Ivacaftor in Infants Aged 4 to Jane C Davies  1 , Claire E Wainwright  2 , Gregory S Sawicki  3 , Mark N Higgins  4 , Daniel Campbell  4 , Christopher Harris  4 , Paul Panorchan  4 , Eric Haseltine  4 , Simon Tian  4 , Margaret Rosenfeld  5 Affiliations Expand Affiliations 1 National Heart & Lung Institute, Imperial College London and Royal Brompton Hospital, London, United Kingdom. 2 Queensland Children's Hospital, University of Queensland, Brisbane, Queensland, Australia. 3 Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts. 4 Vertex Pharmaceuticals Incorporated, Boston, Massachusetts; and. 5 Seattle Children's Hospital, University of Washington School of Medicine, Seattle, Washington. PMID: 33023304 PMCID: PMC7924576 DOI: 10.1164/rccm.202008-3177OC Free PMC article Item in Clipboard

Jane C Davies, Claire E Wainwright, Gregory S Sawicki, Mark N Higgins, Daniel Campbell, Christopher Harris, Paul Panorchan, Eric Haseltine, Simon Tian, Margaret Rosenfeld, Jane C Davies, Claire E Wainwright, Gregory S Sawicki, Mark N Higgins, Daniel Campbell, Christopher Harris, Paul Panorchan, Eric Haseltine, Simon Tian, Margaret Rosenfeld

Abstract

Rationale: We previously reported that ivacaftor was safe and well tolerated in cohorts aged 12 to <24 months with cystic fibrosis and gating mutations in the ARRIVAL study; here, we report results for cohorts aged 4 to <12 months.Objectives: To evaluate the safety, pharmacokinetics, and pharmacodynamics of ivacaftor in infants aged 4 to <12 months with one or more gating mutations.Methods: ARRIVAL is a single-arm phase 3 study. Infants received 25 mg or 50 mg ivacaftor every 12 hours on the basis of age and weight for 4 days in part A and 24 weeks in part B.Measurements and Main Results: Primary endpoints were safety (parts A and B) and pharmacokinetics (part A). Secondary/tertiary endpoints (part B) included pharmacokinetics and changes in sweat chloride levels, growth, and markers of pancreatic function. Twenty-five infants received ivacaftor, 12 in part A and 17 in part B (four infants participated in both parts). Pharmacokinetics was consistent with that in older groups. Most adverse events were mild or moderate. In part B, cough was the most common adverse event (n = 10 [58.8%]). Five infants (part A, n = 1 [8.3%]; part B, n = 4 [23.5%]) had serious adverse events, all of which were considered to be not or unlikely related to ivacaftor. No deaths or treatment discontinuations occurred. One infant (5.9%) experienced an alanine transaminase elevation >3 to ≤5× the upper limit of normal at Week 24. No other adverse trends in laboratory tests, vital signs, or ECG parameters were reported. Sweat chloride concentrations and measures of pancreatic obstruction improved.Conclusions: This study of ivacaftor in the first year of life supports treating the underlying cause of cystic fibrosis in children aged ≥4 months with one or more gating mutations.Clinical trial registered with clinicaltrials.gov (NCT02725567).

Keywords: CFTR potentiator; pancreatic function; pharmacokinetics; safety.

Figures

Figure 1.
Figure 1.
Cohorts in the ARRIVAL study and ivacaftor dosing based on age and weight. *Data from cohorts 1 and 5 were reported previously (16). †Two infants in cohort 3 of part A were aged 3 months. ‡If an infant reached age 6 months during the study, dosing was switched to weight-based dosing. PK = pharmacokinetics; q12h = every 12 hours. Reprinted by permission from Reference .
Figure 2.
Figure 2.
Mean absolute change from baseline in sweat chloride concentration. The mean (SD) sweat chloride value at baseline was 97.4 (16.4) mmol/L in infants aged 4 to

Figure 3.

Mean absolute change from baseline…

Figure 3.

Mean absolute change from baseline in FE-1 (fecal elastase-1) concentration. BL = baseline.

Figure 3.
Mean absolute change from baseline in FE-1 (fecal elastase-1) concentration. BL = baseline.
Figure 3.
Figure 3.
Mean absolute change from baseline in FE-1 (fecal elastase-1) concentration. BL = baseline.

References

    1. Ratjen F, Bell SC, Rowe SM, Goss CH, Quittner AL, Bush A. Cystic fibrosis. Nat Rev Dis Primers. 2015;1:15010.
    1. MacKenzie T, Gifford AH, Sabadosa KA, Quinton HB, Knapp EA, Goss CH, et al. Longevity of patients with cystic fibrosis in 2000 to 2010 and beyond: survival analysis of the Cystic Fibrosis Foundation patient registry. Ann Intern Med. 2014;161:233–241.
    1. Mott LS, Park J, Murray CP, Gangell CL, de Klerk NH, Robinson PJ, et al. AREST CF. Progression of early structural lung disease in young children with cystic fibrosis assessed using CT. Thorax. 2012;67:509–516.
    1. Stick SM, Brennan S, Murray C, Douglas T, von Ungern-Sternberg BS, Garratt LW, et al. Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) Bronchiectasis in infants and preschool children diagnosed with cystic fibrosis after newborn screening. J Pediatr. 2009;155:623–628, e1.
    1. Sly PD, Gangell CL, Chen L, Ware RS, Ranganathan S, Mott LS, et al. AREST CF Investigators. Risk factors for bronchiectasis in children with cystic fibrosis. N Engl J Med. 2013;368:1963–1970.
    1. Singh VK, Schwarzenberg SJ. Pancreatic insufficiency in cystic fibrosis. J Cyst Fibros. 2017;16:S70–S78.
    1. O’Sullivan BP, Baker D, Leung KG, Reed G, Baker SS, Borowitz D. Evolution of pancreatic function during the first year in infants with cystic fibrosis. J Pediatr. 2013;162:808–812, e1.
    1. Farrell PM, Kosorok MR, Rock MJ, Laxova A, Zeng L, Lai HC, et al. Wisconsin Cystic Fibrosis Neonatal Screening Study Group. Early diagnosis of cystic fibrosis through neonatal screening prevents severe malnutrition and improves long-term growth. Pediatrics. 2001;107:1–13.
    1. Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Dřevínek P, et al. VX08-770-102 Study Group. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011;365:1663–1672.
    1. Van Goor F, Yu H, Burton B, Hoffman BJ. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros. 2014;13:29–36.
    1. Yu H, Burton B, Huang CJ, Worley J, Cao D, Johnson JP, Jr, et al. Ivacaftor potentiation of multiple CFTR channels with gating mutations. J Cyst Fibros. 2012;11:237–245.
    1. Davies JC, Wainwright CE, Canny GJ, Chilvers MA, Howenstine MS, Munck A, et al. VX08-770-103 (ENVISION) Study Group. Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation. Am J Respir Crit Care Med. 2013;187:1219–1225.
    1. Davies JC, Cunningham S, Harris WT, Lapey A, Regelmann WE, Sawicki GS, et al. KIWI Study Group. Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2-5 years with cystic fibrosis and a CFTR gating mutation (KIWI): an open-label, single-arm study. Lancet Respir Med. 2016;4:107–115.
    1. De Boeck K, Munck A, Walker S, Faro A, Hiatt P, Gilmartin G, et al. Efficacy and safety of ivacaftor in patients with cystic fibrosis and a non-G551D gating mutation. J Cyst Fibros. 2014;13:674–680.
    1. Moss RB, Flume PA, Elborn JS, Cooke J, Rowe SM, McColley SA, et al. VX11-770-110 (KONDUCT) Study Group. Efficacy and safety of ivacaftor in patients with cystic fibrosis who have an Arg117His-CFTR mutation: a double-blind, randomised controlled trial. Lancet Respir Med. 2015;3:524–533.
    1. Rosenfeld M, Wainwright CE, Higgins M, Wang LT, McKee C, Campbell D, et al. ARRIVAL study group. Ivacaftor treatment of cystic fibrosis in children aged 12 to <24 months and with a CFTR gating mutation (ARRIVAL): a phase 3 single-arm study. Lancet Respir Med. 2018;6:545–553.
    1. Rosenfeld M, Cunningham S, Harris WT, Lapey A, Regelmann WE, Sawicki GS, et al. KLIMB study group. An open-label extension study of ivacaftor in children with CF and a CFTR gating mutation initiating treatment at age 2-5 years (KLIMB) J Cyst Fibros. 2019;18:838–843.
    1. Nichols AL, Davies JC, Jones D, Carr SB. Restoration of exocrine pancreatic function in older children with cystic fibrosis on ivacaftor. Paediatr Respir Rev. 2020;35:99–102.
    1. Gullo L, Graziano L, Babbini S, Battistini A, Lazzari R, Pezzilli R. Faecal elastase 1 in children with cystic fibrosis. Eur J Pediatr. 1997;156:770–772.
    1. Paracchini V, Seia M, Raimondi S, Costantino L, Capasso P, Porcaro L, et al. Cystic fibrosis newborn screening: distribution of blood immunoreactive trypsinogen concentrations in hypertrypsinemic neonates. JIMD Rep. 2012;4:17–23.
    1. McNamara JJ, McColley SA, Marigowda G, Liu F, Tian S, Owen CA, et al. Safety, pharmacokinetics, and pharmacodynamics of lumacaftor and ivacaftor combination therapy in children aged 2-5 years with cystic fibrosis homozygous for F508del-CFTR: an open-label phase 3 study. Lancet Respir Med. 2019;7:325–335.
    1. Castellani C, Massie J, Sontag M, Southern KW. Newborn screening for cystic fibrosis. Lancet Respir Med. 2016;4:653–661.
    1. Rosenfeld M, Wainwright C, Sawicki G, Higgins M, Campbell D, Harris C, et al. 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. Presented at the 34th Annual North American Cystic Fibrosis Conference. October 7–23, 2020 [poster 415]
    1. Davies J, Wang L, Panorchan P, Campbell D, Tian S, Higgins M, et al. Ivacaftor (IVA) treatment in patients 6 to <12 months old with cystic fibrosis with a CFTR gating mutation: results of a 2-part, single-arm, phase 3 study. J Cyst Fibros. 2019;18:S11.
    1. Davies JC, Wang LT, Campbell D, Tian S, Egbuna O, McKee C, et al. Ivacaftor treatment in patients 6 to <12 months old with a CFTR gating mutation: results of a phase 3, two-part, single-arm study. Presented at the 32nd Annual North American Cystic Fibrosis Conference. October 18–20, 2018, Denver, CO [poster 810]
    1. Farrell PM, White TB, Ren CL, Hempstead SE, Accurso F, Derichs N, et al. Diagnosis of cystic fibrosis: consensus guidelines from the Cystic Fibrosis Foundation. J Pediatr. 2017;181S:S4–S15, e1.
    1. Borowitz D, Baker SS, Duffy L, Baker RD, Fitzpatrick L, Gyamfi J, et al. Use of fecal elastase-1 to classify pancreatic status in patients with cystic fibrosis. J Pediatr. 2004;145:322–326.
    1. European Medicines Agency. Amsterdam, the Netherlands: European Medicines Agency; 2020. Kalydeco summary of product characteristics. [accessed 2020 Sep 8]. Available from: .
    1. U.S. Food and Drug Administration. Silver Spring, MD: U.S. Food and Drug Administration; 2020. Drugs@FDA: FDA-approved drugs. [accessed 2020 Sep 8]. Available from: .
    1. Cleghorn G, Benjamin L, Corey M, Forstner G, Dati F, Durie P. Age-related alterations in immunoreactive pancreatic lipase and cationic trypsinogen in young children with cystic fibrosis. J Pediatr. 1985;107:377–381.
    1. Banks PA, Freeman ML Practice Parameters Committee of the American College of Gastroenterology. Practice guidelines in acute pancreatitis. Am J Gastroenterol. 2006;101:2379–2400.
    1. Gillard BK, Simbala JA, Goodglick L. Reference intervals for amylase isoenzymes in serum and plasma of infants and children. Clin Chem. 1983;29:1119–1123.

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