Contributions
Abstract: P1185
Type: Poster
Abstract Category: Therapy - disease modifying - Immunomodulation/Immunosuppression
Background: A gene expression signature associated with endogenous activation of the type I interferon (IFN) system has been observed in a number of autoimmune diseases including relapsing remitting multiple sclerosis (RRMS). It has been hypothesized that high pretreatment expression of IFN signature genes in RRMS patients may be associated with poor response to IFN-beta treatment on the basis that patients with activation of endogenous IFN pathways are less likely to respond to exogenous IFNs.
Objectives: To assess the relationship between pretreatment IFN signature and treatment outcomes in a 384 subject sub-study of ADVANCE, the pivotal trial of Peginterferon beta-1a efficacy in RRMS.
Methods: RNA was isolated from whole blood obtained from subjects at baseline (pretreatment), the relative expression of 20 IFN-induced genes was determined by quantitative PCR and normalized to a panel of 4 house-keeping genes, and a pretreatment IFN signature score was calculated for each subject as the geometric mean of the relative expression values of the 20 genes (which were all highly correlated with one another). The relationship between pretreatment IFN signature score and treatment outcomes at 48 weeks, including annualized relapse rate (ARR) and counts of Gd+ and/or new or newly enlarging T2 hyper-intense lesions, was assessed using negative binomial regression, adjusting for baseline age, disability, and relapse rate among other covariates.
Results: The beneficial effects of Peginterferon beta-1a on relapses and MRI lesions in this sub-study population were similar to those observed in ADVANCE as a whole. There was no association between pretreatment IFN score and on-treatment ARR among placebo-treated subjects (p=0.897). There was also no interaction between peginterferon beta-1a treatment and pretreatment IFN score with regard to the outcome of ARR regardless of dose (p=0.851 for placebo vs. every 2 weeks peginterferon treatment; p=0.497 for placebo vs. every 4 weeks peginterferon treatment). Similar lack of interaction was observed when testing against inflammatory MRI outcomes: Gd+ and new/newly enlarging T2 hyper-intense lesions.
Conclusions: In this large sub-study of a pivotal trial of Peginterferon beta-1a, pretreatment IFN score did not influence efficacy outcomes or treatment response. Peginterferon beta-1a is effective in RRMS regardless of pretreatment IFN score.
Disclosure: Satish Eraly: I am an employee of Biogen and hold equity in the company
Damian Fiore: I am an employee of Biogen and hold equity in the company
Norm Allaire: I am an employee of Biogen and hold equity in the company
Huo Li: I am an employee of Biogen and hold equity in the company
Weihua Tang: I am an employee of Biogen and hold equity in the company
Yue Cui: I am an employee of Biogen and hold equity in the company
Diego Cadavid: I am an employee of Biogen and hold equity in the company
John Carulli: I am an employee of Biogen and hold equity in the company
Abstract: P1185
Type: Poster
Abstract Category: Therapy - disease modifying - Immunomodulation/Immunosuppression
Background: A gene expression signature associated with endogenous activation of the type I interferon (IFN) system has been observed in a number of autoimmune diseases including relapsing remitting multiple sclerosis (RRMS). It has been hypothesized that high pretreatment expression of IFN signature genes in RRMS patients may be associated with poor response to IFN-beta treatment on the basis that patients with activation of endogenous IFN pathways are less likely to respond to exogenous IFNs.
Objectives: To assess the relationship between pretreatment IFN signature and treatment outcomes in a 384 subject sub-study of ADVANCE, the pivotal trial of Peginterferon beta-1a efficacy in RRMS.
Methods: RNA was isolated from whole blood obtained from subjects at baseline (pretreatment), the relative expression of 20 IFN-induced genes was determined by quantitative PCR and normalized to a panel of 4 house-keeping genes, and a pretreatment IFN signature score was calculated for each subject as the geometric mean of the relative expression values of the 20 genes (which were all highly correlated with one another). The relationship between pretreatment IFN signature score and treatment outcomes at 48 weeks, including annualized relapse rate (ARR) and counts of Gd+ and/or new or newly enlarging T2 hyper-intense lesions, was assessed using negative binomial regression, adjusting for baseline age, disability, and relapse rate among other covariates.
Results: The beneficial effects of Peginterferon beta-1a on relapses and MRI lesions in this sub-study population were similar to those observed in ADVANCE as a whole. There was no association between pretreatment IFN score and on-treatment ARR among placebo-treated subjects (p=0.897). There was also no interaction between peginterferon beta-1a treatment and pretreatment IFN score with regard to the outcome of ARR regardless of dose (p=0.851 for placebo vs. every 2 weeks peginterferon treatment; p=0.497 for placebo vs. every 4 weeks peginterferon treatment). Similar lack of interaction was observed when testing against inflammatory MRI outcomes: Gd+ and new/newly enlarging T2 hyper-intense lesions.
Conclusions: In this large sub-study of a pivotal trial of Peginterferon beta-1a, pretreatment IFN score did not influence efficacy outcomes or treatment response. Peginterferon beta-1a is effective in RRMS regardless of pretreatment IFN score.
Disclosure: Satish Eraly: I am an employee of Biogen and hold equity in the company
Damian Fiore: I am an employee of Biogen and hold equity in the company
Norm Allaire: I am an employee of Biogen and hold equity in the company
Huo Li: I am an employee of Biogen and hold equity in the company
Weihua Tang: I am an employee of Biogen and hold equity in the company
Yue Cui: I am an employee of Biogen and hold equity in the company
Diego Cadavid: I am an employee of Biogen and hold equity in the company
John Carulli: I am an employee of Biogen and hold equity in the company