Contributions
Abstract: P682
Type: Poster
Abstract Category: Therapy - disease modifying - 26 Immunomodulation/Immunosuppression
Background: GLD52 (GZ402668) is a humanised anti-CD52 antibody resulting in reduced proinflammatory cytokine release in vitro compared with alemtuzumab, which may translate to reduced infusion-related adverse events (AEs) in patients (pts).
Goal: Assess safety, tolerability and pharmacodynamics of ascending single intravenous (IV) and subcutaneous (SC) doses of GLD52 in pts with progressive MS.
Methods: Phase 1b, randomised, double-blind, placebo-controlled, single-centre, German trial (NCT02282826) enrolled pts aged 18-65 years with PPMS, SPMS, or progressive-relapsing MS. Pts were randomised 3:1 to GLD52 or placebo within each of 4 IV and 3 SC cohorts. Pts randomised to GLD52 received single IV or SC doses of GLD52 with 4-week follow-up. Successive cohorts received an increasing GLD52 dose, or repeated a dose level with differing administration route or premedication (ibuprofen or methylprednisolone). Primary endpoint was AE incidence. Secondary endpoints included T- and B-lymphocyte counts.
Results: 44 pts were randomised across all dose cohorts. Baseline characteristics were similar for IV and SC cohorts (EDSS score: 5.6 vs 5.6; female: 55% vs 50%), except median years since first diagnosis (17.0 vs 5.4). AEs occurred in 93% of IV GLD52 and 80% of IV placebo pts, and 100% of pts treated with SC GLD52 or SC placebo. No AEs with GLD52 were severe or serious, with no Grade 3 or higher AEs reported. Infusion-related reactions occurred in 80% of IV GLD52 pts (placebo: 60%). Administration-associated reactions occurred in 89% of SC GLD52 pts (83% with local skin reactions) vs 83% of placebo pts. Mean T- and B-lymphocyte counts decreased >90% from baseline to end of study in the highest GLD52 IV dose cohort and 2 highest GLD52 SC dose cohorts. Lymphocytes depleted more rapidly with IV (6 hours) vs SC (12-24 hours) GLD52 administration. CD4+ Tregs as a percentage of CD4+ cells increased following GLD52 dosing via both routes of administration. Extent of T- and B-lymphocyte depletion and Treg increase were dose-dependent.
Conclusion: Both IV and SC GLD52 induced robust, dose-dependent T- and B-lymphocyte depletion. Most AEs with GLD52 were mild infusion/administration-related reactions. The absence of severe/serious infusion/administration-related AEs with or without steroid premedication is consistent with improved tolerability potential. Further studies will characterise lymphocyte repopulation and the potential of GLD52 to rebalance the immune system.
Study support: Sanofi.
Disclosure:
DHM, NK-A, MC, XL, and SR: Employees of Sanofi.
AH, FNA, and F-DW: Nothing to disclose.
Abstract: P682
Type: Poster
Abstract Category: Therapy - disease modifying - 26 Immunomodulation/Immunosuppression
Background: GLD52 (GZ402668) is a humanised anti-CD52 antibody resulting in reduced proinflammatory cytokine release in vitro compared with alemtuzumab, which may translate to reduced infusion-related adverse events (AEs) in patients (pts).
Goal: Assess safety, tolerability and pharmacodynamics of ascending single intravenous (IV) and subcutaneous (SC) doses of GLD52 in pts with progressive MS.
Methods: Phase 1b, randomised, double-blind, placebo-controlled, single-centre, German trial (NCT02282826) enrolled pts aged 18-65 years with PPMS, SPMS, or progressive-relapsing MS. Pts were randomised 3:1 to GLD52 or placebo within each of 4 IV and 3 SC cohorts. Pts randomised to GLD52 received single IV or SC doses of GLD52 with 4-week follow-up. Successive cohorts received an increasing GLD52 dose, or repeated a dose level with differing administration route or premedication (ibuprofen or methylprednisolone). Primary endpoint was AE incidence. Secondary endpoints included T- and B-lymphocyte counts.
Results: 44 pts were randomised across all dose cohorts. Baseline characteristics were similar for IV and SC cohorts (EDSS score: 5.6 vs 5.6; female: 55% vs 50%), except median years since first diagnosis (17.0 vs 5.4). AEs occurred in 93% of IV GLD52 and 80% of IV placebo pts, and 100% of pts treated with SC GLD52 or SC placebo. No AEs with GLD52 were severe or serious, with no Grade 3 or higher AEs reported. Infusion-related reactions occurred in 80% of IV GLD52 pts (placebo: 60%). Administration-associated reactions occurred in 89% of SC GLD52 pts (83% with local skin reactions) vs 83% of placebo pts. Mean T- and B-lymphocyte counts decreased >90% from baseline to end of study in the highest GLD52 IV dose cohort and 2 highest GLD52 SC dose cohorts. Lymphocytes depleted more rapidly with IV (6 hours) vs SC (12-24 hours) GLD52 administration. CD4+ Tregs as a percentage of CD4+ cells increased following GLD52 dosing via both routes of administration. Extent of T- and B-lymphocyte depletion and Treg increase were dose-dependent.
Conclusion: Both IV and SC GLD52 induced robust, dose-dependent T- and B-lymphocyte depletion. Most AEs with GLD52 were mild infusion/administration-related reactions. The absence of severe/serious infusion/administration-related AEs with or without steroid premedication is consistent with improved tolerability potential. Further studies will characterise lymphocyte repopulation and the potential of GLD52 to rebalance the immune system.
Study support: Sanofi.
Disclosure:
DHM, NK-A, MC, XL, and SR: Employees of Sanofi.
AH, FNA, and F-DW: Nothing to disclose.