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.