A PHASE III, MULTICENTER, RANDOMIZED, PARALLEL-GROUP, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO EVALUATE THE EFFICACY AND SAFETY OF GANTENERUMAB IN PARTICIPANTS AT RISK FOR OR AT THE EARLIEST STAGES OF ALZHEIMER*S DISEASE

Alzheimer*s disease, a debilitating and progressive neurodegenerative disease,
represents a significant unmet medical need with no fully approved therapeutics
to halt, slow, or prevent the onset of symptoms. The currently available
treatment options primarily include symptomatic
medications and are only approved for the overtly symptomatic stages of AD. The
amyloid hypothesis postulates that amyloid may be an early, key driver of AD
pathophysiology. If this hypothesis is true, then early intervention at the
amyloid-positive, cognitively unimpaired stage (i.e., at-risk stage of
disease), may result in a high efficacy potential for an anti-amyloid antibody
(i.e., gantenerumab), to slow the disease process and
preserve the cognitive and functional abilities of affected individuals. This
is the main hypothesis Study WN42444 (SKYLINE) aims to test.

The primary objective of this secondary prevention study is to evaluate the
efficacy, safety, pharmacodynamics, and pharmacokinetics of gantenerumab, an
anti-amyloid antibody, in amyloid-positive, cognitively unimpaired participants
at risk for or at the earliest stages of
Alzheimer*s disease (AD).

Study WN42444 is a 4-year and 9-month phase III multicenter, randomized,
double-blind, placebo-controlled, parallel group study.
Eligible participants will be randomized in a 1:1 ratio to receive either
gantenerumab or placebo.
If, in the course of the study, a participant progresses to a clinical
diagnosis of mild cognitive impairment (MCI) or dementia due to AD, a *post-
progression dose escalation* period will commence.
During the post-progression dose escalation period, participants who were
randomized to placebo will switch to gantenerumab in a double-blinded manner.
Participants who were randomized to gantenerumab will continue with
gantenerumab (255 mg SC every 1 week [Q1W] or 510 mg SC
every 2 weeks [Q2W]).
All participants who progress to a clinical diagnosis of MCI or dementia due to
AD must comply with all aspects of the post-progression dose escalation
schedules of activities.

The study treatment duration is 211 weeks regardless of the dosing regimen
(i.e., Q1W or Q2W) or whether a participant progresses to a clinical diagnosis
of MCI or dementia due to AD.
The primary comparison for efficacy will be between the following arms:
- Experimental arm: participants randomized to gantenerumab at the beginning of
the study
- Control arm: participants randomized to placebo at the beginning of the
study, irrespective of whether they progressed during the study and thus,
started gantenerumab

The treatment period consists of a dose escalation period and a study dose
period.
Dose escalation (approximately 9 months):
During dose escalation (approximately 9 months), the subject receives
increasing amounts of gantenerumab (group 1) or placebo (group 2).
* Step 1: One injection of 0.8 ml (120 mg gantenerumab or placebo) every 4
weeks for 3 months thereafter
* Step 2: One injection of 1.7 ml (255 mg gantenerumab or placebo) every 4
weeks for 3 months thereafter
then
* Step 3:
1. Two injections of 1.7 ml (510 mg gantenerumab or placebo) every 4 weeks
OR
2. One injection of 1.7 ml (255 mg gantenerumab or placebo) every 2 weeks for 3
months based on your choice thereafter
* Step 4:
1. Two injections of 1.7 ml (510 mg gantenerumab or placebo) every 2 weeks
OR
2. One injection of 1.7 ml (255 mg gantenerumab or placebo) every other week
until the end of the treatment period based on your choice

During the maintenance dose period (approximately 3 years and 3 months), the
injection of the study compound is done once a week or once every 2 weeks,
depending on the dosing regimen chosen by the subject.

If progression:
The subject will receive gantenerumab anyway. A new dose escalation period of 9
months is completed; QW or Q2W according to schedule.
The dose escalation after progression is followed by a maintenance dose with
the target dose and will not extend the total time in the treatment period
(approximately 4 years).

Known Side Effects of Gantenerumab
* Brain microbleeds detected on MRI scans.
* Brain microbleeds can occur spontaneously and are sometimes seen in people
who did not receive gantenerumab or similar drugs. Brain microbleeds are
expected to occur more frequently in people who have a certain type of *APOE*
gene.
* Brain swelling detected on MRI scans
* The vast majority of patients who developed brain swelling while being
treated with gantenerumab reported no symptoms, and the swelling resolved
spontaneously when the study drug was withheld. In a few cases, patients
developed symptoms, which were of mild intensity (for example, headache) and
sometimes serious (for example, confusion or seizure/epilepsy). Brain swelling
is expected to occur more frequently in people who have a certain type of
*APOE* gene.
* Injection site reactions; Injection-site reactions are non-serious, largely
mild to moderate in severity, and self-resolving. Potential Side Effects
* Injection-related or allergic reaction with symptoms such as fever, chills,
low blood pressure, rash, headache, nausea, or vomiting.
* Immune system might develop antibodies to the study drug

An iDMC will evaluate safety data on a regular basis from Study WN42444 in an
unblinded fashion, including the incidence, severity, and nature of adverse
events, serious adverse events, ARIA-E and ARIA-H, ISRs, adverse events of
special interest, ECGs, laboratory abnormalities, and the Mini Mental State
Examination (MMSE).

Based on the available information, no interactions between gantenerumab and
the COVID-19 vaccines are expected to occur, and no other safety concerns have
been identified that would prohibit the vaccination of participants enrolled in
the studies where gantenerumab is being
investigated for the treatment of Alzheimer*s disease. COVID-19 vaccins will be
considered as co-medication

The adverse reactions associated with florbetaben are indicated on the SmPC
(Eu).

There are potential risks associated with the study related assessment /
procedures, as described in the ICF.