Cystic Fibrosis: Improved Treatment Benefits Up To 90 Percen
Elexacaftor–tezacaftor–ivacaftor is a small-molecule cystic fibrosis transmembrane conductance regulator (CFTR) modulator regimen shown to be efficacious in patients with at least one Phe508del allele, which indicates that this combination can modulate a single Phe508del allele. In patients whose other CFTR allele contains a gating or residual function mutation that is already effectively treated with previous CFTR modulators (ivacaftor or tezacaftor–ivacaftor), the potential for additional benefit from restoring Phe508del CFTR protein function is unclear.

The team conducted a trial involving patients 12 years of age or older with cystic fibrosis and Phe508del–gating or Phe508del–residual function genotypes. After a 4-week run-in period with ivacaftor or tezacaftor–ivacaftor, patients were randomly assigned to receive elexacaftor–tezacaftor–ivacaftor or active control for 8 weeks. The primary end point was the absolute change in the percentage of predicted forced expiratory volume in 1 second (FEV1) from baseline through week 8 in the elexacaftor–tezacaftor–ivacaftor group.

Results:

After the run-in period, 132 patients received elexacaftor–tezacaftor–ivacaftor and 126 received active control. Elexacaftor–tezacaftor–ivacaftor resulted in a percentage of predicted FEV1 that was higher by 3.7 percentage points relative to baseline and higher by 3.5 percentage points relative to active control and a sweat chloride concentration that was lower by 22.3 mmol per liter relative to baseline and lower by 23.1 mmol per liter relative to active control.

The change from baseline in the Cystic Fibrosis Questionnaire–Revised respiratory domain score with elexacaftor–tezacaftor–ivacaftor was 10.3 points and with active control was 1.6 points. The incidence of adverse events was similar in the two groups; adverse events led to treatment discontinuation in one patient in the elexacaftor–tezacaftor–ivacaftor group and in two patients in the active control group.

Conclusions:

Elexacaftor–tezacaftor–ivacaftor was efficacious and safe in patients with Phe508del–gating or Phe508del–residual function genotypes and conferred additional benefit relative to previous CFTR modulators.

Source:
https://www.nejm.org/doi/full/10.1056/NEJMoa2100665
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