A Phase III, randomized, double-blind, placebo-controlled, parallel-group, multicenter efficacy and safety study of Gantenerumab in patients with Mild Alzheimer*s disease; part II: open-label extension for participating patients

The clinical benefit of an anti-amyloid therapy is expected to be most
beneficial early in the disease course when brain amyloid is still accumulating
and subsequent neuronal damage may not have progressed significantlyAs
described in Section 1.3.2, clinical data supporting the use of gantenerumab in
AD come from the analysis of the NN19866 PET study that demonstrated a robust
biologic effect in the brain. In this study, brain amyloid was decreased in a
dose-dependent manner in patients with mild to moderate AD who received doses
of gantenerumab IV (200 mg or 60 mg) every 4 weeks (q4w) compared with placebo
(Ostrowitzki et al. 2012). The purpose of Study WN28745 is to establish the
efficacy and safety of gantenerumab as a disease-modifying treatment in
patients with mild AD who may or may not be treated concurrently with approved
treatments for AD.

Part 2:On the basis of results of the WN25203 study and the PRIME study, the
doses of 105 and 225 mg gantenerumab can now be considered to be
sub-therapeutic. Therefore, the double-blind period of the study (part 1) will
be suspended and replaced by the OLE (part 2) with increased dose up to 1200
mg.

The primary efficacy objective for this study was to evaluate the efficacy of
gantenerumab compared with placebo administered to patients by subcutaneous
(SC) injection over 100 weeks as measured by the following co-primary endpoints
(final outcome assessment 4 weeks after the final dose):
* Cognition, as measured by the ADAS-Cog (13-item)
* Function, as assessed by ADCS-ADL

Secondary objectives:
Evaluate the efficacy, safety, tolerability of Gantenerumab versus placebo
administered as subcutaneous injections.

Part 2:
The main objective of the 2-year OLE is to evaluate the safety and tolerability
of gantenerumab at higher doses focusing on physical and neurologic
examinations, vital signs, blood safety tests, ECGs, and adverse event
monitoring. All patients previously enrolled and ongoing in the study will be
eligible to receive active gantenerumab and will be up-titrated gradually to
the highest possible dose up to 1200 mg.

The secondary objectives will include the following:
* To evaluate the effect of higher doses of gantenerumab on imaging biomarkers
(PET and MRI) on CSF biomarkers and on clinical outcome measures (cognition and
function) over time
* To explore pharmacokinetics at the higher gantenerumab doses

Study WN28745 is a Phase III, multicenter, randomized, double-blind,
placebo-controlled, parallel group study to evaluate the efficacy and safety of
gantenerumab in patients with mild AD. Patients with mild AD will be selected
on the basis of clinical diagnosis of probable mild AD according to the
National Institute of Neurological and Communicative Disorders and Stroke/
Alzheimer*s Disease and Related Disorders Association (NINCDS/ADRDA) criteria
or probable major neurocognitive disorder (NCD) due to AD-mild severity using
the Diagnostic and Statistical Manual of Mental Disorders, Version 5 (DSM-5)
criteria, and biomarker evidence for increased amyloid burden. Approximately
175 centers will participate.

Part 2:
All patients (approximately 350 patients) who are actively enrolled in Study
WN28745 (i.e., not discontinued from study drug) will be invited to participate
in the OLE study. Patients will receive open-label gantenerumab up to1200 mg by
SC injection q4w for up to a maximum of
100 weeks (26 doses). Patients will also have follow-up visits at 4, 16 and 52
weeks after the final dose for safety and limited efficacy.

In addition to the initial 2 years in OLE, patients will be given the option to
continue receiving open label gantenerumab treatment until the end of 2020, at
which time anticipated results from other relevant monoclonal antibody
treatments will be available. Patients who discontinue study drug at any time
during OLE, or who complete the first 2 years of OLE only will be asked to
complete follow up visits at 4 and 16 weeks from their last dose (Follow Up 1
and 2, respectively).

Test Product
Gantenerumab will be administered via subcutaneous injection to all subjects
randomized to active, regardless of ApoE genotype, at a dose of 225 mg every 4
weeks for up to a total of 20 doses. Injections will be administered as one
1-mL SC injection to the abdomen.

Comparator
Placebo of similar physical characteristics and identical volume to
gantenerumab will be administered via subcutaneous injection to all subjects
randomized to placebo with the same frequency and administration.

Part 2: Patients participating in Part 2 will receive open-label gantenerumab
administered as SC injections to the abdomen every q4w either as one or
multiple injections from a PFS or extracted from a vial and administered either
by a syringe (300 mg) or a syringe pump (for 450 mg doses and higher).Starting
dose will be 225mg up to 600 mg dependent of ApoE4 genotype and dosage received
durig part 1 of the trial. Dosage will increase over time up to 1200 mg.

Subjects may have side effects from the drugs or procedures used in this
study. Side effects can vary from mild to very serious and may vary from
person to person. Everyone taking part in the study will be watched carefully
for any side effects. However, Roche, the study doctor, and other doctors do
not know all of the side effects that could occur.