Ivacaftor
Ivacaftor (IVA) has been approved for the longest amount of time and is currently approved in the United States (US) for 4 months of age and older based on the ARRIVAL study1. This single arm, phase 3, multicenter study was conducted in infants between 4 and 12 months of age. Of note, based on one infant with elevated concentrations of IVA, infants under 4 months of age and 5 kilograms were not included and will be investigated in a future study. IVA was found to be safe, well tolerated, have similar pharmacokinetics to older patient populations, no adverse events, and no new safety signals. Sweat chloride (SC) decreased by a mean absolute change of -55.7 mmol/L. More exciting however, was the continued support that CFTR modulators may delay or minimize progressive exocrine pancreatic dysfunction. This was demonstrated by an elevation in fecal elastase levels (mean absolute change of 166 micrograms/g) and decreases in immunoreactive trypsinogen (IRT), amylase, and lipase levels. It is exciting to see the effects of earlier treatment with CFTR modulators as younger ages are studied.
Expanding the eligibility of IVA, a phase 3b, randomized, double blind, placebo controlled, single center, crossover study in patients over age 6 years, examined use of IVA over 8 weeks, in 39 patients with at least one copy of 3849+10kbC>T or D1152H mutation2. As per other studies, lung clearance index (LCI2.5), SC, forced expiratory volume in one second percent predicted (FEV1pp) and CF quality of Life Respiratory Domain (CFQ-R) all improved; with a safety profile consistent with prior studies. Interestingly, the study obtained patient derived rectal organoids which showed dose dependent swelling, however, individual clinical responses did not correlate with the degree of swelling. Key outcomes from this study include support for clinical benefit of IVA for these mutations and use of organoids to identify responsive mutations.
Although clinical trials provide information about the effects of IVA, an understanding of real-world, long-term use is also valuable. Four separate reports, from Canada3, the United Kingdom (UK) 4, France5 and the US6 assessed IVA over time. Both the US and France conducted specific studies to observe these effects, the BRIO (cystic fiBR osis I n O bservation) in France (129 patients followed for 24 months post IVA initiation) and the GOAL-e2 (G511D Observational Study - Expanded to additional genotype and Extended for Long Term Follow up) (96 participants, up to 5.5 years post IVA initiation) while the UK report was an evaluation of one center (35 patients over 5 years) and the Canadian report utilized the Canadian CF Registry (144 patients over 4 years). All studies demonstrated improvements in pulmonary function, growth parameters, decreases in pulmonary exacerbations, reductions in Pseudomonas aeruginosa(PA), and no differences from prior reports in safety signals. In the US study, although improvements in SC were seen, there was no correlation with change in FEV1pp or body mass index (BMI) at any of the analyzed time points6. In the UK, an interesting analysis of IVA medication possession ratios (MPR) found an overall decline of 2.5 % per year, with those PwCF who had higher MPR demonstrating greater FEV1 change4. These real-world studies show continued support for the use of ivacaftor to improve a broad array of clinical outcomes with no long term safety concerns.