Safety, Tolerability, Efficacy and Optimal Dose Finding Study of BAF312 in Patients With Relapsing-remitting Multiple Sclerosis

The purpose of this study is to determine the dose-response curve for the MRI-based efficacy
of BAF312 compared with placebo in patients with Relapsing-Remitting Multiple Sclerosis
(RRMS), and to characterize its safety and tolerability for the selection of an optimal dose
in a later phase III study.

Study Design Rationale An adaptive design was chosen to characterize the dose response curve
of BAF312. In a first period of study ("Period 1"), three doses of BAF312 and placebo are
tested for MRI efficacy. Based on an interim analysis (IA) after 3 months of treatment, two
additional active doses for period 2 have been selected , thus allowing to optimize the
overall determination of the dose response curve with 5 data points of active treatment, and
placebo. The doses are kept blinded. The use of Modeling and Simulation allows to establish
the full range and dynamics of the dose-response curve in silico, and hence the definition of
the optimal dose for later phase III studies.

The choice of placebo as treatment control is essential to obtain information on the specific
compared to non-specific effects of active treatment and provides the best way of evaluating
the efficacy and of assessing the true safety and tolerability profile of BAF312. Short-term
placebo exposure (6 (Period 1) or 3 (Period 2) months, respectively) is unlikely to lead to
longer term differences in outcomes [Polman, 2008]. The use of an adaptive design strategy
contributes to a significant reduction of placebo exposure, both in terms of the number of
patients and duration, as compared to conventional trial models.

Patients having completed the study within the protocol may be eligible for the Extension
Phase study where they receive long-term BAF312 treatment (a separate protocol).