Tezacaftor/Ivacaftor
As with the other modulators, tezacaftor/IVA (TEZ/IVA) has also had
explored in additional populations, which have published this past year.
In ages 6 to 11 years (homozygous or heterozygous for F508del
mutations), 66 participants were studied in a phase 3, randomized,
double blind, placebo-controlled trial over 8 weeks19.
No new safety concerns were seen. Statistically significant changes were
seen in SC, LCI2.5, and FEV1pp, although no changes were
seen in CFQ-R, growth parameters, or fecal elastase. Evaluating PwCF
with one copy of F508del, and a gating mutation known to be responsive
to IVA who were studied in a phase 3, randomized, double blind, placebo
control, parallel group study of 153 participants, over age 12
years20. Participants received IVA for 4 weeks
followed by either continued IVA or change to TEZ/IVA over 8 weeks. No
clinically meaningful benefit was seen for FEV1pp, CFQ-R, or SC.
Extension of TEX/IVA usage was examined in participants from prior
TEZ/IVA trials, over age 12 years (EXTEND study). Although, many
participants withdrew due to non-efficacy (especially in those
heterozygous for F508del), 682 participants completed 96 weeks. No new
safety signals were elucidated, however, a relative reduction in rate of
decline of FEV1pp of 61.5% was seen for participants homozygous for
F508del when compared to historical controls21. Those
PwCF who had discontinued LUM/IVA due to respiratory related signs and
symptoms, were evaluated using TEZ/IVA. In the 94 participants who
completed the study over 56 days, the respiratory adverse event rate was
14% compared to placebo rate of 21.3%, with no discontinuations of
TEZ/IVA22. Finally, an alternate analysis, using the
CF Foundation Patient Registry(US CFFPR), statistical modeling explored
the difference in FEV1pp between those PwCF exposed to smoke
(self-reported) compared to those with no exposure23.
It is noteworthy that at baseline, PwCF who were exposed had an almost
8% lower FEV1pp. After initiation of TEZ/IVA those exposed had a
greater decline in FEV1pp compared to those not exposed to smoke,
essentially nullifying the effects of TEZ/IVA. Thus, the published
reports for TEZ/IVA this year show benefit for younger ages (6-11
years), TEZ/IVA longer term (mainly homozygous F508del) use and reduced
respiratory adverse events, however, for those with only one copy
F508del or those exposed to smoke, minimal benefit was seen.