PGx7673: Confirmatory Genetics Reporting and Analysis Plan: Efficacy pharmacogenetic analysis of SLE patients treated with Benlysta in study BEL113750 (eTrack Study ID 207521)

Trial description: This study is a confirmatory pharmacogenetic evaluation of one SNP, rs293983, in the ANO3 gene region that was associated with the SRI4 endpoint in the PGx7644 meta-analysis (eTrack 204901) of systemic lupus erythematosus (SLE) subjects treated with belimumab. The PGx7644 meta-analysis included studies BEL112341, BEL110751 and BEL110752.This PGx evaluation will use data from the 52 week blinded period of BEL113750, a phase III, randomized, parallel group, double-blind study to evaluate the efficacy and safety of 10mg/kg belimumab intravenous (IV) administered at weeks 0, 2, and 4, then every 4 weeks, compared with placebo over a 52-week treatment period in subjects with active systemic lupus erythematosus (SLE) (defined as Safety of Estrogen in Lupus National Assessment Systemic Lupus Erythematosus Disease Activity Index (SELENA SLEDAI) score ≥8) in Northeast Asia. The primary objective is to confirm the association between the rs293983 T allele and improved SRI4 response to belimumab in SLE subjects in BEL113750. A logistic regression model applying an additive genetic model will be used to assess the association of rs293983 genotype with SRI4 response at week 52 in belimumab-treated subjects adjusting for country, baseline SELENA SLEDAI score, and baseline complement levels (C3, C4).A secondary objective is to determine whether there is improved SRI4 response for belimumab 10mg/kg compared to placebo in SLE subjects in BEL113750 within each of the rs293983 genotype groups (CC or combined CT/TT genotypes). A logistic regression model will be used to assess the association of treatment with SRI4 response at week 52 in belimumab or placebo treated subjects adjusting for country, baseline SELENA SLEDAI score, and baseline complement levels (C3, C4) within each rs293983 genotype group.A secondary objective is to determine whether SRI4 response for belimumab 10mg/kg compared to placebo in SLE subjects in BEL113750 is significantly different in the rs293983 genotype groups (CC or combined CT/TT genotypes). A logistic regression model will be used to assess the genotype-by-treatment interaction with SRI4 response at week 52 in belimumab or placebo treated subjects adjusting for country, baseline SELENA SLEDAI score, baseline complement levels (C3, C4), treatment and rs293983 genotype group. Supportive analyses will include analysis of SRI4 response in placebo-treated subjects to allow for contrast with belimumab genetic analysis results.Exploratory analyses may be conducted on the individual components of the SRI score (SELENA SLEDAI score, PGA, BILAG).Exploratory analyses may be conducted for other efficacy related endpoints or using other covariates.Exploratory analysis may be conducted by country.Exploratory analysis may be conducted in subjects with high disease activity at baseline defined by having a positive anti-double-stranded DNA (≥30 IU/mL at baseline) AND low C3 and/or C4 levels at baseline.