Ivacaftor in People with Cystic Fibrosis and a 3849+10kb C→T or D1152H Residual Function Mutation

Abstract

Rationale: Ivacaftor’s clinical effects in the residual function mutations 3849 + 10kb C→T and D1152H warrant further characterization. Objectives: To evaluate ivacaftor’s effect in people with cystic fibrosis aged ≥6 years with 3849 + 10kb C→T or D1152H residual function mutations and to explore the correlation between ivacaftor-induced organoid-based cystic fibrosis transmembrane conductance regulator function measurements and clinical response to ivacaftor. Methods: Participants were randomized (1:1) in this placebo-controlled crossover study; each treatment sequence included two 8-week treatments with an 8-week washout period. The primary endpoint was absolute change in lung clearance index 2.5 from baseline through Week 8. Additional endpoints included lung function, patient-reported outcomes, and in vitro intestinal organoid–based measurements of ivacaftor-induced cystic fibrosis transmembrane conductance regulator function. Results: Of 38 participants, 37 completed the study. The primary endpoint was met; the Bayesian posterior probability of improvement in lung clearance index 2.5 with ivacaftor versus placebo was >99%. Additional endpoints improved with ivacaftor. Safety findings were consistent with ivacaftor’s known safety profile. Dose-dependent swelling was observed in 23 of 25 viable organoid cultures with ivacaftor treatment. Correlations between ivacaftor-induced organoid swelling and clinical endpoints were negligible to low. Conclusions: In people with cystic fibrosis aged ≥6 years with a 3849 + 10kb C→T or D1152H mutation, ivacaftor treatment improved clinical endpoints compared with placebo; however, there was no correlation between organoid swelling and change in clinical endpoints. The organoid assay may assist in identification of ivacaftor-responsive mutations but in this study did not predict magnitude of clinical benefit for individual people with cystic fibrosis with these two mutations. Clinical trial registered with ClinicalTrials.gov (NCT03068312).

Antisense oligonucleotide-based drug development for Cystic Fibrosis patients carrying the 3849+10kb C-to-T splicing mutation

“…Changes in spirometry (i.e. FEV 1 ) ranged from ~2.6-5.8% (12, 13, 36, 45), far short of the benchmark set by highly effective CFTR modulator therapy (46, 47), leaving an unmet need for a more effective therapy. Indeed, as presented in the current paper, in vitro treatment of HNEs heterozygous for the 3849+10kb C-to-T mutation with VX-770 alone, resulted in a minimal CFTR response (Supplementary Figure 5), noting the high degree of cAMP stimulation by forskolin that preceded VX-770 administration may have abrogated the modest effect, as reported previously (48).…”

Review of CFTR Modulators 2020

“…Three other studies in 2020 studied LCI 2.5 as an endpoint for CFTR modulator trials. A randomized, placebo-controlled, crossover study of 38 subjects with either the 3849+10kbCT or D1152H mutation compared LCI 2.5 in those treated with iva versus placebo for 8 weeks 18 . In these subjects with mean baseline FEV1pp of 74 (SD 16.9), baseline LCI 13(SD 4.7), and 89.5% of whom were adults, the difference in LCI 2.5 between iva and placebo groups was -0.66 (95% CI, -1.10 to -0.21) at 8 weeks.…”

“…There have been two studies using organoids to study CFTR modulators in 2020. One group, mentioned above in the LCI endpoint section, studied the effectiveness of iva and compared the clinical and in vitroorganoid endpoints 18 . In the randomized placebo-controlled, crossover study of 38 subjects (37 completed), with either the 3849+10kbCT or D1152H mutation, intestinal organoids cultures were successfully established in 29 out of 33 biopsies, but only 25 intestinal organoid cultures met quality control standards.…”

“…In vitro organoid response was seen but not correlated with sweat chloride or FEV1pp 20 , similar to the above findings. Both authors conclude that the use of organoids are of potential benefit to identify modulator responsive mutations, but may not predict the degree of response the patient will have in terms of clinical parameters like FEV1pp or sweat chloride 18,20 . One researcher postulated that a correlation between intestinal organoids and clinical phenotypes may not exist, as the clinical phenotypes took years to establish and may not be fully reversed by CFTR modulators, or may be impacted by other non-CFTR dependent factors 21 .…”

Enhanced delivery of peptide-morpholino oligonucleotides with a small molecule to correct splicing defects in the lung

“…Splicing mutations may be homozygous or be paired with other CFTR defects such as the common deletion-F508 trafficking mutation ( 3 ), channel gating mutations, or stop mutations. Although modulator drugs have been approved for certain CFTR splicing mutations ( 11 , 12 ) they do not address the underlying molecular defect. For patients where homozygous splicing mutations or a combination of splice and stop codon mutations result in very little CFTR protein production ( 13 , 14 ), the modulator drugs are unlikely to be effective and other therapies will be needed.…”