Effect of bronchodilators in healthy individuals receiving lumacaftor/ivacaftor combination therapy www elsevier com/locate/jcf Journal of Cystic Fibrosis xx (2016) xxx–xxx JCF 01403; No of Pages 4 Sh[.]
JCF-01403; No of Pages Journal of Cystic Fibrosis xx (2016) xxx – xxx www.elsevier.com/locate/jcf Short Communication Effect of bronchodilators in healthy individuals receiving lumacaftor/ivacaftor combination therapy Gautham Marigowda ⁎, Fang Liu, David Waltz Vertex Pharmaceuticals Incorporated, 50 Northern Ave, Boston, MA 02110, United States Received 13 September 2016; revised November 2016; accepted 10 November 2016 Abstract In an open-label, single-center phase pharmacokinetic study in healthy subjects who received lumacaftor (LUM) in combination with ivacaftor (IVA), review of spirometry data showed a transient decline in percent predicted forced expiratory volume in s (ppFEV1) within h of drug administration An additional cohort of healthy subjects with normal baseline ppFEV1 values was studied to evaluate the ppFEV1 response to LUM/IVA administration and assess the effect of long-acting bronchodilators (LABDs) and short-acting bronchodilators (SABDs) on ppFEV1 response The ppFEV1 decline observed at h was attenuated following administration of an LABD and reversed following administration of an SABD Concomitant administration of LUM/IVA with bronchodilators was well tolerated These data show that a transient decline in ppFEV1 was observed in healthy subjects following administration of LUM/IVA combination therapy, which can be ameliorated with LABDs or SABDs © 2016 The Authors Published by Elsevier B.V on behalf of European Cystic Fibrosis Society This is an open access article under the CC BYNC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) Introduction In phase studies, treatment with the combination of lumacaftor (LUM) and ivacaftor (IVA) resulted in clinically meaningful improvements in lung function, rate of pulmonary exacerbations and nutritional status in patients aged 12 years or older with cystic fibrosis (CF) who were homozygous for the F508del-CFTR mutation [1] LUM/IVA was generally well tolerated; however, the incidence of certain respiratory adverse events (AEs), including dyspnea and chest tightness, was higher in LUM/IVA-treated patients than placebo-treated patients These AEs were often associated with initiation of therapy and generally resolved within the first few weeks of treatment [1] In a phase study of patients with CF who had an F508del-CFTR mutation, dose-dependent reductions in percent predicted forced expiratory volume in s (ppFEV1) were observed during the 28-day period of LUM monotherapy [2] Review of spirometry data from an open-label, single-center phase pharmacokinetic study in healthy ⁎ Corresponding author E-mail address: gautham_marigowda@vrtx.com (G Marigowda) volunteers [3] revealed a transient decline in ppFEV1 within h of administration of LUM/IVA combination therapy To better understand this decline, a cohort was added to the latter study to evaluate ppFEV1 response within h of LUM/IVA administration and assess the effect of long-acting bronchodilators (LABDs) and short-acting bronchodilators (SABDs) on ppFEV1 response Methods Healthy male and female volunteers aged 18 to 55 years with ppFEV1 80 or higher, body mass index 18 to 31 kg/m2 and body weight more than 50 kg were eligible; those with a history of regular alcohol consumption, smoking and bronchodilator use within the previous 28 days were excluded Participants were randomized to of dosing sequences (1:1:1:1), each of which included dosing periods (period 1: days −2 to 2; period 2: days to 9; period 3: days 13 to 16) Once during each dosing period on days 1, and 15, LUM 200 mg was administered in combination with IVA 250 mg orally in the morning The peak concentrations in healthy subjects administered LUM 200 mg/IVA 250 mg were projected to be comparable to the peak concentrations in patients http://dx.doi.org/10.1016/j.jcf.2016.11.001 1569-1993/© 2016 The Authors Published by Elsevier B.V on behalf of European Cystic Fibrosis Society This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) Please cite this article as: Marigowda G, et al, Effect of bronchodilators in healthy individuals receiving lumacaftor/ivacaftor combination therapy, J Cyst Fibros (2016), http://dx.doi.org/10.1016/j.jcf.2016.11.001 G Marigowda et al / Journal of Cystic Fibrosis xx (2016) xxx–xxx with CF administered LUM 400 mg/IVA 250 mg As shown in Figs and 2, an SABD (albuterol 2.5 mg or ipratropium 0.5 mg) was administered by inhalation via nebulizer during each dosing period (after the 4-h spirometry assessment) and an LABD (indacaterol 75 μg or tiotropium 18 μg) was administered via inhalation in dosing periods and (12 h prior to and 12 h after LUM/IVA administration); spirometry assessments were performed throughout the study The primary outcome measure was the absolute change in ppFEV1 from before to h after LUM/IVA administration Safety was assessed by the incidence of treatment emergent AEs, vital signs, clinical laboratory tests, electrocardiograms, spirometry and physical examinations A mixed model for repeated measures was used to evaluate the overall effect of LABDs by comparing the absolute change in ppFEV1 from before LUM/IVA to h post LUM/IVA in the presence and absence of LABDs The model included sequence and treatment (albuterol + ipratropium, indacaterol, tiotropium) as fixed effects, period baseline ppFEV1 as a covariate and subject nested within sequence as a random effect Data for ppFEV1 were pooled for administration of an SABD (albuterol, ipratropium) and an LABD (indacaterol, tiotropium) for participants in each dosing sequence The mean age (SD) was 36.5 (10.5) years and mean ppFEV1 (SD) was 96.6 (14.8) We observed a transient decline in ppFEV1 after a single dose of LUM/IVA (mean absolute change [SD] on day at h was −4.1 [5.6] percentage points) The absolute change in ppFEV1 for each individual subject is shown in Fig The decline in ppFEV1 was rapidly reversed following administration of an SABD (Fig 1) The mean (SD) difference in absolute change in ppFEV1 from h to h post LUM/IVA following administration of an SABD in the absence of an LABD was 3.8 (5.8) percentage points (p = 0.003); similar results were observed with beta agonists and anticholinergics (4.0 [5.5] percentage points for albuterol and 3.5 [6.3] percentage points for ipratropium) Moreover, when an LABD was administered 12 h before LUM/IVA, the decline in ppFEV1 was attenuated (Fig 2) The mean absolute change (SD) was −1.4 (4.1) percentage points on days and 15 (average) at h post LUM/IVA The least squares (LS) mean (SE) difference for attenuation of the decline in ppFEV1 in the presence of all LABDs vs in the absence of LABDs was 2.9 (1.4) percentage points (p = 0.046); findings were similar for beta agonists and anticholinergics (LS mean [SE]: 3.1 [1.6] percentage points for indacaterol and 2.8 [1.6] percentage points for tiotropium) As shown in Fig 2, an SABD administered h post LUM/IVA in the presence of an LABD led to further improvement in ppFEV1 Overall, 11 participants (42.3%) reported AEs, all of which were mild (n = 9) or moderate (n = 2) in severity AEs occurring in more than one participant included oropharyngeal Results A total of 26 participants was enrolled; 24 (92.3%) completed the study and (7.7%) withdrew consent and were discontinued after dosing period Baseline characteristics were well balanced Day −1 Day Percent predicted FEV1 (Mean ±SE) 105 Day LUM/IVA 100 Baseline pre-LUM/IVA dosing 95 SABD 90 SABD 85 SABD 80 Screen Day −2 0h 2h 4h 5h 8h Pre 2h 4h 5h 8h Pre 2h 4h 5h 8h Timing of drug administration 0h + spirometry assessments 2h 4h 5h 8h Pre 2h 4h 5h 8h Pre 2h 4h 5h 8h SABD Period LUM/IVA Day −1 SABD SABD Day Day Day Day (Time matched) Percent predicted FEV1 Pre 2h 4h 5h 2h 4h 5h 8h Mean 96.6 94.2 92.4 96.2 94.7 94.7 93.9 95.1 98.2 98.9 −2.3 −4.1 −0.3 −1.8 −0.8 0.4 3.5 4.2 Absolute difference 8h Pre Fig Percent predicted FEV1 before and after LUM/IVA administration in the absence of LABD (period 1) Data are mean ppFEV1 during period and error bars indicate standard error FEV1, forced expiratory volume in s; LUM/IVA, lumacaftor/ivacaftor; SABD, short-acting bronchodilator; SE, standard error Please cite this article as: Marigowda G, et al, Effect of bronchodilators in healthy individuals receiving lumacaftor/ivacaftor combination therapy, J Cyst Fibros (2016), http://dx.doi.org/10.1016/j.jcf.2016.11.001 G Marigowda et al / Journal of Cystic Fibrosis xx (2016) xxx–xxx Day (Period 2) Day 14 (Period 3) Day (Period 2) Day 15 (Period 3) Percent predicted FEV1 (Mean ±SE) 105 Day (Period 2) Day 16 (Period 3) LUM/IVA 100 Baseline pre-LUM/IVA dosing 95 LABD LABD SABD 90 SABD SABD 85 80 Day Pre 6/13 2h 4h 5h 8h Pre 2h 4h 5h 8h Pre 2h 4h 5h 8h Timing of drug administration Pre + spirometry assessments 2h 4h 5h 8h 12h Pre 2h 4h 5h 8h 12h Pre 2h 4h 5h 8h SABD Period Period LABD SABD Day Day 14 LABD SABD Day Day 15 Day Day 16 Days and 15 Day and 16 (Time Matched) Percent predicted FEV1 Pre 2h 4h 5h 8h Pre 2h 4h Mean 98.1 97.4 96.7 97.3 97.6 97.7 98.5 99.2 99.5 98.7 −0.7 −1.4 −0.8 −0.5 0.8 1.5 1.9 Absolute difference 5h 8h Fig Percent predicted FEV1 before and after LUM/IVA administration in the presence of LABD (periods and 3) Data are mean ppFEV1 during periods and (average) and error bars indicate standard error FEV1, forced expiratory volume in s; LABD, long-acting bronchodilator; LUM/IVA, lumacaftor/ivacaftor; SABD, short-acting bronchodilator; SE, standard error Absolute change in ppFEV1 (Percentage points) pain in (11.5%), cough in (7.7%) and viral infection in (7.7%) One AE of dyspnea was reported and considered possibly related to study drug; it occurred within day of initiating treatment, was mild in severity and resolved The transient decline in ppFEV1 observed after LUM/IVA administration was not reported as an AE No clinically relevant trends were observed in laboratory tests or vital signs Discussion Our findings reveal that administration of LUM/IVA resulted in a transient decline in ppFEV1 in healthy subjects with normal baseline ppFEV1 values, a response attenuated by pre-treatment with an LABD and reversed with an SABD These results suggest that bronchoconstriction could contribute to the occurrence of 30 25 20 15 10 –5 –10 –15 –20 –25 –30 Individual subjects, hours post dose on day Fig Absolute change in ppFEV1 at h post LUM/IVA in the absence of a bronchodilator (day 1) Waterfall plot showing the absolute change in ppFEV1 at h post LUM/IVA on day in the absence of a bronchodilator Each bar represents data for an individual subject LUM/IVA, lumacaftor/ivacaftor; ppFEV1, percent predicted forced expiratory volume in s Please cite this article as: Marigowda G, et al, Effect of bronchodilators in healthy individuals receiving lumacaftor/ivacaftor combination therapy, J Cyst Fibros (2016), http://dx.doi.org/10.1016/j.jcf.2016.11.001 G Marigowda et al / Journal of Cystic Fibrosis xx (2016) xxx–xxx certain respiratory AEs (i.e., dyspnea and chest tightness) observed in some CF patients upon initiation of LUM/IVA [1] Recent evidence suggests that loss of CF transmembrane conductance regulator (CFTR) function may play a role in the airway smooth muscle dysfunction that is common in patients with CF [4]; however, it appears that CFTR modulation may ameliorate this Using a porcine model, CFTR was found to localize to the sarcoplasmic reticulum compartment of airway smooth muscle, where it regulates Ca2+ reuptake and airway smooth muscle basal tone Loss of CFTR was found to increase basal tone, while CFTR potentiation with IVA was found to reduce airway reactivity in that study [4] Furthermore, in a phase clinical study in patients with CF and the G551D-CFTR mutation, there was not an increased incidence of respiratory AEs (i.e., dyspnea and chest tightness) with IVA monotherapy [5] These findings suggest that a potential bronchoconstrictive response does not occur with IVA monotherapy The apparent bronchoconstrictive effect with LUM is thus likely an off-target effect Importantly, LUM/IVA was well tolerated when administered concomitantly with bronchodilators in this study Future studies to evaluate whether bronchodilator pre-treatment would ameliorate the occurrence of dyspnea and/or chest tightness in some CF patients beginning treatment with LUM/IVA may be warranted Declaration of interests GM, FL and DW are employees of Vertex Pharmaceuticals Incorporated and may own stock or stock options in that company Acknowledgments This work was sponsored by Vertex Pharmaceuticals Incorporated Editorial coordination and support were provided by Dhrupad Patel, PharmD, an employee of Vertex Pharmaceuticals Incorporated who may own stock or stock options in that company Medical writing and editorial support were provided by Michelle Yochum, PhD, and Paula Stuckart MY and PS are employees of Infusion Communications, which received funding from Vertex Pharmaceuticals Incorporated References [1] Wainwright CE, Elborn JS, Ramsey BW, Marigowda G, Huang X, Cipolli M, et al Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR N Engl J Med 2015;373:220–31 [2] Boyle MP, Bell SC, Konstan MW, McColley SA, Rowe SM, Rietschel E, et al A CFTR corrector (lumacaftor) and a CFTR potentiator (ivacaftor) for treatment of patients with cystic fibrosis who have a phe508del CFTR mutation: a phase randomised controlled trial Lancet Respir Med 2014;2: 527–38 [3] Pawaskar D, Marigowda G, Waltz D, Mahnke L, Panorchan P The effect of ciprofloxacin, itraconazole, and rifampin on the pharmacokinetics of lumacaftor in combination with ivacaftor in healthy individuals Pediatr Pulmonol 2014;49(S38):286 [4] Cook DP, Rector MV, Bouzek DC, Michalski AS, Gansemer ND, Reznikov LR, et al Cystic fibrosis transmembrane conductance regulator in sarcoplasmic reticulum of airway smooth muscle Implications for airway contractility Am J Respir Crit Care Med 2016;193:417–26 [5] Ramsey BW, Davies J, McElvaney G, Tullis E, Bell SC, Dřevínek P, et al A CFTR potentiator in patients with cystic fibrosis and the G551D mutation N Engl J Med 2011;365:1663–72 Please cite this article as: Marigowda G, et al, Effect of bronchodilators in healthy individuals receiving lumacaftor/ivacaftor combination therapy, J Cyst Fibros (2016), http://dx.doi.org/10.1016/j.jcf.2016.11.001 ... Waltz D, Mahnke L, Panorchan P The effect of ciprofloxacin, itraconazole, and rifampin on the pharmacokinetics of lumacaftor in combination with ivacaftor in healthy individuals Pediatr Pulmonol 2014;49(S38):286... forced expiratory volume in s Please cite this article as: Marigowda G, et al, Effect of bronchodilators in healthy individuals receiving lumacaftor/ivacaftor combination therapy, J Cyst Fibros... short-acting bronchodilator; SE, standard error Please cite this article as: Marigowda G, et al, Effect of bronchodilators in healthy individuals receiving lumacaftor/ivacaftor combination therapy,