CFTR Modulator Therapy Care Guidelines

To aid clinicians, patients, and families in the best use of modulators, the Cystic Fibrosis Foundation sponsored the creation of guidelines to inform discussions and support decision-making.

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CFTR Modulator Therapy Care Guidelines Executive Summary

Ren CL, Morgan RL, Oermann C, et al. Cystic Fibrosis Pulmonary Guidelines: Use of CFTR Modulator Therapy in Patients with Cystic Fibrosis. Ann Am Thorac Soc. 2018 Mar. doi: 10.1513/AnnalsATS.201707-539OT.PMID: 29342367

Since the original description of cystic fibrosis in the 1930s, clinical management has focused on treating symptoms and delaying end-organ effects. Cystic fibrosis transmembrane conductance regulator (CFTR) modulators are a promising new class of small-molecule medications that can partially restore function in mutated CFTR. The first of these therapies was ivacaftor (Kalydeco®), which is a potentiator of CFTR function in patients with certain gating mutations that result in loss of ion conductance. The U.S. Food and Drug Administration (FDA) initially approved this medication for clinical use in patients with G551D mutations in 2012.

Only about 10 percent of patients with CF in the United States carry mutations that are responsive to ivacaftor. Approximately 50 percent of patients with CF are homozygous for the mutation F508del, and another 40 percent are heterozygous for this mutation. F508del results in folding defects leading to decreased CFTR at the cell surface, as well as gating defects causing decreased conductance. Lumacaftor can partially correct the folding defect in F508del-CFTR, resulting in slightly increased surface protein, but ivacaftor is also needed to improve conductance. In 2015, the FDA approved lumacaftor/ivacaftor (Orkambi®) for patients with CF ages 12 years or older homozygous for F508del. Since that time, labeling has expanded for this genotype to include patients ages 2 years and older.

To aid clinicians, patients, and families in the best use of these medications, the CF Foundation sponsored the creation of a guideline development committee consisting of independent CF caregivers from multiple disciplines and patient representatives. The objective of the committee was to develop guidelines to help inform discussions and provide support for decision-making between CF care teams and patients and families.

Methodology

A multidisciplinary committee was formed consisting of individuals with expertise and experience in CF care including:

  • Medical providers.
  • An adult with CF.
  • A parent of a child with CF.

Because of the CF Foundation's potential conflict of interest in the creation of these guidelines, no CF Foundation staff member participated in the writing or development of the recommendations. The committee created a series of clinical questions focusing on issues of interest and importance to CF clinicians, patients, and their families. A systematic review was conducted of peer-reviewed literature, specifically randomized controlled trials, and was included for meta-analysis.

This was the first CF guideline to use the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) methodology to assess the evidence and develop recommendations.

The committee chose not to address clinical situations (for example, ivacaftor therapy for patients ages 12 years or older with CF who carry at least one copy of the G551D mutation, or if the question was of low priority and unlikely to change practice) for which recommendations have already been published (such as guidelines for chronic medications to maintain lung health and preschool-aged care clinical care guidelines). All recommendations listed below refer to the details of the question listed above the accompanying table.

The committee suggested that decisions on whether to prescribe lumacaftor/ivacaftor depend on several factors. Providers should consider whether their patients would benefit substantially from treatment and would tolerate the side effects. Other considerations include possible drug-drug interactions, insurance coverage, and cost.

Recommendations

Question 1: Should ivacaftor versus no CFTR modulator treatment be used for individuals with a CF diagnosis due to gating mutations other than G551D or R117H (for example, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, or G1349D)?

Recommendations Level of Evidence
1. Use of ivacaftor in children ages 2-5 years Strong Recommendation
Based on published preschool guidelines
(Those younger than 2 years, the committee makes no recommendations.)
2. Use of ivacaftor in children ages 6-11 years with forced expiratory volume in one second (FEV1) <40% predicted Conditional Recommendation
Very low certainty in the evidence
3. Use of ivacaftor in children ages 6-11 years with FEV1 40%-90% predicted Conditional Recommendation
Low certainty in the evidence
4. Use of ivacaftor for children ages 6-11 years with FEV1 >90% predicted Conditional Recommendation
Very low certainty in the evidence
5. Use of ivacaftor for individuals ages 12-17 years with FEV1 <40% predicted Conditional Recommendation
Low certainty in the evidence
6. Use of ivacaftor for individuals ages 12-17 years with FEV1 40%-90% predicted Conditional Recommendation
Moderate certainty in the evidence
7. Use of ivacaftor for individuals ages 12-17 years with FEV1 >90% predicted Conditional Recommendation
Moderate certainty in the evidence
8. Use of ivacaftor for individuals ages 18 years or older with FEV1 <40% predicted Conditional Recommendation
Low certainty in the evidence
9. Use of ivacaftor for individuals ages 18 years or older with FEV1 40%-90% predicted Conditional Recommendation
Moderate certainty in the evidence
10. Use of ivacaftor for individuals ages 18 years or older with FEV1 >90% predicted Conditional Recommendation
Moderate certainty in the evidence

Question 2: Should ivacaftor versus no CFTR modulator treatment be used for individuals with a CF diagnosis due to the R117H mutation?

Recommendations Level of Evidence
1. Suggests against the use of ivacaftor for children ages 0-5 years Conditional Recommendation
Very low certainty in the evidence
2. Use of ivacaftor for children ages 6-11 years with FEV1 <40% predicted Conditional Recommendation
Very low certainty in the evidence
3. Use of ivacaftor for children ages 6-11 years with FEV1 40%-90% predicted Conditional Recommendation
Very low certainty in the evidence
4. Suggests against the use of ivacaftor for children ages 6-11 years with FEV1 >90% predicted Conditional Recommendation
Low certainty in the evidence
5. Use of ivacaftor for individuals ages 12-17 years with FEV1 <40% predicted Conditional Recommendation
Very low certainty in the evidence
6. Use of ivacaftor for individuals ages 12-17 years with FEV1 40%-90% predicted Conditional Recommendation
Very low certainty in the evidence
7. Suggests against the use of ivacaftor for individuals ages 12-17 years with FEV1 >90% predicted Conditional Recommendation
Moderate certainty in the evidence
8. Use of ivacaftor for individuals ages 18 years or older with an FEV1 <40% predicted Conditional Recommendation
Very low certainty in the evidence
9. Use of ivacaftor for individuals ages 18 years or older with an FEV1 40%-90% predicted Conditional Recommendation
Moderate certainty in the evidence
10. Use of ivacaftor for individuals ages 18 years or older with an FEV1 >90% predicted Conditional Recommendation
Moderate certainty in the evidence

Question 3: Should lumacaftor/ivacaftor combination drug versus no CFTR modulator treatment be used in individuals with two copies of the F508del mutation?

Recommendations Level of Evidence
1. Use of lumacaftor/ivacaftor therapy in children ages 0-5 years The committee makes no recommendation for or against this therapy *
2. Use of lumacaftor/ivacaftor in children ages 6-11 years with FEV1 <40% predicted Conditional Recommendation
Very low certainty in the evidence
3. Use of lumacaftor/ivacaftor for children ages 6-11 years with an FEV1 40%-90% predicted Conditional Recommendation
Very low certainty in the evidence
4. Use of lumacaftor/ivacaftor for children ages 6-11 years with FEV1 >90% predicted Conditional Recommendation
Very low certainty in the evidence
5. Use of lumacaftor/ivacaftor for individuals ages 12-17 years with FEV1 <40% predicted Strong Recommendation
Moderate certainty in the evidence
6. Use lumacaftor/ivacaftor for individuals ages 12-17 years with FEV1 40-90% predicted Strong Recommendation
Moderate certainty in the evidence
7. Use of lumacaftor/ivacaftor for individuals ages 12-17 years with an FEV1 >90% predicted Conditional Recommendation
Low certainty in the evidence
8. Use ivacaftor/lumacaftor for individuals ages 18 years or older with FEV1 <40% predicted Strong Recommendation
Moderate certainty in the evidence
9. Use lumacaftor/ivacaftor for individuals ages 18 years or older with FEV1 40%-90% predicted Strong Recommendation
Moderate certainty in the evidence
10. Use of lumacaftor/ivacaftor for individuals ages 18 years or older with FEV1 >90% predicted Conditional Recommendation
Low certainty in the evidence

*The committee created these guidelines prior to the FDA announcement on Aug. 7, 2018 expanding lumacaftor/ivacaftor to children ages 2 to 5. Updated guidelines will need to be considered based on evaluation of benefit, tolerance, possible drug-drug interactions, and cost.

Unanswered Questions/Future Directions

  1. Since the publication of the guideline, the FDA has made additional approvals to extend the age range for therapies and approved new CFTR modulators. The executive summary guideline does not address these newer therapies. (See Additional Reading below).
  2. The use of CFTR modulator agents to treat CF is a prime example of precision medicine. One recent approval by the FDA has been informed by in vitro studies. Future guidelines committees will have to evolve their methodologies to allow consideration of mixed methods of evidence for rare mutations, including some that are limited to a single individual.
  3. The trials considered for these guidelines focused on improvement of lung function or reduction of exacerbations. In younger groups with limited disease, even a highly effective agent may not demonstrate improvement in an individual. Longer-term studies that focus on preventing loss of function may be needed in these populations.
  4. The use of other chronic therapies in the setting of modulator therapies remains an open question. Whether the use of CFTR modulating agents can reduce the therapeutic burden of other therapies deserves further study.

Additional Reading

  1. Bessonova L, Volkova N, Higgins M, et al. Data from the US and UK cystic fibrosis registries support disease modification by CFTR modulation with ivacaftor. Thorax. 2018 Aug;73(8):731-740. doi: 10.1136/thoraxjnl-2017-210394. Epub 2018 May 10.
  2. Burgener EB, Moss RB. Cystic fibrosis transmembrane conductance regulator modulators: precision medicine in cystic fibrosis. Curr Opin Pediatr. 2018 Jun;30(3):372-377. doi: 10.1097/MOP.0000000000000627.
  3. Donaldson SH, Pilewski JM, Griese M, et al. Tezacaftor/Ivacaftor in Subjects with Cystic Fibrosis and F508del/F508del-CFTR or F508del/G551D-CFTR. Am J Respir Crit Care Med.
  4. Gentzsch M, Mall MA. Ion Channel Modulators in Cystic Fibrosis. Chest. 2018 Aug;154(2):383-393. doi: 10.1016/j.chest.2018.04.036. Epub 2018 May 8.
  5. Kim J, Davies Z, Dunn C, Wine JJ, Milla C. Ivacaftor restores CFTR-dependent sweat gland fluid secretion in cystic fibrosis subjects with S945L alleles. J Cyst Fibros. 2018 Mar;17(2):179-185. doi: 10.1016/j.jcf.2017.12.005. Epub 2017 Dec 24.
  6. Kirby T. Tezacaftor-ivacaftor is safe and efficacious in patients with cystic fibrosis with Phe508del mutations. Lancet Respir Med. 2018 Jan;6(1):13-14. doi: 10.1016/S2213-2600(17)30439-3. Epub 2017 Dec 14.
  7. Pranke IM, Hatton A, Simonin J, et al. Correction of CFTR function in nasal epithelial cells from cystic fibrosis patients predicts improvement of respiratory function by CFTR modulators. Sci Rep. 2017 Aug 7;7(1):7375. doi: 10.1038/s41598-017-07504-1.
  8. Rowe SM, Daines C, Ringshausen FC, et al. Tezacaftor-Ivacaftor in Residual-Function Heterozygotes with Cystic Fibrosis. N Engl J Med. 2017 Nov 23;377(21):2024-2035. doi: 10.1056/NEJMoa1709847. Epub 2017 Nov 3.
  9. Southern KW, Patel S, Sinha IP, Nevitt SJ. Correctors (specific therapies for class II CFTR mutations) for cystic fibrosis. Cochrane Database Syst Rev. 2018 Aug 2;8:CD010966. doi: 10.1002/14651858.CD010966.pub2.
  10. Taylor-Cousar JL, Munck A, McKone EF, et al. Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del. N Engl J Med. 2017 Nov 23;377(21):2013-2023. doi: 10.1056/NEJMoa1709846. Epub 2017 Nov 3.
  11. Cystic Fibrosis Foundation. FDA Approves Kalydeco for Infants With CF. cff.org. 2019 Apr 30.

This executive summary was prepared by:

Angela Delecaris, MD (Indiana University) and Edward T. Naureckas, MD (University of Chicago)

The guidelines were published in March 2018, they were reviewed in April 2019 and it was determined that no update is needed at this time.

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