Contributions
Abstract: P1166
Type: Poster
Abstract Category: Therapy - disease modifying - 26 Immunomodulation/Immunosuppression
Background: GLD52 (GZ402668) is a humanised anti-CD52 antibody that results in reduced proinflammatory cytokine release in vitro compared with alemtuzumab, which may translate to improved tolerability in patients.
Goal: Assess pharmacodynamic effects on innate and adaptive immune cells of ascending single intravenous (IV) and subcutaneous (SC) doses of GLD52 in patients with progressive MS.
Methods: A phase 1b, randomised, double-blind, placebo-controlled trial (NCT02282826; TDU13475) enrolled patients aged 18-65 years with progressive MS (PPMS, SPMS or progressive relapsing MS) in a single centre in Germany. Patients were randomised 3:1 to GLD52 or placebo within each of 4 IV and 3 SC cohorts. Patients randomised to GLD52 received single IV or SC doses of GLD52 with 4-week follow-up; successive cohorts received an increasing GLD52 dose, or a repeated dose level with differing route of administration (IV or SC) or pre-medication (ibuprofen or methylprednisolone). Secondary endpoints included pharmacodynamic effects on innate (plasmacytoid dendritic cells [pDCs] and natural killer [NK] cells) and adaptive immune cells (CD4+ and CD8+ T cells, CD4+ Treg cells and CD19+ B cells).
Results: 44 patients were randomised across all dose cohorts. Baseline characteristics were similar between IV and SC cohorts (Expanded Disability Status Scale score: 5.6 vs 5.6; female: 55% vs 50%), except median years since first diagnosis (17.0 vs 5.4). pDC counts remained stable following IV and SC GLD52 and were comparable to placebo. NK cell counts showed marked depletion following both SC and IV GLD52 versus placebo, but recovered by Day 10. CD4+, CD8+ and CD19+ lymphocyte counts decreased dose-dependently and more rapidly with IV versus SC administration. Mean counts were >90% lower than baseline at end of study in the 2 highest IV and SC dose cohorts. CD4+ Tregs as a percentage of CD4+ cells increased following both routes of administration.
Conclusion: Both IV and SC GLD52 induced robust, dose-dependent T- and B-lymphocyte depletion. NK cells were transiently depleted and recovered within 2 weeks, whereas pDCs were unaffected. Further studies will characterise cell repopulation and relationship to GLD52's mechanism of action.
Study support: Sanofi.
Disclosure:
DHM, NK-A, XL and SR: Employees of Sanofi.
AH, FNA and F-DW: Nothing to disclose.
Abstract: P1166
Type: Poster
Abstract Category: Therapy - disease modifying - 26 Immunomodulation/Immunosuppression
Background: GLD52 (GZ402668) is a humanised anti-CD52 antibody that results in reduced proinflammatory cytokine release in vitro compared with alemtuzumab, which may translate to improved tolerability in patients.
Goal: Assess pharmacodynamic effects on innate and adaptive immune cells of ascending single intravenous (IV) and subcutaneous (SC) doses of GLD52 in patients with progressive MS.
Methods: A phase 1b, randomised, double-blind, placebo-controlled trial (NCT02282826; TDU13475) enrolled patients aged 18-65 years with progressive MS (PPMS, SPMS or progressive relapsing MS) in a single centre in Germany. Patients were randomised 3:1 to GLD52 or placebo within each of 4 IV and 3 SC cohorts. Patients randomised to GLD52 received single IV or SC doses of GLD52 with 4-week follow-up; successive cohorts received an increasing GLD52 dose, or a repeated dose level with differing route of administration (IV or SC) or pre-medication (ibuprofen or methylprednisolone). Secondary endpoints included pharmacodynamic effects on innate (plasmacytoid dendritic cells [pDCs] and natural killer [NK] cells) and adaptive immune cells (CD4+ and CD8+ T cells, CD4+ Treg cells and CD19+ B cells).
Results: 44 patients were randomised across all dose cohorts. Baseline characteristics were similar between IV and SC cohorts (Expanded Disability Status Scale score: 5.6 vs 5.6; female: 55% vs 50%), except median years since first diagnosis (17.0 vs 5.4). pDC counts remained stable following IV and SC GLD52 and were comparable to placebo. NK cell counts showed marked depletion following both SC and IV GLD52 versus placebo, but recovered by Day 10. CD4+, CD8+ and CD19+ lymphocyte counts decreased dose-dependently and more rapidly with IV versus SC administration. Mean counts were >90% lower than baseline at end of study in the 2 highest IV and SC dose cohorts. CD4+ Tregs as a percentage of CD4+ cells increased following both routes of administration.
Conclusion: Both IV and SC GLD52 induced robust, dose-dependent T- and B-lymphocyte depletion. NK cells were transiently depleted and recovered within 2 weeks, whereas pDCs were unaffected. Further studies will characterise cell repopulation and relationship to GLD52's mechanism of action.
Study support: Sanofi.
Disclosure:
DHM, NK-A, XL and SR: Employees of Sanofi.
AH, FNA and F-DW: Nothing to disclose.