Contributions
Abstract: EP1421
Type: ePoster
Abstract Category: Pathology and pathogenesis of MS - Genetics /Epigenetics and Pharmacogenetics
Background: Copaxone (glatiramer acetate) has consistently demonstrated an annual relapse rate (ARR) reduction of ~30% compared with placebo, and a favorable safety profile, in clinical trials and in clinical practice for over two decades. On an individual level, patients show variable responses, some achieving significantly higher response rates. Involvement of genes with high inter-individual variability in Copaxone´s mechanism of action (MOA), e.g. HLA-DRB1*1501, as well as prior research, support potential contribution of genetics to level of response.
Objectives: To identify a genetic signature associated with relapse-based response to Copaxone.
Methods: DNA was collected from consenting RRMS patients in the discovery cohorts: FORTE [Copaxone 20mg or 40mg daily] and GALA [Copaxone 40mg TIW or placebo] studies. Non-prognostic, response-associated single-nucleotide polymorphisms (SNPs) were identified using the Illumina HumanOmni5-Quad array. Predictive modeling was then performed in the combined FORTE and GALA cohorts to develop a multi-SNP signature for "relapse free" response during the follow up period. The signature was subsequently assessed in consenting RRMS patients from five additional, independent Copaxone-treated cohorts and an Avonex-treated cohort (BRAVO study).
Results: A 4-SNP signature was identified as associated with Copaxone response. Copaxone-treated signature-positive patients demonstrated lower ARR as compared to signature-negative patients in GALA and FORTE (>50% reduction), as well as in the five confirmatory cohorts. Lower ARR was not observed in signature-positive Avonex-treated patients. The genetic association with Copaxone response was shown to be driven largely by a subset of patients, in whom ~10% of the overall patients were predicted as responders with specificity and sensitivity of 91% and 45%, respectively. The majority (55%-66%) of Copaxone responders cannot be identified by this genetic signature alone, indicating contribution of multiple factors to the clinical response to Copaxone.
Conclusions: Response to Copaxone is a multi-factorial trait. In a small subset of patients association was detected with genetic determinants involved in immunomodulatory and neurological pathways. These findings are consistent with the complex immunogenic MoA of the antigen Copaxone, in which a combination of multiple partially undefined factors contributes to the overall clinical phenotype.
Disclosure:
CR is affiliated with University of British Columbia and was contracted by Teva Pharmaceutical to perform analyses for this report.
FT, JS, and BZ performed analyses for this report and are employees of Immuneering Corporation which is partially owned by Teva Pharmaceutical Industries.
DL, MD, MT, VK, IG, and MRH performed analyses for this report and are employees of Teva Pharmaceutical Industries.
Abstract: EP1421
Type: ePoster
Abstract Category: Pathology and pathogenesis of MS - Genetics /Epigenetics and Pharmacogenetics
Background: Copaxone (glatiramer acetate) has consistently demonstrated an annual relapse rate (ARR) reduction of ~30% compared with placebo, and a favorable safety profile, in clinical trials and in clinical practice for over two decades. On an individual level, patients show variable responses, some achieving significantly higher response rates. Involvement of genes with high inter-individual variability in Copaxone´s mechanism of action (MOA), e.g. HLA-DRB1*1501, as well as prior research, support potential contribution of genetics to level of response.
Objectives: To identify a genetic signature associated with relapse-based response to Copaxone.
Methods: DNA was collected from consenting RRMS patients in the discovery cohorts: FORTE [Copaxone 20mg or 40mg daily] and GALA [Copaxone 40mg TIW or placebo] studies. Non-prognostic, response-associated single-nucleotide polymorphisms (SNPs) were identified using the Illumina HumanOmni5-Quad array. Predictive modeling was then performed in the combined FORTE and GALA cohorts to develop a multi-SNP signature for "relapse free" response during the follow up period. The signature was subsequently assessed in consenting RRMS patients from five additional, independent Copaxone-treated cohorts and an Avonex-treated cohort (BRAVO study).
Results: A 4-SNP signature was identified as associated with Copaxone response. Copaxone-treated signature-positive patients demonstrated lower ARR as compared to signature-negative patients in GALA and FORTE (>50% reduction), as well as in the five confirmatory cohorts. Lower ARR was not observed in signature-positive Avonex-treated patients. The genetic association with Copaxone response was shown to be driven largely by a subset of patients, in whom ~10% of the overall patients were predicted as responders with specificity and sensitivity of 91% and 45%, respectively. The majority (55%-66%) of Copaxone responders cannot be identified by this genetic signature alone, indicating contribution of multiple factors to the clinical response to Copaxone.
Conclusions: Response to Copaxone is a multi-factorial trait. In a small subset of patients association was detected with genetic determinants involved in immunomodulatory and neurological pathways. These findings are consistent with the complex immunogenic MoA of the antigen Copaxone, in which a combination of multiple partially undefined factors contributes to the overall clinical phenotype.
Disclosure:
CR is affiliated with University of British Columbia and was contracted by Teva Pharmaceutical to perform analyses for this report.
FT, JS, and BZ performed analyses for this report and are employees of Immuneering Corporation which is partially owned by Teva Pharmaceutical Industries.
DL, MD, MT, VK, IG, and MRH performed analyses for this report and are employees of Teva Pharmaceutical Industries.