Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele

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Middleton PG, Mall MA, Drevinek P, et al. Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele. N Engl J Med. 2019;381:1809-19.

Clinical Question

In patients 12 years or older with cystic fibrosis with Phe508del, how does the safety and efficacy of elexacaftor-tezacaftor-ivacaftor compare to placebo?

Bottom Line

The efficacy of elexacaftor-tezacaftor-ivacaftor was confirmed in this trial in patients 12 years or older who were heterozygous for the Phe508del CFTR mutation and effectively modulates the function of Phe508del CFTR.

Major Points

Cystic fibrosis (CF) is an autosomal, recessive, multi-organ system disease that affects approximately 80,000 people worldwide. Patients with CF have a life expectancy of about 40 years, with a majority of patients dying from lung disease.



Guidelines

Design

  • Multicenter, double-blind, randomized, placebo-controlled trial
  • N=403
    • Elexacaftor-tezacaftor-ivacaftor (n=200)
    • Placebo (n=203)
  • Setting: 115 sites in 13 countries (Australia, Austria, Belgium, Canada, Czechia, France, Germany, Greece, Italy, Netherlands, Sweden, UK, USA)
  • Enrollment: June 2018 to April 2019
  • Analysis: mITT
  • Primary outcome: absolute change from baseline in percentage of predicted FEV1 at week 4

Population

Inclusion Criteria

  • 12 years or old with CF and Phe508del
  • FEV1 of 40 to 90%
  • Stable CF disease

Exclusion Criteria

  • Acute upper or lower respiratory infection
  • Pulmonary exacerbation or lung infection
  • History of any illness or clinical condition (cirrhosis, solid or hematologic transplantation, alcohol or drug abuse, cancer)
  • Abnormal lab values at screening (Hgb, bilirubin, AST, ALT, renal function)

Baseline Characteristics

  • Mean age: 25 years
  • Mean BMI: 21
  • Mean predicted FEV1: 61
  • Mean sweat chloride concentration: 102 mmol/L
  • Mean adherence: >98% in both groups

Interventions

  • Elexacaftor (200 mg once daily) in triple combination with tezacaftor (100 mg once daily) and ivacaftor (150 mg every 12 hours) or matched placebo

Outcomes

Comparisons are intensive therapy vs. standard therapy.

Primary Outcomes

Absolute change in percentage of FEV1 at week 4
13.6 vs -0.2 (difference of 13.8; 95% CI 12.1 to 15.4; P<0.001)

Secondary Outcomes

Absolute change in percentage of FEV1 through week 24
13.9 vs -0.4 (difference of 14.3; 95% 12.7 to 15.8; P<0.001)
Pulmonary exacerbations through week 24 (number of events)
41 vs 113 (rate ratio 0.37; 95% CI 0.25 to 0.55; P<0.001)
Absolute change in sweat chloride concentration through week 24
-42.2 vs -0.4 (-41.8; 95% CI -44.4 to -39.3; P<0.001)
Absolute change in CFQ-R respiratory domain score through week 24
17.5 vs -2.7 (20.2; 95% CI 17.5 to 23; P<0.001)
Absolute change in BMI at week 24
1.13 vs 0.09 (1.04; 95% CI 0.85 to 1.23; P<0.001)
Absolute change in sweat chloride concentration through week 4
-41.2 vs 0.1 (-41.2; 95% CI -44 to -38.5; P<0.001)
Absolute change in CFQ-R respiratory domain score through week 4
18.1 vs -1.9 (20.1; 95% CI 16.9 to 23.2; P<0.001)

Subgroup Analysis

Treatment results were consistent among subgroup analyses in patients with an absence of CFTR protein production due to a minimal-function mutation and those with missense or in-frame deletion mutations.

Adverse Events

No significant differences were found between groups in terms of adverse effects. 10% of patients in either group experienced side effects consistent with CF complications. Common noted adverse effects include infective pulmonary exacerbation of CF, increased sputum, headache, diarrhea, cough, upper respiratory tract infection, nasopharyngitis, oropharyngeal pain, hemoptysis, and fatigue.

Criticisms

  • Not randomized by concealed allocation

Funding

Vertex

Further Reading

Heijerman HGM, McKone EF, Downey DG, et al. Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial. Lancet 2019;394:1940-48.

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