Trial Development
Beyond approval, there continues to be a proportion of the CF community
that does not have a specific CFTR modulator therapy. Globally, some
countries may have immediate access, and others have no access. Some of
the lack of access may be due to the specific mutations within a
population. In Turkey, for example, only 122 patients (9%) of 1488 CF
patients in their registry are eligible for iva and 539 (27.2%) for
ETI, just based on the mutations present in their
population61. Similarly, in the Canadian registry,
patients diagnosed in adulthood had reduced eligibility for modulators
at 83%, meaning that there are no CFTR modulators for the rarer
mutations seen in some individuals with CF who have are diagnosed into
adulthood62. The first step to highlighting the rarer
mutations that do not have access to modulators is to accurately
describe the populations of individuals with CF in studies. McGarry
points out in two letters to the editor (Lancet and NEJM), that race and
ethnicity were not included as part of the demographic information for
the two phase 3 large, randomized controlled trials of ETI, despite a
known increased burden and more severe pulmonary disease in minority
patients63,64.
In addition to the need for other CFTR modulators to impact the entire
CF population, there is a continued therapeutic need for the development
of medications for infection, inflammation, and mucus clearance, among
other areas. The variation in access to modulators, the inadequate
therapeutic success in various populations, and the need for new trial
designs is leading to a shift in preparations for future clinical
trials. Several worldwide meetings among clinical trial experts took
place to discuss these concerns and develop recommendations as well as
extend collaborations, identify areas for harmonization, and gain
efficiencies to promote ethical, feasible, and credible study designs
amidst the changing landscape of CF care65-68. Further
details of this work can be found in the mentioned references.
Furthermore, patient and clinician experience will be important in the
selection of CFTR modulators, as well as on the selection of treatments
to continue to reduce treatment burden in CF69,70. In
a survey of 60 adults and 30 caregivers, regarding what influenced
patients’ decision to start a modulator, the most impactful influence
was providers/care team, followed by parents and then the individual
themselves69. Surprisingly, social media only
accounted for a small amount of influence at 13%. A separate survey of
pwCF, families and acquaintances as well as clinicians, inquired about
interest in withdrawal of therapies in patients on CFTR
modulators70. Overwhelmingly, there was widespread
support by 80% (541/645) of the community, and 95% (206/218) of
clinicians. Moreover, this type of study was also surveyed as feasible,
as 83% (299/359) of the community reported not having reduced or
stopped taking their other chronic medications. The SIMPLIFY trial,
which is under way, will test the effects and safety of stopping inhaled
hypertonic saline or dornase alfa in teens and adults with CF who are
also taking the triple-combination modulator, ETI71.
To work toward therapy for all mutations that cause CF, research has
continued. One such area is premature stop codons, a group not currently
treatable with modulators. Ataluren is a read- through medication that
underwent phase 3 studies, without success, however it was noted that
those patients who were not on inhaled aminoglycosides had a treatment
efficacy signal. Therefore, a randomized, double blind,
placebo-controlled trial, in patients over age 6 with FEV1pp between
40% and 90%, who were not on inhaled aminoglycosides, was conducted in
279 enrolled patients over 48 weeks72. Both the
treatment and placebo group had a decline in FEV1pp with no difference
between the groups. Furthermore, BMI, PEx rates, and respiratory quality
of life did not differ.
Further exploring ataluren effect, using N-of-1 trial design, two
patients (31-year-old with W1282X/G542X and a 32-year-old with
W1282X/W1282X) had therapy with combined ataluren and ivacaftor73. In the first patient, iva was added to ataluren
for 2 separate 2 week periods and compared to ataluren alone and iva
alone. No change in sweat chloride, FEV1pp, or BMI was seen on any
combination, but iva alone had some modest benefit in nasal potential
difference (NPD). The CFQ-R respiratory domain improved during both
ataluren/iva and iva alone time periods. For the second patient, who was
already on iva, ataluren was added for approximately 11 months. There
was a slight increase in BMI with combination therapy (19.8
kg/m2 versus 19.3 kg/m2 in iva
alone) and improvement in NPD (-22.5 mV versus -6.7 mV in iva alone).
Higher CFQ-R scores were seen on iva alone (88.9 versus 78.9). No
changes were seen in FEV1pp or sweat chloride. The authors concluded
that the results were mixed.
In a trial mentioned above in the LCI section, one group performed
N-of-1 studies in 24 pwCF, over age 12 years, with at least one missense
or splicing mutation, using a randomized, double blind,
placebo-controlled, within patient, crossover study design examining iva
benefit 19. After 2 weeks of iva, FEV1pp had a
treatment difference of 2.3%; after 8 weeks the FEV1pp treatment
difference was 4.0%. Additional outcomes showed improved LCI, sweat
chloride, weight, and BMI.
A study in Germany attempted to use GLPG2737, a novel CFTR corrector, in
a phase 2a, randomized, double blind, placebo controlled, parallel group
study comparing 14 patients who had add on of GLPG2737 to lum/iva to 8
patients on lum/iva alone over 28 days74. The primary
outcome was met, with reduced sweat chloride mean difference of -19.6
mmol/L (p=0.0210). Secondary exploratory outcomes, FEV1pp and CFQ-R
respiratory domain, did not significantly differ, however the study was
not powered to find differences. The authors posit that drug
interactions between GLPG2737 and lum led to lower exposure to GLPG2737
than predicted from in vitro studies, possibly accounting for the
lower FEV1pp findings.
Another new modulator, icenticaftor (QBW251) underwent a randomized,
double blind, placebo-controlled, dose escalation study over 14 days in
healthy volunteers followed by pwCF75. Icenticaftor,
in combination with lum has shown superior in vitro effect in sustaining
membrane expression and function compared to iva, therefore is
postulated to have improved effect. This study of monotherapy with
icenticaftor showed it was well tolerated, and in patients with class 3
or 4 mutations (n=24), a treatment difference in LCI2.5of -1.13, FEV1pp of 6.46%, and sweat chloride of -8.36mmol/L was seen.
However, in patients homozygous for F508del (n=25), the study was
stopped at interim analysis due to no treatment difference
(LCI2.5 0.48 and FEV1pp of 0.53%).
Working to find a therapy that can be applied to any mutation, antisense
oligonucleotides have been under investigation. Eluforsen was evaluated
in a randomized, double blind, placebo-controlled, dose escalation,
phase 1B study in adults with CF and FEV1pp ≥70%76.
Eluforsen, given via nebulization for up to 4 weeks, was found to be
well tolerated with no dose limiting toxicities, and no related adverse
events. As variable doses were given, exploratory efficacy outcomes
varied. Patients with FEV1pp ≤90% had a difference of 8% compared to
placebo at 6.25mg dosing and 10.9% at 12.5mg dosing, although this
encouraging efficacy signal should be interpreted cautiously as there
were small numbers of patients (n=34, 36 in 2 cohorts). CFQ-R
respiratory symptom score was statistically significantly improved
(range difference to placebo of 12.91 to 19.13 points) in three doses,
however sweat chloride values did not change.