [8]. A similar study in CF subjects between the ages of 6 and 11 years found that 1/58 (1.72%) patients developed cataracts within 24 weeks of starting lumacaftor combined with ivacaftor, although the exact type of cataract was not specified [9]. Notably, these cataracts were not considered to be visually significant [10]. Additional studies evaluating the risk of cataract formation in pediatric patients on ivacaftor are currently ongoing [11]. Given the anticipated rise in the number of patients who will be on Trikafta in the future, however, the association between ivacaftor therapy and cataract development is one that ophthalmologists should be made aware of.


Vertex Pharmaceuticals Incorporated recommends that patients with CF undergo baseline and follow-up eye examinations when initiating ivacaftor treatment [12]. Similarly, other sources recommend that regular eye screenings should be conducted for children on ivacaftor under the age of 12 years old; however, the level of risk for younger patients versus older patients has not yet been fully defined [3] Although additional comorbidities and their effects on the development of ivacaftor-associated cataracts cannot be excluded, clinicians should still be aware of and assess for cataracts in their CF patients on CFTR modulators to prevent any vision-threatening complications.


  1. Naehrig* S, Chao* CM, Naehrlich L. Cystic Fibrosis. Dtsch Arztebl Int. 2017;114(33-34):564-574.
  2. Taylor-Cousar JL, Mall MA, Ramsey BW, et al. Clinical development of triple-combination CFTR modulators for cystic fibrosis patients with one or two F508del alleles. ERJ Open Res. 2019;5(2):00082-02019.
  3. 3.0 3.1 3.2 Taylor-Cousar JL, Mall MA, Ramsey BW, et al. Clinical development of triple-combination CFTR modulators for cystic fibrosis patients with one or two F508del alleles. ERJ Open Res. 2019;5(2):00082-02019.
  4. Condren ME, Bradshaw MD. Ivacaftor: A Novel Gene-Based Therapeutic Approach for Cystic Fibrosis. J Pediatr Pharmacol Ther. 2013;18(1):8-13.
  5. Guevera MT, McColley SA. The safety of lumacaftor and ivacaftor for the treatment of cystic fibrosis. Expert Opin Drug Saf. 2017;16(11):1305-1311.
  6. Kramer EL, Clancy JP. CFTR Modulator Therapies in Pediatric Cystic Fibrosis: Focus on Ivacaftor. Expert opinion on orphan drugs. 2016;4(10):1033.
  7. Roll-Over Study of Ivacaftor in Cystic Fibrosis Pediatric Subjects With a CF Transmembrane Conductance Regulator Gene (CFTR) Gating Mutation - Study Results - ClinicalTrials.gov. Accessed May 10, 2022. https://clinicaltrials.gov/ct2/show/results/NCT01946412
  8. Vertex Pharmaceuticals Incorporated. A Phase 3, Rollover Study to Evaluate the Safety and Efficacy of Long-Term Treatment With Lumacaftor in Combination With Ivacaftor in Subjects Aged 12 Years and Older With Cystic Fibrosis, Homozygous or Heterozygous for the F508del-CFTR Mutation. clinicaltrials.gov; 2017. Accessed May 9, 2022. https://clinicaltrials.gov/ct2/show/results/NCT01931839
  9. Vertex Pharmaceuticals Incorporated. A Phase 3, Open-Label Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Lumacaftor in Combination With Ivacaftor in Subjects 6 Through 11 Years of Age With Cystic Fibrosis, Homozygous for the F508del-CFTR Mutation. clinicaltrials.gov; 2017. Accessed May 9, 2022. https://clinicaltrials.gov/ct2/show/study/NCT01897233
  10. The Royal College of Opthalmologists. Advice for clinicians on Cataract Related to CFTER Modifying Drug of Cystic Fibrosis. Published online 2019. https://www.rcophth.ac.uk/wp-content/uploads/2021/11/Cataract-related-CFTER-for-cystic-fibrosis.pdf
  11. Vertex Pharmaceuticals Incorporated. An Ocular Safety Study of Ivacaftor-Treated Pediatric Patients 11 Years of Age or Younger With Cystic Fibrosis. clinicaltrials.gov; 2016. Accessed April 14, 2022. https://clinicaltrials.gov/ct2/show/NCT01863238
  12. Vertex Pharmaceuticals Incorporated. Kalydeco physician label. Published online 2015. http://pi.vrtx.com/files/uspi_ivacaftor.pdf
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