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: ARRIVAL is a single-arm Phase 3 study characterizing PK, safety, and tolerability of ivacaftor (IVA) in children <24 months (mo) with CFTR gating mutations. We reported data from the 6 to <12 mo and 12 to <24 mo cohorts showing that IVA is safe and well tolerated (Davies et al. Presented at: 42nd ECFS Conference; June 5-8, 2019; Liverpool, UK; Rosenfeld et al. Lancet Respir Med. 2018;6:545-553) and now present results for the 4 to <6 mo cohort. Methods: Infants received IVA q12h for 4 days in Part A (5 to <7 kg: 25 mg; 7 to <14 kg: 50 mg) and 24 wk in Part B (<6 mo: 25 mg q12h; ≥6 mo: weight-based dosing as in A). Primary endpoints were safety (A, B), including serum lipase and amylase, and PK (A). Secondary/tertiary endpoints (B) included PK and changes in sweat chloride (SwCl), growth, fecal elastase-1 (FE-1), and serum immunoreactive trypsinogen (IRT). Results: Twelve infants, 6 each in A (mean [SD] age, 4.2 [0.98] mo) and B (4.5 [0.55] mo), received IVA. PK was consistent with that in older groups, and most AEs were mild/moderate. Cough was the most common AE in B (n = 3 [50.0%]). Two infants had serious adverse events (A: thrombocytopenia; B: bronchiolitis), both assessed as not/unlikely related to IVA (omeprazole was the suspected causal agent of thrombocytopenia). No deaths or AEs leading to treatment interruption or discontinuation occurred. No notable transaminase elevations or clinically relevant findings in laboratory tests (except 1 thrombocytopenia noted above), vital signs, or electrocardiogram parameters were reported. Improvements were seen in SwCl and FE-1 (Table). Baseline (BL) elevations of serum IRT and lipase, although not amylase, improved. All growth parameters increased on average during the study. Conclusions: This first study of CFTR modulation in infants 4 to <6 mo suggests that IVA can be dosed safely in infants; in particular, no notable LFT elevations were observed. Substantial improvements in SwCl indicate improved CFTR function. Improvements in lipase, IRT, and FE-1 demonstrate the potential of IVA to reduce pancreatic inflammation and obstruction and improve function. Our findings are consistent with observations in children 6 to <12 mo and 12 to <24 mo treated with IVA and support treating the underlying cause of CF in children ≥4 mo. Further data will accrue during the extension 770-126 study (NCT03277196).L6336561252021-02-01 <br />