Ivacaftor in 4- to <6-month-old infants with cystic fibrosis and a gating mutation: Results of a 2-part, single-arm, phase 3 study

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 (Table presented) 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 immunor-eactive 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).L6345432422021-03-24 <br />