Objectives: To assess safety, pharmacokinetics (PK), pharmacodynamics, and efficacy of IVA dosing for 24 weeks in infants with CF aged 1 to <4 months.

Objectives LUM/IVA has been shown to be safe and effective in people with CF, including children. This registry-based study evaluated long-term efficacy and safety of LUM/IVA in children aged 2 through 5 years at treatment initiation. Methods LUM/IVA cohorts included children with CF homozygous for F508del (F/F) in the European CF Society Patient Registry who initiated LUM/IVA therapy between 15 January 2019 (approval) and 31 December 2020. Longitudinal trends in key outcomes were compared to 3 modulator-naïve cohorts: matched concurrent cohort of children heterozygous for F508del and minimal function mutation (F/MF) from same countries (AT,LU,DK,FR,IE,NL,SE,SI,CH,UK,DE) as LUM/IVA cohort (F/MF comparator [COMP]); matched concurrent cohort of F/F children from countries (HR,IT,CZ,LT,NO,PL) without commercial access to LUM/IVA as of 2020 (F/F COMP); and a historical cohort of F/F children from the same countries as LUM/IVA cohort. Results LUM/IVA cohort matched to F/MF COMP included 681 children and LUM/IVA cohort matched to F/F COMP included 183 children. As of 31 December 2021, >90% remained on treatment (mean exposure 23 months). LUM/IVA cohorts had increases in BMI percentiles relative to F/MF COMP and F/F COMP (mean difference in absolute change from baseline 8.4 [95% CI: 5.5, 11.3] and 11.8 [95% CI: 5.9, 17.7], respectively) as well as to historical cohort, and reductions in pulmonary exacerbations (table 1) and hospitalizations relative to baseline, and relative to the F/F COMP in 2021. Interim results from this study support the benefits of LUM/IVA initiation in children with CF aged 2 through 5 years. Please refer to page A283 for declarations of interest related to this abstract.

Objectives: LUM/IVA has been shown to be safe and effective in people with CF, including children. This registry-based study evaluated long-term efficacy and safety of LUM/IVA in children aged 2 through 5 years at treatment initiation. Table(abstract: WS16.04).Annual risk of pulmonary exacerbation leading to hospitalization YearMatched to F/MF COMPMatched to F/F COMPLUM/IVA Cohort (n = 681) Risk, %F/MF Concurrent COMP Cohort (n = 681) Risk, %Relative Risk (95% CI)LUM/IVA Cohort (n = 183) Risk, %F/F Concurrent COMP Cohort (n = 183) Risk, %Relative Risk (95% CI)Baseline (2018)18.714.91.26 (0.99,1.59)22.021.51.02 (0.69, 1.51)Enrollment (2019)1Treatment effect is not expected to be notable during enrollment years.17.313.31.30 (1.01,1.67)16.919.30.88 (0.56, 1.36)Enrollment (2020)1Treatment effect is not expected to be notable during enrollment years., 2Outcome patterns in 2020 and 2021 are potentially affected by the COV1D-19 pandemic.14.39.91.44 (1.07,1.93)13.113.70.96 (0.56, 1.62)202129.210.30.89 (0.64, 1.25)6.021.40.28 (0.14, 0.54)1 Treatment effect is not expected to be notable during enrollment years.2 Outcome patterns in 2020 and 2021 are potentially affected by the COV1D-19 pandemic. Open table in a new tab Methods: LUM/IVA cohorts included children with CF homozygous for F508del (F/F) in the European CF Society Patient Registry who initiated LUM/IVA therapy between 15 January 2019 (approval) and 31 December 2020. Longitudinal trends in key outcomes were compared to 3 modulator-naïve cohorts: matched concurrent cohort of children heterozygous for F508del and minimal function mutation (F/MF) from same countries (AT,LU, DK,FR,IE,NL,SE,SI,CH,UK,DE) as LUM/IVA cohort (F/MF comparator [COMP]); matched concurrent cohort of F/F children from countries (HR, IT,CZ,LT,NO,PL) without commercial access to LUM/IVA as of 2020 (F/F COMP); and a historical cohort of F/F children from the same countries as LUM/IVA cohort. Results: LUM/IVA cohort matched to F/MF COMP included 681 children and LUM/IVA cohort matched to F/F COMP included 183 children. As of 31 December 2021, >90% remained on treatment (mean exposure 23 months). LUM/IVA cohorts had increases in BMI percentiles relative to F/MF COMP and F/F COMP (mean difference in absolute change from baseline 8.4 [95% CI: 5.5, 11.3] and 11.8 [95% CI: 5.9, 17.7], respectively) as well as to historical cohort, and reductions in pulmonary exacerbations (Table) and hospitalizations relative to baseline, and relative to the F/F COMP in 2021. Conclusion: Interim results from this study support the benefits of LUM/IVA initiation in children with CF aged 2 through 5 years. #ECFSPR collaborators Andreas Pfleger (AT), Elise Lammertijn* (BE), Duška Tješic?-Drinkovic? (HR), Pavel Dr?evínek (CZ), Milan Macek Jr.* (CZ), Hanne Vebert Olesen (DK), Lydie Lemonnier-Videau (FR), Pierre-Régis Burgel* (FR), Elpis Hatziagorou* (GR), Godfrey Fletcher (IE), Rita Padoan (IT), Annalisa Orenti* (IT), Federico Ambrogi* (IT), Simone Gambazza (IT), Elına Aleksejeva (LV), Anna-Maria Charatsi (LU), Domenique Zomer (NL), Egil Bakkeheim (NO), Lukasz Woz?niacki (PL), Uroš Krivec (SI), Christina Krantz (SE), Anders Lindblad* (SE), Andreas Jung (CH), Sarah Clarke (UK), Siobhán B. Carr* (UK). *ECFSPR Scientific Committee

Background: Clinical studies show IVA is safe and effective in people with CF, including young children. Aims and objectives: To evaluate long-term safety and efficacy of IVA in children aged 2–5 y at treatment initiation from US and UK CF registries. Methods: IVA cohorts from US CF Foundation Patient Registry and UK CF Registry included children aged 2–5 y with CFTR gating mutations who initiated IVA Mar 18, 2015–Dec 31, 2016(US) or Jan 1, 2017–Dec 31, 2017(UK). Longitudinal trends in key outcomes were compared to a concurrent cohort of modulator-untreated children homozygous for F508del-CFTR and a historical cohort of modulator-naïve children with CFTR gating mutations. Results: IVA cohorts included 150(US) and 52(UK) children; as of Dec 31, 2020, >90% remained on treatment (mean exposure 5.2[US] and 3.7[UK] y). US IVA cohort had reductions in pulmonary exacerbations and increases in weight (Figure); increases in other nutritional parameters and decreases in hospitalizations, pancreatic enzyme supplement use, and P. aeruginosa prevalence versus the untreated concurrent comparator and historical modulator-naïve cohorts were also seen. Results from UK and US cohorts were consistent. Conclusions: Interim results of this registry-based study support the long-term benefits of early IVA initiation on CF disease progression. Sponsor: Vertex Pharmaceuticals Incorporated.

Introduction and Objectives Ivacaftor, a CFTR potentiator, was shown as safe and beneficial over 24 weeks in young children with CF and a gating mutation (Davies JC, et al. Lancet Respir Med. 2016;4:107–15). This prespecified interim analysis of an ongoing observational study evaluates long-term effectiveness of ivacaftor in children aged 2–5 years with gating mutations vs concurrent comparator (COMP) and historical (HIST) cohorts untreated with CFTR modulators. Methods US CF Foundation Patient Registry and UK CF Registry data were analysed; enrolment periods: 18 March 2015 to 31 December 2016 (US); 1 January to 31 December 2017 (UK). Two matched cohorts were established per registry: ivacaftor cohort, including children aged 2–5 years with a gating CFTR mutation at ivacaftor initiation; COMP cohort, including children homozygous for F508del-CFTR who were CFTR modulator therapy-naïve and matched up to 5:1 to the ivacaftor cohort on age, sex and BMI z score. Cohorts are being followed up to evaluate and compare patterns in key outcomes, including pulmonary exacerbations (PEx), hospitalisations, nutritional parameters and Pseudomonas aeruginosa prevalence, among others. Interim analyses based on follow-up through December 2018 are presented; final analysis will include data through December 2022. Given the COMP cohort attrition over time due to CFTR modulator therapy initiation, HIST cohorts, including CFTR modulator-naïve children aged 2–5 years with gating mutations (2005 [US] or 2008 [UK]), provide important additional context. Results US ivacaftor, COMP and HIST cohorts included 150, 728 and 112 children; UK cohorts included 52, 236 and 36 children, respectively. In the US, ivacaftor-treated children (mean exposure, 38.4 months) had significantly lower annual risk of PEx than the COMP cohort; trends were also favourable vs the HIST cohort (figure 1). Similarly, favourable trends were observed in patterns of hospitalisations (PEx and other reasons), nutritional parameters and P. aeruginosa prevalence. UK cohort findings (mean ivacaftor exposure, 20.6 months) were generally consistent with US data. No new safety concerns were identified (no discernible trends in transaminase elevations; no deaths or transplants [ivacaftor cohorts]). Conclusions Interim results show favourable trends across multiple clinical outcomes, supporting the effectiveness of ivacaftor in children aged 2–5 years at initiation. Please refer to page A239 for declarations of interest related to this abstract.

Introduction and Objectives ARRIVAL, a single-arm Phase 3 study, characterises pharmacokinetics, safety and tolerability of ivacaftor in children aged <24 months with CFTR gating mutations. Data from 6 to <12 and 12 to <24 months cohorts show that ivacaftor is safe and well tolerated (Davies JC, et al. Presented at ECFS 2019; Rosenfeld M, et al. Lancet Respir Med. 2018;6:545–53); results for the 4 to <6 months cohort are presented here. Methods Infants received ivacaftor q12h for 4 days (Part A; 5 to <7 kg: 25 mg; 7 to <14 kg: 50 mg) and 24 weeks (Part B; <6 months: 25 mg q12h; ≥6 months: weight-based dosing per A). Primary endpoints: safety (A, B), including serum lipase and amylase, and pharmacokinetics (A). Secondary/tertiary endpoints (B): pharmacokinetics, changes in sweat chloride (SwCl), growth, faecal elastase-1 (FE-1) and serum immunoreactive trypsinogen (IRT). Results Twelve infants, six each in A (mean [SD] age, 4.2 [0.98] months) and B (4.5 [0.55] months), received ivacaftor. Pharmacokinetics was consistent with older groups; most AEs were mild/moderate. Most common AE in B was cough (n=3; 50%). Two infants had SAEs (A: thrombocytopenia [suspected causal agent: omeprazole]; B: bronchiolitis), both assessed as not/unlikely related to ivacaftor. No deaths or AEs leading to treatment interruption/discontinuation occurred. No notable transaminase elevations or clinically relevant findings in laboratory tests (except one thrombocytopenia), vital signs or electrocardiogram parameters were reported. Improvements were seen in SwCl and FE-1 (Table). Baseline elevations of serum IRT and lipase, although not amylase, improved. All growth parameters increased on average. Conclusions This first CFTR modulation study in infants aged 4 to <6 months suggests ivacaftor can be dosed safely in infants; no notable liver function test elevations were observed. Substantial improvements in SwCl indicate improved CFTR function. Improvements in lipase, IRT and FE-1 demonstrate potential of ivacaftor to reduce pancreatic inflammation and obstruction and improve function. Findings are consistent with observations in children aged 6 to <12 and 12 to <24 months treated with ivacaftor supporting treating the underlying cause of CF in children aged ≥4 months. Further data will accrue during the extension 770–126 study (NCT03277196). Please refer to page A239 for declarations of interest related to this abstract.

Objectives ARRIVAL (NCT02725567) is a single-arm, Phase 3 study of the pharmacokinetics (PK) and safety of ivacaftor (IVA) in patients aged <24 months with cystic fibrosis (CF) with ≥1 CFTR gating mutation. We present results of the completed 6- to <12-month cohorts. The study is ongoing for patients aged <6 months. Methods Patients received IVA (5 to <7 kg, 25 mg; 7 to <14 kg, 50 mg) every 12 hours for 4 days in part A (A) and 24 weeks in part B (B). Primary endpoints were PK (A) and safety (A, B), including serum lipase and amylase. Secondary/exploratory endpoints (B) included PK and changes in sweat chloride (SwCl), growth, serum immunoreactive trypsinogen (IRT) and faecal elastase (FE-1). Results A and B enrolled 6 and 11 patients; mean age (standard deviation [SD]) was 7.7 (1.9) and 9.0 (1.3) months, respectively. PK from 4 days of IVA dosing in A informed dosing in B, in which exposure was consistent with that observed in adult patients. IVA was generally safe and well tolerated in both parts. In A, one patient had adverse events (AEs) (constipation, vomiting and sleep disorder) considered to be related to study drug. There were no deaths, serious AEs (SAEs) or AEs leading to study drug interruption or discontinuation. In B, one patient had increased alanine aminotransferase (>3 to ≤5 × upper limit of normal) that normalised with continued dosing; three patients reported SAEs (none were deemed related to IVA). Improvements were seen in multiple efficacy endpoints (table 1). Conclusion These results suggest that IVA can be dosed safely in patients aged 6 to <12 months; substantial improvements in SwCl indicate improved CFTR function. Increases in FE-1 and reductions in lipase and IRT suggest there is a window of opportunity in early life for improving pancreatic function. These findings are consistent with those in children aged 12 to <24 months treated with IVA and support treating the underlying cause of CF in infants with IVA. Sponsor Vertex Pharmaceuticals Incorporated.