(173) Effectiveness of Elexacaftor/Tezacaftor/Ivacaftor in children with cystic fibrosis: The Pediatric PROMISE study

Background: Elexacaftor/Tezacaftor/Ivacaftor is a CFTR modulator combination approved for CF patients 6 and older with at least one Elexacaftor/Tezacaftor/Ivacaftor-responsive CFTR allele. Efficacy and safety in 6-< 12 year old children were assessed in one open label and one placebo-controlled Phase 3 trial. The PROMISE study is an ongoing U.S. multicenter, observational, prospective cohort study examining efficacy in the post-approval “real world” setting among people with CF prescribed Elexacaftor/Tezacaftor/Ivacaftor clinically. Here, we report preliminary one-month follow-up data from the Pediatric Substudy in 6 to < 12 year old children.

Methods: Key eligibility criteria included a diagnosis of CF, at least one Elexacaftor/Tezacaftor/Ivacaftor-responsive CFTR variant and age of 6 to < 12 years old at Elexacaftor/Tezacaftor/Ivacaftor initiation. The primary outcome was the change in lung clearance index (LCI) by multiple breath washout. Secondary outcomes reported here include changes in percent predicted (pp) FEV1, sweat chloride and CFQ-R respiratory domain score. Changes from baseline to the one-month follow up visit were analyzed with a paired t-test on a complete-case cohort.

Results: 125 participants at 20 sites were enrolled in the Pediatric Substudy of which 119 had completed the 1 month visit at the time of analysis. Mean ± SD age at initiation of Elexacaftor/Tezacaftor/Ivacaftor was 9.2 ± 1.8 years and 44% were female at birth. There were 65 (52%) F508del homozygous participants, 34 (27%) F508del heterozygous participants with a minimal function second allele, and 26 (21%) participants with other CFTR variants (heterozygotes with gating or residual function second alleles, or with no F508del alleles). Results at baseline, 1 month and the change (mean, 95% CI) are reported in the Table. As shown, LCI, ppFEV1, sweat chloride and the CFQ-R respiratory domain score all improved significantly from baseline to the 1 month visit.

Conclusions: In this ongoing, prospective, observational post-approval study of Elexacaftor/Tezacaftor/Ivacaftor in children, preliminary results at one month of follow up indicate significant improvements in LCI, ppFEV1, sweat chloride and self-reported respiratory symptoms. At this interim analysis, the magnitude of change for all outcome measures was lower than that reported in the Phase 3 clinical trials in this age range, noting that baseline lung function was better in the current study similar to what has previously been observed for the PROMISE study in subjects 12 years and older [1]. Future reports will evaluate a broader range of endpoints for up to 4 years.

Acknowledgements: Funded by the Cystic Fibrosis Foundation.

References: [1] Nichols DP, Paynter AC, Heltshe SL, Donaldson SH, Frederick CA, Freedman SD, Gelfond D, Hoffman LR, Kelly A, Narkewicz MR, Pittman JE, Ratjen F, Rosenfeld M, Sagel SD, Schwarzenberg SJ, Singh PK, Solomon GM, Stalvey MS, Clancy JP, Kirby S, Van Dalfsen JM, Kloster MH, Rowe SM; PROMISE Study group. Clinical Effectiveness of Elexacaftor/Tezacaftor/Ivacaftor in People with Cystic Fibrosis: A Clinical Trial. Am J Respir Crit Care Med. 2022 Mar 1;205(5):529-539. doi: 10.1164/rccm.202108-1986OC.