Title: PGx250: An Exploratory Pharmacogenetic Analysis of Asthma Exacerbations in African-Americans treated

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1 GSK Medicine: Fluticasone propionate/salmeterol Study No.: SFA Title: PGx250: An Exploratory Pharmacogenetic Analysis of Asthma Exacerbations in African-Americans treated with Advair Start Date (FPA actual): 30-Apr-2008 Completion Date (CSR actual): 20-May-2011 Rationale: Asthma is a heterogeneous disease with variable signs and symptoms among patients. Asthma exacerbations are defined as acute episodic events that require urgent action on the part of the patient and physician to prevent a serious outcome, such as hospitalization, intubation for respiratory failure or death from asthma (ATS definition, 2008). Objectives: The primary objective was to characterize associations between selected polymorphisms and asthma exacerbations. The secondary objective of these pharmacogenetics (PGx) analyses was to determine the contributions of variation in candidate genes and polymorphisms using genetic samples collected in SFA (CCI18781+GR33343). Asthma exacerbations are reported to be associated with polymorphisms in the interleukin-4 (IL-4), interleukin-13 (IL-13) and interleukin-4 receptor (IL-4R) genes. Indication: Asthma exacerbation Study Investigators/Centers: GSK conducted the genetic experiment using consented DNA samples collected in study SFA Research Methods: Assay of Candidate Genes: The candidate genes (ABCC1, ADRB2, ALOX5, CHI3L1, IL-13, IL-4, IL-4R, LTA4H, LTC4S) were selected based on published association to asthma exacerbations. 2-adrenergic receptor (ADRB2) was selected since the protein encoded by this gene is the drug target for salmeterol. A total of 41 single nucleotide polymorphisms (SNPs) covering all genes were selected for genotyping. These 41 SNPs were either selected from the literature because of a previous association with asthma exacerbations or functional effect; additional tagging SNPs were genotyped for ADRB2. Out of the 41 SNPs, there were 40 SNPs for which an assay was successfully designed and genotyped. All genotyping was performed in a blinded manner (GlaxoSmithKline, RTP, NC, USA). The majority of genotypes were generated using the Flow Accelerated SNP Typing (FAST) platform, which is a modification of a single base chain extension assay [Tantisira, 2001]. The remaining genotypes were generated using Amplifluor or sequencing. There was 100% concordance between the FAST and Amplifluor assays. To further investigate the relationship between genetic variants in the ADRB2 gene and asthma exacerbation, a comprehensive SNP discovery and gene sequencing experiment was initiated with Wake Forest University to identify novel polymorphisms. A 5.3 Kb region of ADRB2 was sequenced using 70 African American subjects who experienced asthma exacerbations in Study SFA DNA sequencing was performed using the ABI BigDye Terminator sequencing kit (Applied Biosystems, Inc., Foster City, CA, USA). The data was analyzed using the DNA sequence analysis program Sequencher v4.8 (Gene Codes, Ann Harbor, MI) [Hawkins, 2006]. Number of subjects: All subjects who provided written informed consent to participate in GSK Study SFA103153, met all of the criteria for entry into the clinical study, and received investigational product were eligible for participation in the PGx research. Subjects provided separate written informed consent prior to participation in the PGx research. There were 363 subjects requested for genotyping from SFA for evaluation of asthma exacerbation. Of the 363 subjects requested, there were fifteen excluded due to low DNA yield, gender conflict and/or consent withdrawn. The intent-to-treat (ITT) population in Study SFA randomized 475 subjects, 239 to the fluticasone (FSC) 1

2 100/50 arm and 236 to the fluticasone propionate (FP) 100 arm. Thus the genetics analysis population is 67.8% of the ITT population. Diagnosis and main criteria for inclusion: During the double-blind treatment period of SFA103153, an asthma exacerbation was defined as any of the following: Worsening of asthma, that in the opinion of the investigator, required treatment with an oral corticosteroid Hospitalization for the treatment of asthma Unscheduled urgent care for acute asthma symptoms that required intervention (e.g., unscheduled clinic visit, MD office visit, emergency room visit) 30% decrease in forced expiratory flow (FEV1) from the baseline obtained at the randomization visit (Visit 3) Morning (AM) peak expiratory flow (PEF) below the AM PEF Stability Limit on any 2 consecutive days (AM PEF Stability Limit was a 30% decrease from the mean AM PEF on the 7 consecutive days prior to Visit 3). Results from the clinical trial were published [Bailey, 2008] and can also be referenced in the clinical study report: RM2006/00867/00. Treatment administration: SFA was a 52-week, randomized, double-blind, parallel group trial conducted on an outpatient basis. Subjects were of African descent by self-report, 12 to 65 years of age with persistent asthma who were symptomatic while on inhaled corticosteroid (ICS) therapy. Subjects entered a 2-week screening period, continued their baseline ICS and were provided albuterol inhalation aerosol for relief of symptoms. After the screening period, eligible subjects entered a 4-week run-in period, and replaced their baseline ICS with open-label FP 250mcg DISKUS BID. The run-in period served to assess the subject s eligibility for randomization including baseline asthma symptoms, albuterol use, compliance with study procedures, and provided the baseline for efficacy and safety parameters. After the run-in period, eligible subjects were randomly assigned to one of two treatment arms for 52 weeks: Fluticasone propionate/salmeterol 100/50mcg DISKUS BID (referred to as FSC 100/50) Fluticasone propionate 100mcg DISKUS BID (referred to as FP 100) Criteria for evaluation: The phenotype under evaluation was asthma exacerbation. Asthma exacerbations are defined as acute episodic events that require urgent action on the part of the patient and physician to prevent a serious outcome, such as hospitalization, intubation for respiratory failure or death from asthma [ATS, 2008]. Data source: Clinical data from clinical study SFA Study Design: Retrospective, non-interventional pharmacogenetic investigation Study Population: The PGx analysis population comprised of the 348 subjects form study SFA who provided consent for the genetic investigation and sufficient amount of DNA for the genotyping experiment. Study Exposures, Outcomes: The genetic analysis utilized all subjects from both the Fluticasone propionate and fluticasone propionate / salmeterol treatment arms that provided informed consent and a DNA sample for analysis. The genetics analysis utilized 67.8% of the ITT population. Data Analysis Methods: An exact test was used for departure from Hardy-Weinberg equilibrium (HWE) and Linkage Disequilibrium (LD) was 2

3 tested using a chi-square test. Markers showing substantial evidence of departure (p<0.001) were investigated for laboratory errors or other causes of departure from equilibrium. If no specific cause for such departures were found and corrected, the marker concerned was omitted from the analyses. The primary analysis was a comparison of the primary endpoint among genotypes in the Arg16Gly polymorphism in the ADBR2 gene. It was tested at a significance level Hochberg adjustments were applied to evaluations of the primary endpoint for all other polymorphisms such that the overall error rate is For each secondary endpoint, Hochberg [Hochberg, 1988] adjustments were applied to all evaluations of the polymorphisms on that endpoint such that the overall error rate is Logistic regression models were used to assess the effect of each genetic marker on asthma exacerbations. Odds ratios and their 95% confidence intervals were calculated for each genetic marker and any other covariates included in the model. The following variable served as the dependent variable for the logistic regression models: At least one asthma exacerbation during the double-blind treatment period Hypothesis H01 was addressed first with models that do not include double-blind treatment as a covariate. Hypothesis H02 included double-blind treatment and its interaction with genotype as covariates. In order to assess the predictive ability of the genetic markers for asthma exacerbations, logistic regression models were constructed based on stepwise selection that considers all genetic markers as terms. Poisson regression models were used to assess the effect of each genetic marker on the rate of asthma exacerbations per subject per year. Independent variables in the models included genotype and baseline covariates identified above. Hypothesis H01 was addressed first with models that do not include double-blind treatment as a covariate and H02, included double-blind treatment and its interaction with genotype as covariates. The time to first asthma exacerbation was defined as the number of days between the first reported exacerbation occurring on or after randomization and date of randomization + 1. Times were summarized with descriptive statistics by genotype and allele. To allow for adjustment by covariates, Cox proportional hazards models were constructed for time to first asthma exacerbation to compare genotypes. Subjects who experience no asthma exacerbations during the study will be censored at the time of completion or withdrawal from the study. Timedependent covariates were introduced in the models to test the proportional hazards assumption. The secondary endpoints change from baseline in FEV1 and symptom-free days at Week 4, Week 12, and Week 52 of the double-blind treatment period, were modeled for markers in the ADRB2 gene only. Each model included the independent variables and terms for genotype, treatment, and genotype-by-treatment interaction. Effects were declared statistically significant at the 0.05 level. Separate models were constructed for each genetic marker. Limitations: The analysis did not include all subjects in SFA Since DNA collection is not mandatory for the subject, the genetic analysis only uses a subset of the entire ITT population that participated in the study. For this analysis, the genetics population was 67.8% of the ITT population. However, the proportion of subjects consenting to participation in genetic sampling was evenly balanced between the two treatment arms, and the demographics were similar between the Genetics and ITT populations. The primary endpoint of the genetics analysis was the occurrence or absence of an asthma exacerbation. Not all subjects with exacerbation were included in the genetic analysis. Of all subjects who experienced an exacerbation, 77.8% of those in the FP and 87.2% of those in the FSC arm were included in the genetic analysis. Given the available sample size, the power to declare a marker with an odds ratio of 2.5 as significant ranged from about 35% (risk allele frequency of about 20%) to about 80% (risk allele frequency of about 50%). Given the relatively low power of this analysis, the findings should be considered as exploratory, requiring replication in a larger, independent sample. 3

4 Study Results: Demographics The demographics (Table 1) and baseline characteristics (Table 2) for the genetics subset were similar to the total clinical trial. Subjects in both treatment groups had a mean duration of asthma of >19 years. As expected, subjects had a greater percentage of mothers with a history of asthma, and 40% of subjects had a sibling with asthma. Table 1 Baseline Demographics-Genetics Population FSC 100/50 N=161 FP 100 N=161 Age (Standard Deviation (SD)) 31.8 (13.6) 33.1 (13.7) Gender Female 96 (60%) 102 (63%) Male 65 (40%) 59 (37%) Race African-American / African Heritage 157 (98%) 157 (98%) Mixed Race 4 (2%) 4 (2%) Height (SD) cm (9.4) (9.58) Weight (SD) kg 85.8 (24.1) 88.8 (26.9) BMI (SD) 30.5 (8.6) 31.3 (9.1) Baseline pulmonary function was also similar between the total population and genetic subset and for each of the treatment arms (Table 2). Table 2 Baseline Pulmonary Function-Genetics Population FEV1 L (SD) % Predicted FEV1 (SD) % Reversibility (SD) FSC 100/50 N=161 FP 100 N= (0.47) 2.30 (0.49) 77.5 (9.1) 77.5 (9.2) 20.2 (8.6) 22.0 (12.6) FEV1 L refers to forced expiratory volume in 1 second as measured in Litres Exacerbation Frequency For the SFA intent to treat population, there were 54/236 subjects with an exacerbation in the FP arm, and 47/239 in the FSC arm. In the genetics subset (n=322), we had DNA available from 42 and 41 of the exacerbation cases for the FP and FSC arms respectively. This represents a collection rate of 77.8% and 87.2% of the exacerbation cases for the FP and FSC arms. There were no obvious differences in demographics comparing the subjects with an exacerbation to those without with the exception of a slightly increased weight and BMI of 32.3 vs respectively. No differences were observed in baseline pulmonary function. The logistic regression analysis from models which included all genetic markers found only BMI p=0.003 (Odds Ratio (OR) 1.053, ( )) and IL-13 (RS20541) p=0.044 (OR C,C vs. T,T: ( ); OR C,T vs. 4

5 % of with > 1 Exacerbation % of with > 1 Exacerbation T,T: ( )) to be significant. Logistic regression models were also used to assess the effect of each genetic marker separately on asthma exacerbations. The primary analysis of the ADRB2 Arg16Gly polymorphism (RS ) showed no significant association with exacerbation frequency. In testing H01 in models that do not include treatment arm as a covariate, only one polymorphism was significant (p=0.041 IL-4R RS ) (Table 3). Table 3 Association with Exacerbation Frequency Gene Polymorphism P Value Odds Ratios (95% CI) IL4R RS A,A vs. G,G ( ) A,G vs. G,G ( ) IL-13 RS C,C vs. T,T ( ) C,T vs. T,T ( ) +Unadjusted for multiple tests; not significant after Hochberg adjustment. For the IL-13 RS20541 SNP, 55.6% of the subjects (5/9) with the TT genotype had at least 1 exacerbation compared with 22.7% (48/211) of the CC subjects. A post-hoc logistic regression analysis which included both linear and quadratic terms in the model identified a p value of and for the linear and quadratic terms respectively for IL-4R (RS ) and and for IL-13. These are graphically presented in Figure 1 and 2. Figure 1 Effect of on Exacerbation Frequency IL-4R (RS ) AA AG GG Figure 2 Effect of on Exacerbation Frequency IL-13 (RS2054) CC CT TT 5

6 % of with > 1 Exacerbation In Figure 1, there were 90, 147 and 75 subjects for the AA, AG and GG genotypes. The significance appears to be driven by the heterozygote genotype AG and thus very difficult to interpret. In Figure 2 there are 211, 102 and 9 subjects in the CC, CT and TT genotypes. Gene by Treatment Interactions Including treatment as a covariate, several markers showed a p value of ~0.05. Table 4 Summary of markers from logistic regression using treatment as a covariate Gene Polymorphism Name P Value+ ADRB2 RS RS RS FCER2 RS Unadjusted for multiple tests; not significant after Hochberg adjustment. The polymorphisms in the ADRB2, RS , RS and RS are in the coding region of the gene at base pair positions 252, 523 and 1053 from the start site. The coding changes are synonymous, resulting in no change in the amino acid sequence of the protein, and are not known to have any functional significance. All 3 polymorphisms are in strong linkage disequilibrium. RS has been reported to be associated with exacerbations in African-Americans but not Caucasians [Lima, 2006]. The FCER2 polymorphism (RS ) is a T>C change at position 2206 (A>G base change) close to the intronexon 9 boundary. The C allele has been demonstrated to result in reduced expression of FCER2 [Tantisira, 2007] only in subjects taking inhaled corticosteroids. A post-hoc logistic regression analysis including a linear and quadratic gene by treatment interaction term in the model was conducted. For the ADRB2 SNP (RS ) the p value for the quadratic and linear terms was and respectively. For the FCER2 SNP (RS ) the p value for the quadratic and linear terms was and respectively. Figure 3 Effect of by Treatment Interaction on Exacerbation Frequency for ADRB2 (RS ) AA AG GG FSC FP 6

7 % of with > 1 Exacerbation Figure 4 Effect of by Treatment Interaction on Exacerbation Frequency for FCER2 (RS ) AA AG GG FSC FP The number of subjects with >1 exacerbation for genotype AA, AG and GG for ADRB2 (RS ) was 7, 19 and 15 for the FSC treatment group and 1, 23 and 18 for the FP group. The number of subjects with >1 exacerbation for genotype AA, AG and GG for FCER2 (RS ) was 9, 23 and 9 for the FSC treatment group and 8, 17 and 17 for the FP group. For the ADRB2 SNPs, it is hard to draw any conclusions because of the low number of subjects with the AA genotype in the FP treatment arm. For FCER2 (RS ) in the FSC treatment arm, 18.4% of the G,G genotypes had an exacerbation as compared with 34% of the G,G genotypes in the FP arm. Rate of Exacerbations Poisson regression models were used to assess the effect of each genetic marker on the rate of asthma exacerbations per subject per year. The summary of associations for a genotype effect and genotype by treatment interaction are presented in Tables 5 and 6. Table 5 Summary of Effect on Rate of Asthma Exacerbations Gene Polymorphism Name P Value IL-4 RS Unadjusted for multiple tests; not significant after Hochberg adjustment. Table 6 Summary of Gene by Treatment Interactions for Rate of Asthma Exacerbations Gene Polymorphism Name P Value+ ADRB2 RS RS RS FCER2 RS RS IL-4R RS Unadjusted for multiple tests; not significant after Hochberg adjustment. 7

8 Time to First Exacerbation (Days) RS (FCER2) was also reported above to be associated with the number of exacerbations. The second polymorphism associated with rate of exacerbation RS was not associated with the number of exacerbations (p=0.063). The SNP in the IL-4R gene (RS ) was seen above to be associated with the number of asthma exacerbations. Time to First Exacerbation In the genetics population the time to first exacerbation was ~10 days longer in the FSC treatment arm compared with the FP arm (269.9 vs days respectively). Results from the Cox Regression models demonstrated that RS20541 (IL-13) was the only association observed (p=0.023) with time to first exacerbation for the combined genetic effect across both treatment arms. This is displayed graphically in Figure 3. This SNP had a p value of for exacerbation frequency. The number of subjects for the CC, CT and TT genotypes is 97, 59 and 5 for the FSC treatment arm, and 114, 43 and 4 for the FP treatment arms respectively. The difference in time to first exacerbation for the CC to TT genotypes is 50.6 days in the FSC arm, and 42.9 days in the FP arm respectively. Figure 5 IL-13 (RS20541) Time to First Exacerbation FSC FP 100 CC CT TT Table 7 reports the associations observed for the gene by treatment interaction for the time to first exacerbation. Table 7 Gene by Treatment Interaction for the Time to First Exacerbation Gene Polymorphism Name P Value+ ADRB2 RS RS RS Unadjusted for multiple tests; not significant after Hochberg adjustment. The ADRB2 polymorphisms are the same as observed for rate of asthma exacerbations. Because demographics may influence susceptibility to exacerbations, especially BMI, we looked within each of the genotypes for the SNPs listed in the tables above. There were no obvious differences in age, gender, height or BMI. The time to first exacerbation for the ADRB2 SNP (RS ) is illustrated in Figure 6. 8

9 Time to First Exacerbation (Days) Figure 6 ADRB2 (RS ) Time to First Exacerbation FSC FP 100 CC CG GG In Figure 6, the CC genotype (ADRB2 SNP RS ) for the FP treatment arm, as compared to the CG and GG genotypes, is associated with a prolonged time to first exacerbation. The genotyping results for patients who received FSC are difficult to interpret, since only the heterozygote (CG) has a decreased time to first exacerbation. Conclusions: 1. The overall collection rate for the genetics population was 67.8%, while the exacerbation cases were represented at 77.8 and 87.2% of the total exacerbations. There were also no major differences between the ITT and Genetics populations. Thus, the genetics population appears to be a fair representation of the total study population. 2. For the primary endpoint, the polymorphism in ADRB2 Arg16Gly (RS ) was not associated with asthma exacerbations. For the remaining markers, there was no statistically significant association when corrected for multiple tests using Hochberg s method. 3. Polymorphisms in the IL-4, IL-4R and IL-13 genes appear to be independent of treatment, as there was no significant treatment x genotype interaction in the rate of asthma exacerbation rate for IL4R. Polymorphisms in FCER2 and ADRB2 only had p values 0.05 for the treatment by genotype interaction. For ADRB2, (markers RS , RS and RS ) the minor allele had a higher frequency of exacerbations in the FSC treatment arm. For example, for RS in the AA genotype, 7/18 (38.9%) had an exacerbation in the FSC arm vs. 1/18 (5.6%) in the FP arm. The other genotypes (AG and GG) were similar for both treatments. For FCER2, (RS ) exacerbations in the GG genotype appear to be higher in the FP treatment arm where 17/50 (34%) had an exacerbation in the FP arm vs. 9/49 (18.4%) in the FSC arm. 4. Because the ADRB2 polymorphisms are non-synonymous (code for the same amino acid in the ADRB2 protein), and the non-significant p values, it is unlikely that these polymorphisms represent true associations with exacerbations. 9

10 References: ATS (American Thoracic Society). An Official American Thoracic Society/European Respiratory Society Statement: Asthma Control and Exacerbations. Available at Bailey W, Castro M, Matz J, White M, Dransfield M, Yancey S, Ortega H. Asthma Exacerbations in African Americans Treated for 1 Year with Combination Fluticasone Propionate and Salmeterol or Fluticasone Propionate Alone. Curr Med Res Opin (6): Hawkins GA, Tantisira K, Meyers DA, Ampleford EJ, Moore WC, Klanderman B, Liggett SB, Peters SP, Weiss ST, -control study. Am J Respir Crit Care Med. 2006; 174: Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. Biometrika. 1988; 75: Lima JJ, Holbrook JT, Wang J, Sylvester, JE, Blake KV, Blumenthal, MN, Castro, M, Hanania N, Wise R. The C523A adrenergic receptor polymorphism associates with markers of asthma severity in African Americans. Journal of Asthma. 2006;43:3: Tantisira KG, Silverman ES, Mariani TJ, Xu J, Richter BG, Klanderman BJ, Litonjua AA, Lazarus R, Rosenwasser LJ, Fuhlbrigge AL, Weiss ST. J ALLERGY CLIN IMMUNOL. 2007;120:6: Taylor JD, Briley D, Nguyen Q, Long K, Iannone MA, Li MS, Ye F, Afshari A, Lai E, Wagner M, Chen J, and Weiner MP. A Flow Cytometric Platform for High Throughput Single Nucleotide Polymorphism Analysis. Biotechniques. 2001; 30: Last updated: 02 Sep

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