Elexacaftor/Tezacaftor/Ivacaftor
Elexacaftor/TEZ/IVA (ETI) is the most exciting highly effective
modulator available in the US since late 2019. In the past year, there
were two phase 3 trials reported: one in 258 participants over age 12
with one F508del mutation and a gating or residual function mutation
already on IVA or TEZ/IVA and transitioned to ETI over 8
weeks24 and a second trial over 24 weeks in 6-11 year
old participants with two copies F508del or a F508del and a minimal
function mutation25. Neither study had changes in
safety signal, and both demonstrated improvements in FEV1pp, SC, CFQ-R.
Additionally, growth parameters were improved in the 6–11-year-old
evaluation. It is important to note those PwCF who were already on IVA
or TEZ/IVA, demonstrated a between group difference of 3.5% in FEV1pp,
thus showing additional improvement with ETI above IVA or TEZ/IVA.
Moreover, indication for ETI was shown in a patient with N1303K/E193X
mutations who had improvement in the lab, followed by improvements in
FEV1pp, BMI, CT scan of the chest, and sinus
imaging26. Thus, ETI has been shown to be effective in
those transitioning from other modulators, the 6–11-year-old age group
and an individual with the N1303K/E193X mutation.
The long term effects of ETI in PwCF over 12 years of age, was reported
in three studies, a post approval multicenter study at four German
centers27, the PROMISE study, the US’s post approval,
real -world observational study28, and an interim
analysis of the open label extension study for participants from the
clinical trials29. Timing differed between the
studies, from 8-16 weeks post ETI initiation27,
through 6 months of ETI use28, or once all
participants completed 24 weeks in the clinical
trials29. None of the studies showed additional safety
concerns. Participants had improvements in FEV1pp, BMI, and SC (if not
previously on ETI as part of clinical trial). It is also important to
note that patients already on a modulator who transitioned to ETI had
additional improvements in clinical outcomes (FEV1pp increased
6.1-9.2%, SC decreased -23.9 to 43.4 mmol/L)28. Both
the PROMISE and the German evaluations demonstrated a correlation
between SC changes and FEV1pp27,28; whereby the
PROMISE reported for every 10-point decrease in SC there was a 0.89%
increase in FEV1pp28. As with prior findings with
LUM/IVA, the PROMISE study found a larger decline in SC in
females28. Improvements in nasal potential difference
(NPD) and intestinal current measurement (ICM), with improvements up to
40-50% of normal CFTR levels, in the German
studies27. Changes in NPD did not correlate with FEV1
or BMI; however, ICM was noted to have a weak correlation. From PROMISE,
self-reported use of pulmonary maintenance medications usage decreased
by 6% for dornase alpha, 9.8 % for hypertonic saline, 9.1% for
azithromycin, and 34% for inhaled antibiotics.
Expanding usage of ETI to population not studied in the original
clinical trials, use for PwCF and ADL, based primarily on a FEV1pp
<40% or referral/evaluation for lung transplantation
demonstrated improvements in FEV1pp30-34,
BMI31-34, CFQ-R32,34, and decreases
in antibiotic use/exacerbations32,34. Where reported,
oxygen use was decreased/eliminated32,34, with one
study demonstrating a decrease in noninvasive ventilation
use31. Most importantly, transplantation status
primarily changed in a positive direction, with decreases in transplant
related discussions, referrals, and wait list
numbers30-33. Overall, lung transplants decreased by
56.4% in France, attributed to ETI, as the COVID related decrease in
non -CF indications only dropped 26.4%31. When data
from prior to 2002 was comparted to late 2020/early 2021, France saw a
tenfold reduction in transplantation rate35.
Similarly, according to an analysis of the International Society of
Health Lung Transplantation, between 1990-2017, there was a decrease in
CF as an indication for lung transplantation36.
Therefore, the use of highly effective modulators have changed the
landscape of lung transplantation.