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Acute and chronic lung function responses to salmeterol and salmeterol plus fluticasone propionate in relation to arg16gly β2-adrenergic polymorphisms*

All rights reserved: reproduction in whole or part not permitted Acute and chronic lung functionresponses to salmeterol andsalmeterol plus fluticasonepropionate in relation to Arg16Gly 2-adrenergic polymorphisms*Steven W. Yanceya, Michael Klotsmanb, Hector G.
Ortegaa, Lisa D. Edwardsa and Wayne H. AndersonaaGlaxoSmithKline, Research Triangle Park, NC, USA bSDG Life Sciences, Redwood City, CA, USA Address for correspondence: Wayne H. Anderson, PhD, GlaxoSmithKline, Five Moore Drive,PO Box 13398, Research Triangle Park, NC 27709-3398, USA. Tel.: þ1 919 483 5309;Fax: þ1 919 315 0311; Key words: Asthma – -adrenergic receptor – Genetics – Long-acting Objective: There is conflicting clinical evidence describing recorded on Day 1 and Week 12. In addition, other single nucleotide polymorphisms (SNPs) associated with asthma dilators for patients with Arg16Gly 2-adrenergic receptor outcomes we assessed at positions À47, þ79 and þ491 (ADRB2 ) genotype differences. Furthermore, the role of inhaled corticosteroids (ICS) in modulating Arg16Gly clinical Results: No statistically significant associations responses is not well understood. The objective of this between Arg16Gly genotypes and serial FEV1 clinical study was to investigate the effects of Arg16Gly poly- responses to SAL and FSC were observed following morphism on the 12 hour post-dose bronchodilator acute assessment. In addition, the FEV1 response was response to the LABA salmeterol (SAL) or SAL plus preserved following 12 weeks of treatment with SAL and fluticasone propionate (FSC) on first administration and FSC and was not altered by Arg16Gly genotypes analyzed.
These results may not be generalizable to other ethnic design and methods: Genotyping was retro- groups since they are derived predominantly from spectively performed in patients with persistent asthma randomized to SAL or FSC who were participating in three Conclusions: In subjects with persistent asthma, the Curr Med Res Opin Downloaded from by Francis A Countway Library of Medicine on 06/14/10 similar double-blind clinical trials of 12 week duration.
ADRB2 Arg16Gly polymorphism does not alter lung function The primary outcome was area under the curve (AUC) for responses to SAL or FSC over the 12 hour dosing interval 12 hour serial FEV1 by treatment and Arg16Gly genotype, genetic factors1–4. Variation in the 2-adrenergic recep-tor (ADRB2)5,6 may be of clinical relevance because it mediates the effects of 2-agonist bronchodilators5,7,8.
medications has been documented and is likely caused For example, Hawkins and colleagues recently reported by multiple factors, including severity of disease, envir- variations in regulatory regions, including the promoter onmental exposures, treatment compliance, and region and the 30-UTR, that contribute to haplotypic *This work was presented as a poster at the ATS International Conference, Orlando, FL, USA, May 2004 structure and to genetic association with asthma- To further investigate the effects of Arg16Gly poly- related phenotypes9. In that study, single nucleotide morphism on the therapeutic response to salmeterol polymorphisms (SNPs) associations observed with (SAL), we analyzed data from three similar randomized lung function phenotypes varied between ethnic trials in which genetic samples were collected. The groups. In contrast Taylor and colleagues reported no 12 hour serial forced expiratory volume in one second significant relationship between haplotypes pairs and (FEV1) response following the first dose of SAL or bronchodilator response in patients with asthma10.
fluticasone propionate plus SAL combination (FSC) It is important to acknowledge that given combinations on Day 1 and after 12 weeks of therapy were character- of polymorphisms at the locus these will occur more ized to evaluate whether Arg16Gly genotypes modu- frequently than would be predicted purely by assessing late this pharmacological response. Additionally, based the allelic frequency of the individual polymorphisms on previous reports on other SNPs associated with in isolation. Thus, linkage disequilibrium results in the asthma outcomes we assessed whether nucleotide posi-tion -47 from the start codon (BUP-Cys-19Arg), þ79 occurrence of haplotypes across regions that can be (Gln27Glu), þ491 (Thr164Ile) and common ADRB2 used as a genetic signature in populations. Other haplotypes modulated lung function responses over a associations between ADRB2 SNPs and response to 2-agonists have been reported11–13, but the clinicalsignificance The ADRB2 is a highly polymorphic locus and there are data suggesting altered functional responses (down regulation profiles) for the Arg-Gly16 and the Data were pooled from all available randomized clinical Gln-Glu27 polymorphisms16,17. Although, the major- ity of studies have focused on the common Arg16 Triangle Park, NC) in which both DNA sampling and polymorphism, polymorphisms at other codons have 12 hour serial spirometry was performed. The three also examined the potential risk factors for asthma identified studies were designed to evaluate the efficacy and asthma related phenotypes, but a large effect has and safety of SAL and FSC in: (1) adolescent and adult been excluded. In addition, a rare polymorphism subjects whose asthma was sub-optimally controlled (Thr-Ile164) was found to alter agonist binding proper- ties and adenylyl cyclase activation in one study using [Protocol SAS30001]27; (2) subjects whose asthma transformed cell populations18. Individuals with the was sub-optimally controlled with ICS, inhaled short- Ile164 polymorphism failed to respond as effectively acting 2-agonists, or SAL [Protocol SAS30003]28; and to catechol ligands and displayed altered duration of (3) in subjects whose asthma was inadequately con- action of salmeterol, possible due to altered binding trolled with ICS [Protocol SAS30004]29. General of the long lipophilic tail of this molecule to regions data such as age, gender, ethnicity, baseline pulmonary of transmembrane domain 419. It is currently postu- function, and morning peak expiratory flow (AM PEF) lated that the ADRB2 variant genotype at the codon were collected in all randomized participants that con- 16 (B16-Arg/Arg) is associated with poor therapeutic tributed data to the original protocol-specific analyses.
profiles for short-acting 2-agonists such as albu- Prior to study enrollment, the aims of the pharmaco- terol20,21 and isoproterenol22. However, the clinical genetic research were fully explained and informed response in Arg16Gly patients to long-acting beta- consent was obtained. The study protocols and agonists (LABA) used alone or in combination with informed consent forms were reviewed and approved inhaled corticosteroids (ICS) is less well understood.
by the appropriate institutional review board (IRB) for Curr Med Res Opin Downloaded from by Francis A Countway Library of Medicine on 06/14/10 Pharmacogenetic studies to date have not measured the bronchodilator response over 12 hours to LABA,but have relied on morning pretreatment measures of pulmonary function. For example, in a retrospectiveanalysis, Wechsler and colleagues23 reported modulat- General study designs were similar across the pooled ing effects of Arg16Gly on morning lung function studies. Each study enrolled patients 12 years of age and responses for patients receiving salmeterol with or older with documented reversible airway disease. The without concomitant ICS. In contrast, larger retrospec- randomized treatment period for each protocol was tive studies by Taylor and Bleecker have shown no asso- 12 weeks and the randomized treatments consisted of ciations between Arg16Gly and clinical responses to SAL, fluticasone propionate (FP), the combination morning lung function measures to either salmeterol of SAL and FP (at equivalent doses to SAL or FP or salmeterol plus inhaled corticosteroids24–26.
alone within a study), and placebo in two studies.
-receptor polymorphisms and response to salmeterol The screening population consisted of beta-agonist L-hours for FSC, respectively), the power to detect a users only for one study, ICS users only for another difference of 3.0 L-hours (or 0.25 L over 12 hours) study, and a mixed population for the third study. In ranged from 74–99% depending on the observed each protocol, patients entered a 2 week run-in period during which they continued their pre-study medica- Equilibrium (HWE) were assessed by a chi-square tions and discontinued any controller medication on goodness-of-fit test. Haplotype probabilities were esti- the day of randomization. Patients were instructed mated among Caucasian patients using an expectation/ to stop their rescue medication at least 6 hours prior maximization algorithm33. Genetic analyses were per- to the scheduled visits (Day 1 and Week 12). However, formed using the HelixTree software package (Golden during the study, patients were allowed to use SABA for relieving acute symptoms. For the analyses, patients Area under the 12 hour serial FEV1 curve (AUC) was receiving FP88 mcg or FP220 mcg were categorized summarized by genotype and time. Analyses of var- into a single group (FP) and likewise FSC 88/42 mcg iance (ANOVA) adjusting for investigative site, or FSC 220/42 mcg were categorized into a single gender, prior steroid use, ethnic origin, duration of asthma, age, and baseline lung function were conducted Twelve-hour serial spirometry was performed on to test for differences among genotypes for each of Day 1 immediately after the first dose of study drug, Day 1, Week 12, and the difference between Day 1 and at Week 12 following the last dose of study drug.
and Week 12. Similar analyses were conducted to Spirometry was performed in accordance with examine the effect of haplotypes. Statistical signifi- American Thoracic Society guidelines30 and observa- cance was defined as p50.05 with a two-sided test.
tions were collected at 30 minutes, and 1, 2, 3, 4, 6, All statistical analyses were conducted using the SAS 8, 10, and 12 hours post-dose. The area under the serial Version 8.2 (SAS Institute; Cary, NC).
FEV1 curve in relation to baseline (AUC[bl]) of FEV1was calculated. AM PEF, albuterol use, asthma symp-toms and nighttime awakenings were recorded daily by Demographic, clinical and pulmonary function charac- teristics are shown for three groupings: by treatment, Genotyping was performed in a blinded manner at a by protocol, and by Arg16Gly polymorphisms stratified by treatment assignment. Demographic and Triangle Park, NC) using collected blood samples.
baseline asthma characteristics were similar across the Previously characterized coding SNPs in the 2-adre- three populations at baseline, although retrospective nergic receptor gene (HUGO nomenclature: ADRB2; grouping by treatment, protocol, and genotype did Sequence Accession ID: NM_000024)31, found in the not result in complete balancing. Patients in the -upstream peptide (BUP) at nucleotide position -47 SAS30001 protocol had lower percent predicted from the start codon (BUP-Cys-19Arg), at amino acid FEV1 and more nighttime awakenings. Of note, these positions þ46 (Arg16Gly), þ79 (Gln27Glu) and patients were controlled with SABA only. In the case of þ491 (Thr164Ile) were genotyped. Polymorphisms baseline distribution by treatment, Arg/Arg SAL base- in the ADRB2 gene were detected by the 50 nuclease line percent predicted FEV1 was lowest in this sub- assay for allele discrimination32. The primers (F: group compared with other subgroups (Table 1). In contrast, the nighttime awakening per week was the GATGGCCAGGAC) and probes were synthesized lowest in the Arg/Arg FSC patients at baseline, but Curr Med Res Opin Downloaded from by Francis A Countway Library of Medicine on 06/14/10 by Key Stone (Foster City, CA) and PE Applied this small difference would have no clinical impact.
Biosystems (Foster City, CA). A total of 6% duplicate Genetic samples were available for 106 of 274 (39%) samples were added and genotyped in a blinded manor.
and 112 of 281 (40%) of SAL and FSC recipients, There was 100% concordance between duplicates. All markers were in Hardy Weinberg equilibrium.
After the first dose of SAL, FEV1 increased and bronch- Analyses were conducted on all subjects randomized to odilation was maintained over 12 hours in all Arg16Gly SAL or FSC with genetic data available. Based on the genotypes (Figure 1, panel A). The 12 hour serial FEV1 maximum observed standard deviations at Day 1 and AUCs (mean Æ standard error of the mean [SEM]) Week 12 (3.9 and 3.4 L-hours for SAL and 3.3 and 2.8 were 6.7 Æ 0.9, 4.9 Æ 0.5, and 6.8 Æ 0.7 L-hours for ß 2009 Informa UK - Curr Med Res Opin 2009; 25(4) -receptor polymorphisms and response to salmeterol Curr Med Res Opin Downloaded from by Francis A Countway Library of Medicine on 06/14/10 -receptor polymorphisms and response to salmeterol % Predicted
Change from Baseline
Figure 1. Twelve-hour serial percent predicted FEV1 (mean Æ standard error of the mean) after Day 1 (panel A) and 12 weeks of therapy (panel B) for subjects treated with salmeterol (SAL) Table 2. Twelve-hour serial FEV1 areas under the curve (AUCs) after Day 1 and 12 weeks of therapy for subjectstreated with salmeterol (SAL) and fluticasone propionate plus salmeterol combination (FSC) by genotype subgroups *Data expressed as L-hours, mean Æ standard error of the meanaIncludes subjects treated with salmeterol (SAL) 42 mcgbIncludes subjects treated with fluticasone propionate plus SAL combination (FSC) 88/42 mcg and FSC 220/42 mcgcOverall p-values for Day 1, Week 12, and Week 12 - Day 1 were 0.085, 0.613, and 0.581, respectivelydOverall p-values for Day 1, Week 12, and Week 12 - Day 1 were 0.848, 0.354, and 0.374, respectively the Arg/Arg, Arg/Gly, and Gly/Gly polymorphisms, in all Arg16Gly genotypes (Figure 2, panel A). On respectively (Table 2). There were no significant Day 1, the FEV1 mean change from baseline and overall response characteristics for FSC was similar to that of SAL. The 12 hour serial FEV1 AUC for FSC was Following 12 weeks of treatment, the baseline for 7.0 Æ 1.6, 6.3 Æ 0.5, and 6.8 Æ 0.6 L-hours (mean Æ SAL was higher than at Day 1 and the morning dose SEM) for the Arg/Arg, Arg/Gly, and Gly/Gly poly- of SAL again increased FEV1 and the bronchodilator morphisms, respectively (Table 2). There were no sig- Curr Med Res Opin Downloaded from by Francis A Countway Library of Medicine on 06/14/10 effect was maintained over 12 hours in all Arg16Gly nificant AUC differences among the three genotypes genotypes (Figure 1, panel B). Serial FEV1 AUCs over 12 hours were 8.8 Æ 2.5, 4.6 Æ 0.7, and 6.7 Æ 1.0 Following 12 weeks of treatment, the baseline for L-hours (mean Æ SEM) for the Arg/Arg, Arg/Gly, FSC was higher than at Day 1 and the Week 12 morn- and Gly/Gly polymorphisms, respectively (Table 2).
ing dose of FSC again increased FEV1 with minimal loss The AUC comparisons between genotype subgroups of effect over 12 hours in all Arg16Gly genotypes at Week 12 were not significantly different (p ¼ 0.613).
(Figure 2, panel B). Serial FEV1 AUCs over 12 hourswere 8.0 Æ 1.8, 8.7 Æ 0.9, and 9.3 Æ 0.8 L-hours(mean Æ SEM) Gly/Gly polymorphisms, respectively (Table 2). The After the first dose of FSC, FEV1 increased and the AUC comparisons between FSC genotype subgroups bronchodilator effect was maintained over 12 hours at Week 12 were not significantly different (p ¼ 0.354).
ß 2009 Informa UK - Curr Med Res Opin 2009; 25(4) -receptor polymorphisms and response to salmeterol % Predicted 1
Change from Baseline
Figure 2. Twelve-hour serial percent predicted FEV1 (mean Æ standard error of the mean) after Day 1 (panel A) and 12 weeks of therapy (panel B) for subjects treated with fluticasone propionate plus salmeterol combination (FSC) Table 3. Localization of single nucleotide polymorphisms (SNPs) and identification of haplotypes of the 2-adrenergic receptor gene (ADRB2) among 342 Caucasiansa aGenetic data from patients in placebo (n ¼ 78) and fluticasone propionate (n ¼ 109) treatment arms were used to generatehaplotype frequency estimates, but clinical parameters from these treatment arms were not evaluated in the present analysis Because haplotypes may be more informative than (i.e., AM PEF). In contrast, this study provides direct individual SNPs, associations between haplotype pairs evidence that Arg16Gly polymorphisms do not alter and outcomes were evaluated. Analysis was restricted lung function responses of SAL or FSC over their to the five most frequently observed haplotype pairs: defined period of therapeutic efficacy (12 hours) after AA (n ¼ 39), AB (n ¼ 53), AC (n ¼ 28), BB (n ¼ 30) the first dose or following chronic treatment.
and BC (n ¼ 23) (Table 3). No significant differences A number of studies suggest that ADRB2 Arg16Gly between haplotype pairs were identified at Day 1 or polymorphisms may be important in modulating Week 12. While it is difficult to definitively rule out responses to 2-agonist therapy for asthma7. For exam- a haplotype effect due to sample size limitations, ple, in a report from retrospectively derived data from response to regularly scheduled use of FSC did not two different studies, Wechsler et al.23 suggest that Curr Med Res Opin Downloaded from by Francis A Countway Library of Medicine on 06/14/10 appear to be modified by ADRB2 haplotype pairs.
patients with asthma harboring the Arg/Arg genotypeat codon 16 of the ADRB2 may have an impaired ther-apeutic response to SAL, in either the presence or absence of concurrent ICS. In one study subjectsreceived SAL or placebo while ICS was withdrawn, The current study is unique in that the outcome while in the second study subjects received SAL and continuous ICS. Interpretation of these findings is lim- terizes the acute and chronic bronchodilator responses ited since only 12 and 8 Arg/Arg patients in each of the to SAL and FSC over 12 hours which encompasses the studies, respectively, were available for analysis.
defined period of pharmacologic activity. Previous Similarly, our study is limited in this respect as the pharmacogenetic studies have reported single point number of Arg/Arg patients was 13 for the SAL in time, pre-dose trough lung function values analysis and 15 for the FSC analysis.
-receptor polymorphisms and response to salmeterol These observations are consistent with those function response in patients treated with salmeterol reported by Bleecker et al., who retrospectively evalu- or FSC over the 12 hour dosing interval following ated FSC and formoterol and budesonide use and acute and chronic dosing. The positive and undifferen- asthma control with respect to Arg16Gly geno- tiated pharmacogenetic response to salmeterol in the types25,26. In these studies, pre-dose AM PEF, asthma presence of ICS is reassuring, and future research symptoms, and rescue albuterol use were all improved should be expanded into studies with sufficient race/ and sustained over chronic treatment independent of ethnic diversity studying a larger number of less Arg16Gly genotypes. In addition, Taylor et al. evalu- common variants and also a more severe asthma ated asthma control during long-term treatment with salbutamol and salmeterol on the background of ICSuse (490% of patients) with respect to Arg16Gly gen-otypes24. It was shown that Arg/Arg patients on albu- terol experienced higher exacerbation rates comparedto placebo (1.91 per year versus 0.81; p ¼ 0.005), but Declaration of interest: S.W.Y., H.G.O., L.D.E., and no adverse changes (i.e., decline in PEF or an increase in W.H.A. are employees of GlaxoSmithKline. M.K. was exacerbation rates) were observed for patients receiving an employee of GlaxoSmithKline at the time of the SAL regardless of Arg16Gly polymorphism. The disparate finding between short-acting 2-adrenergicagonist and LABA reported by Taylor et al. raises theissue of whether the pharmacological properties ofspecific -agonist molecules may also be important in reconciling and interpreting reported pharmacogenetic 1. Bateman ED, Boushey HA, Bousquet J, et al. Can guideline- associations. Because intrinsic properties of 2-agonists defined asthma control be achieved? The Gaining Optimal vary34, conclusions drawn from clinical studies that Asthma controL study. Am J Respir Crit Care Med 2004;170:836-44 investigate associations between bronchodilation and 2. Drazen JM, Silverman EK, Lee TH. Heterogeneity of therapeu- ADRB2 SNPs may not be comparable between short- tic responses in asthma. Br Med Bulletin 2000;56:1054-70 3. Palmer LJ, Silverman ES, Weiss ST, et al. Pharmacogenetics of among different LABAs. Alternately, it is plausible asthma. Am J Respir Crit Care Med 2002;165:861-6 4. Taylor DR, Kennedy MA. Beta-adrenergic receptor polymorph- that pharmacogenetic clinical outcomes and ADRB2 isms and drug responses in asthma. Pharmacogenomics 2002; SNPs only manifest when asthma control is lost which occurs less with LABA as compared with SABA.
5. Reihsaus E, Innis M, MacIntyre N, et al. Mutations in the gene encoding for the beta 2-adrenergic receptor in normal and asth- All retrospective studies have inherent limitations. In matic subjects. Am J Respir Cell Mol Biol 1993;8:334-9 the current study, the authors restricted the genotyping 6. Drysdale CM, McGraw DW, Stack CB, et al. Complex promo- analysis to only few SNPs although there are other ter and coding region beta 2-adrenergic receptor haplotypesalter receptor expression and predict in vivo responsiveness.
SNPs reported in association with 2-agonist respon- siveness. In addition, due to limited racial/ethnic varia- 7. Tantisira KG, Weiss ST. The pharmacogenetics of asthma: an bility in the sample, the haplotype analysis was restricted to Caucasians. Studies have shown that the 8. Liggett SB. Beta2-adrenergic receptor pharmacogenetics. Am J frequency of polymorphisms in the -receptor may be 9. Hawkins GA, Tantisira K, Meyers DA, et al. Sequence, altered by ethnicity9,35. Even more broadly, disease sus- haplotype, and association analysis of ADRB2 in a multiethnic ceptibility and other pharmacogenetic associations are asthma case–control study. Am J Respir Crit Care Med 2006;174:1101-9 linked with genetic differences based on ethnicity36–38.
10. Taylor DR, Epton MJ, Kennedy MA, et al. Bronchodilator In addition, rare ADRB2 haplotypes may be more response in relation to adrenoceptor haplotype in patients Curr Med Res Opin Downloaded from by Francis A Countway Library of Medicine on 06/14/10 important in characterizing pharmacogenetic response with asthma. Am J Respir Crit Care Med 2005;172:700-3 11. Martinez FD, Graves PE, Baldini M, et al. Association between to -agonists39. While we did look at responses to genetic polymorphisms of the beta2-adrenoceptor and response common haplotypes and did not find pharmacogenetic to albuterol in children with and without a history of wheezing.
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CURRICULUM VITAE RICHARD F. BERGSTROM, PH.D. OCTOBER 2011 PERSONAL DATA EDUCATION Taylor University, Upland, IN, Major: Chemistry University of Pittsburgh, School of Pharmacy, Pittsburgh, PA, Bachelor of Butler University, College of Pharmacy, Indianapolis, IN, Master of Science in Pharmacology (Thesis Advisor: Dr. James E. Berger and Dr. John F. Quay at Eli Lilly and Compan

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