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.