Alternative mutations
Each modulator is approved for specific mutations, but exploration of
effectiveness in other mutations occurs. Sometimes, specific modulators
are found to not be effective for specific mutations, which is very
useful negative data. Tez/iva was examined in pwCF heterozygous for
F508del and a minimal function mutation in a randomized, double blind,
placebo controlled, parallel group, phase 3 trial in patients ≥12 years
of age. FEV1pp did not improve 32. Specifically, the
trial had predetermined criteria for futility. Predetermined levels for
FEV1pp were met at 12 weeks; the treatment difference for FEV1pp was
1.79%, which was below the predetermined futility boundary of 2.5%.
The within tez/iva group improvement for absolute FEV1pp was 1.53%,
again less than the predetermined level of 1.75%, thus the trial was
stopped for futility. No differences in BMI, CFQ-R respiratory domain,
or PEx rate were seen32. This research highlights that
tez/iva is not effective for pwCF with F508del/minimal function
mutations. In patients heterozygous for F508del and a gating mutation, a
multicenter, international, randomized, double blind, parallel group,
phase 3 trial compared tez/iva to iva alone in 153 patients over age 12
years, over 8 weeks33. No difference in FEV1pp, sweat
chloride or CFQ-R respiratory domain were seen, though the reduction of
sweat chloride level was lower with the combination treatment compared
to iva alone (-5.8 difference). The conclusion was that tez/iva did not
demonstrate any additional clinical efficacy over iva alone, but it was
safe and well tolerated.