2017 - Budapest - Hungary

PAGE 2017: Benefit-Risk assessment
Nadia Terranova

Simulation analysis of absolute lymphocytes counts (ALC) and relapse rate (RR) following cladribine (re-)treatment rules in subjects with relapsing-remitting multiple sclerosis (RRMS)

Nadia Terranova (1), Christine Hicking (2), Fernando Dangond (3), Alain Munafo (1)

(1) Quantitative Pharmacology, Merck Institute for Pharmacometrics, Lausanne, Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany;(2) Global BioStatistics, Merck KGaA, Darmstadt, Germany;(3) Global Clinical Development NDD, Fertility and Endocrinology, EMD Serono, Billerica, MA.

Objectives: Cladribine’s mechanism of action in RRMS involves lymphocytes. Treatment guidelines aimed at decreasing the risk of developing severe sustained lymphopenia following cladribine treatment have been developed. They imply modifications of the nominal dosing regimen based on ALC monitoring prior to the 2nd year treatment. A Clinical Trial Simulation (CTS) analysis [1] was performed to investigate the impact of such treatment rules on the occurrence of qualifying relapses.

Methods: The simulation analysis involved models and results from previously performed ALC dynamics and RR modeling. A virtual population treated with cladribine tablets total cumulative dose of 3.5 mg/kg was first generated by considering patients of a cladribine Phase 3 trial (CLARITY) as target population [2].

Alternative guidelines allowing postponements of cladribine treatment in Year 2 for up to 9 months, to allow for ALC recovery to Grade 0 or 1 before retreating, were then investigated. For each (re-)treatment scenario, lymphocyte dynamics were simulated at the patient level by allowing postponements according to the defined rules. Resulting individual dosing regimens were then used to obtain corresponding RR dynamics for each virtual patient.

The R package mlxR 2.2.0 was employed for simulations, with models encoded in MLXTRAN.

Results: The simulation workflow was validated with a virtual population of 5000 subjects [3]. Specifically, percentages of subjects with lymphopenia grades, as well as the probability of being relapse-free in the virtual population, well reproduced those observed in the target population.

Results showed that i) only very few subjects (≤1%) would not recover to Grade 0 or 1 with postponements up to 6 months, ii) in those subjects qualifying for postponement, the proportion not experiencing Grade ≥3 lymphopenia at any time during Year 2 was increased (from 15% to 24%) when the mitigation rule was applied, and iii) such a delay of up to 6 months had essentially no effect on the probability of experiencing (1 to 6) relapses during Year 2 of cladribine treatment. This suggests that the efficacy of cladribine could be sustained if its administration needs to be interrupted to allow resolution of lymphopenia.

Conclusions: This CTS analysis supported the risk minimization measure of (re-)treatment guidelines to manage severe lymphopenia, while preserving cladribine tablets efficacy on the considered clinical endpoint.

[1] Holford, N., Ma, S. C., & Ploeger, B. A. Clinical trial simulation: a review. Clinical Pharmacology & Therapeutics (2010) 88(2), 166-182.
[2] Giovannoni, G., Comi, G., Cook, S., Rammohan, K., Rieckmann, P., Sørensen, P. S., ... & Greenberg, S. J. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. New England Journal of Medicine (2010) 362(5), 416-426.  
[3] Tannenbaum, S. J., Holford, N. H., Lee, H., Peck, C. C., & Mould, D. R. Simulation of correlated continuous and categorical variables using a single multivariate distribution. Journal of pharmacokinetics and pharmacodynamics (2006) 33(6): 773-794.

Reference: PAGE 26 (2017) Abstr 7326 [www.page-meeting.org/?abstract=7326]
Oral: Benefit-Risk assessment
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