Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Two Year Study to Evaluate the Effect of Subcutaneous RO4909832 on Cognition and Function in Prodromal Alzheimer's Disease with Option for up to an Additional Two Years of Treatment and up to Three Years of an Open-Label Extension with Active Study Treatment

RO4909832 (Mab31) is a human antibody directed against the amyloid plaques
present in the brains of people with Alzheimer's disease. The deposition of
amyloid in the brains plays an important role in the pathogenesis of this
disease. Animal Models of passive immunization with anti-amyloid antibodies
showed a decrease in amyloidosis and show improvement of cognitive functions.
There is a great need to improve the treatment of Alzheimer's disease,
especially for drugs that affect the course of the disease. Passive
immunization with anti-amyloid antibodies, could improve the treatment of
Alzheimer's disease. This study is an early stage of Alzheimer's disease
(prodromal) investigating the effect of RO4909832. By decreasing amyloid amount
in an early stage of the disease, it is assumed that less damage is done. PET
scan data from the Phase 1 study (MAD study) raise the suggestion that an
amyloid-reducing effect of gantenerumab occurs during the period of 6 months at
doses of 60 and 200 mg IV.

Dosing in the double-blind placebo-controlled Parts 1 and 2 with the originally
selected doses for Study WN25203 (105 and 225 mg) was suspended on 19 December
2014, following a planned interim futility analysis that estimated a low
probability for meeting the prespecified primary outcome measure.
Additional analyses indicated that higher doses of gantenerumab may potentially
have clinically relevant effects on cognition and function.

To assess short-term and long-term safety and tolerability of gantenerumab
(RO4909832) given at doses up to 1200
mg subcutaneous (SC) every 4 weeks (Q4W).

Secondary Objective of the Open-label extension:
- To evaluate of the effect of 1200 mg gantenerumab SC Q4W over time on
hippocampal volume, whole brain volume, ventricular enlargement,
and possibly other volumetric measures of the brain.
- To evaluate of the effect of 1200 mg gantenerumab SC Q4W on changes in
amyloid load over time by Positron Emission Tomography
(PET) Imaging using Florbetapir 18F , an amyloid PET ligand
- To evaluate the effect of 1200 mg gantenerumab SC Q4W over time on clinical
outcomes (cognition and function), as assessed with the CDRSOB, the ADAS-Cog,
the MMSE, the FCSRT-IR, the CDR global score, the FAQ, and to determine the
presence of and time to onset of dementia. After 3 years in part 3, only MMSE
will be administered.
- To explore pharmacokinetics by determining the relationship of plasma
concentrations of gantenerumab on other responses
- To assess incidence of antigantenerumab antibodies, and if relevant, evaluate
its effect on the pharmacokinetic, pharmacodynamic, efficacy
and safety parameters

This is an multicenter open-label extension study (part 3 of study WN25203)
with active study treatment.
During Part 3 study, subjects will receive gantenerumab Q4W that will be
uptitrated starting from 105 or 225 mg based on the ApoE genotype to up to 1200
mg to reach the doses expected to give clinically meaningful effect in a less
than 1 year.

All subjects participating in the open-label extension (Part 3) will receive
1200 mg gantenerumab Q4W. Dosing will be started at 105 or 225 mg based on the
ApoE genotype. Dose will be uptitrated up to 1200 mg.

For more information, please see the answer on question number E9.