Li Zhang (1), Vanaja Kanamaluru (1), Qiang Lu (1)
(1) Sanofi, Bridgewater, NJ, US
Objectives : GLD52 (GZ402668) is a humanized IgG1 monoclonal antibody that binds to human cluster of differentiation 52 (CD52) and induces lymphocyte depletion through antibody dependent cellular cytolysis (ADCC) and complement-dependent cytolysis (CDC)1. This analysis aimed to: 1) develop a mechanism-based population PK/PD (Pop PK/PD) model to quantitatively describe the time profile of T lymphocytes depletion and repopulation in progressive multiple sclerosis (MS) patients follow GLD52 treatment; and 2) assess exposure-response (E-R) relationship in support of GLD52 dose selection for Phase 3 studies.
Methods : The Pop PK/PD model was developed based upon GLD52 serum concentration and total T lymphocytes from 33 patients with progressive MS from a Phase 1, first-in-human, ascending single intravenous (IV) and subcutaneous (SC) dose study (NCT02282826). The time course of GLD52 E-R relationship was described by a mechanism-based Pop PK/PD model with direct and indirect treatment effect on T lymphocytes dynamics (depletion and repopulation). The validation of the final model was performed using visual predictive checks. Clinical trial simulation (CTS) was conducted using the Pop PK/PD model to predict the extent of T lymphocytes depletion to support the selection of dose for Phase 3 studies.
Results : GLD52 elicited rapid and dose-dependent T lymphocytes depletion in the first month followed by slow repopulation. The median T lymphocytes decreased > 90% from baseline to Month 1 in the highest IV cohort and 2 highest SC dose cohorts. Lower dose showed incomplete depletion and earlier recovery of T lymphocytes. The PK of GLD52 was best described by a 2-compartment model with first order absorption and linear elimination, with typical clearance and steady-state volume of distribution of 0.66 L/day and 8.96 L, respectively. The depletion of T lymphocytes was directly stimulated by GLD52 systemic concentration with an Emax function to mimic the GLD52-elicited T lymphocytes lysis via either ADCC or CDC. The migration of T lymphocytes into circulating blood was indirectly inhibited by GLD52 via proportional suppression. Moreover, a feedback regulation was added to mimic the slow repopulation of T lymphocytes in progressive MS patients after GLD52 treatment. T lymphocytes migration time was estimated as 2.44 days, which was within the literature reported time window of lymphocytes trafficking in humans2. CTS revealed that full treatment courses with the highest SC dose would result in T lymphocytes depletion that was similar in extent to those observed for another anti-CD52 monoclonal antibody alemtuzumab in MS patients.
Conclusion: The time course of depletion and repopulation of T lymphocytes following GLD52 treatment in progressive MS patients was successfully characterized by a mechanism-based Pop PK/PD model. Full treatment courses of GLD52 administered by SC injection were predicted to elicit T lymphocytes depletion comparable to alemtuzumab in MS patients.
References:
[1] Margolin DH, Karimi-Anderesi N, Chirieac M, Frosio C, Luo X, Hueser A, Albach F, Wagner FD. Safety, tolerability, and pharmacodynamics of intravenous and subcutaneous doses of the anti-CD52 antibody GLD52 in patients with progressive MS: a randomized, controlled, single ascending dose trial. Neurology (2017) 88 : P5.375.
[2] Mager DE, Lin SX, Blum RA, Lates CD and Jusko WJ. Dose equivalency evaluation of major corticosteroids : Pharmacokinetics and cell trafficking and cortisol dynamics. J Clin Pharmacol (2003) 43: 1216.
Reference: PAGE 27 (2018) Abstr 8764 [www.page-meeting.org/?abstract=8764]
Poster: Drug/Disease Modelling - Other Topics