Dose Titration Regimen Attenuates Bradyarrhythymic Events with BAF312 during Treatment Initiation (P01.131)

Abstract

Objective: To report effects of BAF312 dose titration on cardiac conduction during treatment initiation in a phase II double-blind, randomised, placebo-controlled study in patients with multiple sclerosis (RRMS). Background A previous study in healthy volunteers indicated that dose titration during treatment initiation can reduce the bradyarrhythymic events typically seen with sphingosine-1-phosphate receptor modulators. 1 Design/Methods: Patients were randomised to two sequential cohorts: Cohort 1 (n=188), once-daily BAF312 0.5mg, 2mg, 10mg, or placebo for 6mos; Cohort 2 (n=109), 0.25mg, 1.25mg or placebo for 3mos. Dose titration was not used in Cohort 1. Patients completing the core study were eligible to participate in an extension study. Following a protocol amendment, all patients in Cohort 2 and the extension study had an initial 10 day dose titration during which, enhanced cardiac monitoring was implemented. Results: Cohort 1: on Day 1, a dose-dependent reduction in mean heart rate was observed and five transient symptomatic 2 nd degree atrioventricular blocks (AVBs) were reported (five patients: three receiving 2mg, two receiving 10mg); two patients received medication for the events, all events resolved within 24 hours. Thirteen asymptomatic events of 2 nd degree AVBs were observed in twelve patients (0.5mg – 2; 2mg – 4; 10mg – 4; placebo – 2 patients, respectively) on 24-hour ambulatory ECGs during the first week of treatment. Cohort 2 and extension: the reduction in mean heart rate was less pronounced with the dose titration regimen. No symptomatic 2 nd degree AVBs were observed. Two patients on placebo and one patient on 2mg experienced asymptomatic 2 nd degree AVBs; all events occurred during the sleeping hours. No episodes of syncope, Mobitz Type II or third degree heart block occurred during the study. Conclusions: In patients with RRMS, a dose-titration regimen with BAF312 attenuates bradyarrhthymic events during treatment initiation, confirming previous observations in healthy subjects. 1 References 1 Legangneux et al. AAN 2011. Supported by: Novartis-sponsored. Disclosure: Dr. DiMarco has received personal compensation for activities with Sanofi, Astellas, Novartis, Medtronic, St. Jude, Tau Therapeutics, Sequel, and Biotronik as a consultant.Dr. DiMarco has received personal compensation in an editorial capacity for Elsevier.Dr. DiMarco has received research support from Boston Scientific. Dr. Selmaj has received personal compensation for activities with Genzyme, Ono, and Biogen Idec. Dr. Kappos has received research support from Acorda Therapeutics, Actelion, Allozyne, BaroFold, Inc., Bayer Pharmaceuticals Corporation, Bayhill Therapeutics, Biogen Idec, Boehringer Ingelheim Pharmaceuticals, Inc, Elan Corporation, Genmab, GlaxoSmithKline, Inc., Glenmark Pharma, Merck Serono, MediciNova, Novartis, Sanofi-Aventis Pharmaceuticals, Santhera Pharmaceuticals, Shire, Roche Diagnostics, Teva Neuroscience, UCB Pharma, Pfizer Inc, Swiss MS Society, Swiss National Research Foundation, European Union, Gianni Rubatto Foundation, Novartis and Roche Research Foundations. Dr. Jordaan has received personal compensation for activities with Novartis. Dr. Mendzelevski has received personal compensation for activities with Novartis, Teva, Galderma, Astex Pharmaceuticals, MediWould, Mersana Therapeutics, Nabriva Therapeutics, and Xention. Dr. Goncalves has received personal compensation for activities with Novartis as an employee. Dr. Zhang-Auberson has received personal compensation for activities with Novartis as an employee.