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Cystic fibrosis: triple therapy shows promising results

BMJ 2019; 367 doi: (Published 04 November 2019) Cite this as: BMJ 2019;367:l6347
  1. Elisabeth Mahase
  1. The BMJ

The triple therapy Trikafta (elexacaftor, tezacaftor, and ivacaftor) has the potential to lead to “transformative improvements in the lives of people with cystic fibrosis,” two phase III trials indicate.

The studies, funded by the drug company Vertex, looked at the efficacy and safety of Trikafta in patients with one copy of Phe508del—the most common gene mutation that causes cystic fibrosis—and patients with two Phe508del mutations.

Both trials reported positive results for the drug, which could benefit many patients, as up to 90% of all people with cystic fibrosis have at least one copy of the Phe508del mutation, and almost 50% have two copies.

The findings came after NHS England was able to secure a deal with Vertex, after lengthy negotiations over pricing, to provide three of the company’s other cystic fibrosis drugs on the NHS.1 These are Orkambi (lumacaftor-ivacaftor), Symkevi (tezacaftor-ivacaftor), and Kalydeco (ivacaftor). As part of this agreement Vertex will also submit Trikafta to the UK National Institute for Health and Clinical Excellence for appraisal.

In the US the Washington Post has reported that Trikafta will cost $311 000 (£240 000; €280 000) a year.2

In the first paper, published in the New England Journal of Medicine,3 403 patients (aged 12 or over) with one mutation were randomised to receive at least one dose of active treatment or placebo. It found that Trikafta, when compared with placebo, resulted in a percentage of predicted forced expiratory volume in 1 second (FEV1) that was 13.8 points higher at four weeks and 14.3 points higher at 24 weeks.

The rate of pulmonary exacerbations was 63% lower in the Trikafta group, the respiratory domain score on the cystic fibrosis questionnaire (revised) was 20.2 points higher (indicating a higher patient reported quality of life with regard to respiratory symptoms), and the sweat chloride concentration was 41.8 mmol/L lower (P<0.001 for all comparisons).

The study reported that Trikafta was “generally safe and had an acceptable side-effect profile,” with discontinuation of the trial regimen as a result of adverse events occurring in just 1% of patients.

The second paper, published in the Lancet,4 then looked at Trikafta in patients with two Phe508del mutations and compared outcomes with patients taking just tezacaftor-ivacaftor. During the study (August to December 2018) all 113 patients received tezacaftor-ivacaftor for the first four weeks, after which 52 patients were randomly assigned to tezacaftor (100 mg orally once daily) plus ivacaftor (150 mg orally every 12 hours), while 55 were assigned to elexacaftor (200 mg orally once daily) plus tezacaftor and ivacaftor for four weeks.

The Trikafta group reported improvements in the primary outcome of FEV1: least squares mean treatment difference of 10 percentage points (95% confidence interval 7.4 to 12.6). Improvements were also seen in the key secondary outcomes of sweat chloride concentration (LSM treatment difference −45.1 mmol/L (−50.1 to −40.1)) and CFQ-R RD score (LSM treatment difference 17.4 points (11.8 to 23.0)).

The researchers concluded, “Elexacaftor plus tezacaftor plus ivacaftor [Trikafta] provided clinically robust benefit compared with tezacaftor plus ivacaftor alone, with a favourable safety profile, and shows the potential to lead to transformative improvements in the lives of people with cystic fibrosis who are homozygous for the Phe508del mutation.”

Trikafta was “well tolerated, with no discontinuations,” they said. Serious adverse events occurred in two of the participants receiving Trikafta and in one receiving tezacaftor plus ivacaftor.


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