A Phase 2b/3 Randomized, Double-blind, Placebo-Controlled, Parallel Group, Multicenter
Study Investigating the Efficacy and Safety of JNJ-54861911 in Subjects who are
Asymptomatic At Risk for Developing Alzheimer*s Dementia

Alzheimer*s disease (AD) is a fatal neurodegenerative disease that is
manifested by progressive cognitive deficits and memory loss, as well as by
behavioral problems such as anxiety. With the increasing number of elderly in
the population, AD is a growing medical concern. No treatment
is currently available that targets the underlying cause of these symptoms.

The hallmark pathologic features of AD are neurofibrillary tangles, which
consist of hyperphosphorylated tau protein and amyloid plaques, whose main
constituent is amyloid-beta (Aβ). In amyloid plaques, Aβ1-42 peptide is
overrepresented relative to other forms of Aβ
(eg, Aβ1-40). Aβ1-42 has a high tendency to aggregate, forming oligomers and
fibrils as well as amyloid plaques. The oligomers and fibrils of Aβ formed
immediately after amyloid precursor protein (APP) cleavage have been
demonstrated to be neurotoxic. Aβ accumulation and
amyloid deposition are thought to be early, potentially initiating events in
the pathogenesis of AD, formulated as the amyloid cascade hypothesis.

Convergent data from positron emission tomography (PET) amyloid imaging and
cerebrospinal fluid (CSF) markers in both genetic and sporadic forms of AD
suggest that the pathophysiological process begins many years prior to the
onset of dementia. The accumulation of Aβ in particular is thought to be a very
early event that may trigger and accelerate neurodegeneration and lead to
cognitive decline. Thus, very early intervention with an anti-amyloid agent may
hold the greatest promise for slowing the inexorable disease progression of AD.

Agents that prevent the formation of Aβ overall, or Aβ1-42 specifically, have
been proposed as potentially disease-modifying agents for the treatment of AD.
Aβ is generated from the APP as mentioned above. The N-terminus of Aβ is
cleaved by the β-site amyloid precursor protein
cleaving enzyme 1 (BACE-1), and then γ-secretase cleaves the C-terminal end.
BACE-1 cleavage is the first and rate-limiting step. As such, it is
hypothesized that BACE-1 inhibition can reduce the production of toxic amyloid
forms and impact the progression of AD. The observed correlation between the
catalytic efficiency of BACE-1 for its substrate APP and the occurrence of AD
supports this hypothesis. The Swedish APP mutant (KM670/671NL), which is a more
efficient substrate for BACE-1 (±10x), causes a rare familial form of AD that
is inherited
in a dominant Mendelian fashion. At the other end of the spectrum, an allelic
variant of APP (A673T), which is a less efficient substrate for BACE-1 (±
0.5x), is protective against sporadic AD in the wider population.

JNJ-54861911 is an orally administered BACE inhibitor (BACEi) being developed
for the treatment of AD. JNJ-54861911 reduces production of Aβ fragments by
inhibiting BACE-1 processing of APP, with the aim of reducing amyloid plaque
formation.

Primary Objective:
The primary objective of this study is to determine whether treatment with
JNJ-54861911 slows cognitive decline compared with placebo treatment, as
measured by a composite cognitive measure, the Preclinical Alzheimer Cognitive
Composite (PACC), in amyloid-positive subjects who are asymptomatic at risk for
developing Alzheimer*s dementia.

Secondary Objectives:
- Change from Baseline in Cognitive Function Index (CFI) to Month 54
- Change from Baseline in Alzheimer*s Disease Cooperative Study Activities of
Daily Living - Prevention Instrument (ADCS-ADL-PI) Total Score to Month 54
- Change from Baseline in Repeatable Battery for the Assessment of
Neuropsychological Status (RBANS) Total Scale Score to Month 51
- Change from Baseline in Clinical dementia Rating Sum of Boxes (CDR-SB) Score
to Month 54
- Change from Baseline in Neuropsychological Assessment Battery Daily Living
Tests (NAB-DLTs) Score to Month 54
- Number of participants with Adverse Events (AEs) and Serious Adverse Events
(SAEs)
- Trough Plasma Concentration (Ctrough) of JNJ54861911
- Area Under the Plasma Concentration Time Curve from 0 to tau Hours After
Dosing (ACUCtau)
- Change in mean Cerebral Fibrillar Amyloid Accumulation
- Change from Baseline of Neurodegeneration by Assessing Changes in imaging
Biomarkers

This is a multicenter, double-blind, placebo-controlled, randomized,
parallel-group study assessing the efficacy and safety of JNJ-54861911 over
approximately 4.5 years of treatment in subjects (60 to 85 years of age) who
are asymptomatic and at risk for developing Alzheimer*s dementia due to
evidence of elevated amyloid accumulation based on CSF or amyloid PET imaging.
The study will be conducted in an outpatient setting, with a planned
recruitment of approximately 1,650 randomized subjects (550 per treatment
group). It is planned that a total of 1,155 subjects (38 5per group) will
complete the Month 54 (Year 4.5) assessments, assuming a 30% attrition rate.
The number of subjects randomized can be increased based on blinded sample size
re-estimation, but the study enrollement will be capped at 2400 subjects. Some
design elements of this Phase 2b/3 study can be modified during the study based
on emerging external data. The potential changes include optimization of the
primary endpoint and the timing of the primary analysis. Sample size may be
adjusted using blinded aggregated study data. Unblinded interim analyses (IAs)
may be performed to assess futility.

The study will consist of 3 phases: a screening phase of approximately 90 days
in which subject eligibility will be assessed; a double-blind treatment phase
during which eligible subjects will receive a fixed dose of randomly assigned
study drug once daily for up to 4.5 years; and a follow-up phase to be
conducted 7 to 28 days after the last dose of study drug (ie, after the last
visit of the double-blind treatment phase). In
addition to the longitudinal follow-up of subjects* screening biomarker(s) (ie,
amyloid PET and/or CSF), subjects will have the opportunity to participate in 1
or more longitudinal pharmacodynamic (PD) substudies: CSF for biomarkers and
drug exposure, amyloid PET imaging, and tau PET imaging. When sufficient
longitudinal biomarker data has been collected, further collection of biomarker
data can be terminated to reduce patient and site burden.

Following screening and baseline evaluations, subjects who meet all of the
study inclusion criteria and none of the study exclusion criteria will be
assigned randomly to 1 of 2 doses of JNJ-54861911 or placebo in a 1:1:1 ratio.
Randomization will be stratified by country and by apolipoprotein E (APOE) *4
carrier status (carrier vs noncarrier). The dose levels of JNJ-54861911
selected are in the dose range expected to be well tolerated and to achieve a
substantial reduction in CSF Aβ at steady state based on results of single and
multiple ascending dose studies in healthy elderly subjects and preliminary
results in a population with predementia Alzheimer*s disease.

An independent Data Monitoring Committee (DMC) will be commissioned for this
study to review safety and other relevant data on an ongoing basis, and to
review findings from the potential IAs and make recommendations based on
prespecified decision rules.

During the double-blind treatment phase, the randomly assigned investigational
product will consist of JNJ-54861911 5 mg (administered as one tablet
JNJ-54861911 of 5 mg), JNJ-54861911 25 mg (administered as a single tablet
JNJ-54861911 of 25 mg) or placebo (administered as 1 corresponding placebo
tablet). All study medication tablets will be identical in appearance. Study
medication should be self-administered by subjects orally once daily with a
glass of noncarbonated water, preferably between
07:00 and 11:00 hours (7:00-11:00 AM).
The first dose of study drug should be self-administered by the subject at the
site as described above, and at all subsequent scheduled visits, subjects
should self-administer their study medication on site. Subjects having
difficulties reaching the site during morning hours will be permitted to
administer drug later during the day (eg, with lunch), but every attempt should
be made to ensure consistency in the time of study drug administration during
the course of the study. Subjects who forget to take their daily dose in the
morning as directed will be instructed to take
their daily dose later that day, as long as it is before 1600 hours (4:00 PM).
Subjects who forget to take their morning dose of study drug and cannot take
their daily dose of study drug before 1600 hours (4:00 PM) will be instructed
not to take any dose during that day and to resume
dosing the following day. Subjects who are no longer capable of ensuring
compliance with their daily medication schedule,
in the judgment of the investigator (eg, due to progression to dementia), will
be required to have support in the handling and administration of study drug
(eg, study informant, partner, caregiver, or nurse practitioner).

For some blood tests it is aksked if feasible not to eat or drink before. This
applies for the visits Screening visit GH, M0, M1, M2, M3, M4, M5, M6, M8, M10,
M12, M15, M18, M21, M24, M27, M30, M33, M36, M39, M42, M45, M48, M51, M54, ET
and follow-up visit.

Participation of the subject will be approximately 5 years. During the
double-blind treatment phase, subjects will be asked to orally self-administer
once daily JNJ-54861911 5 mg (as one 5-mg tablet of JNJ-54861911), JNJ-54861911
25 mg (administered as one 25-mg tablet of JNJ-54861911), or placebo
(administered as 1 matching placebo tablet) with a glass of noncarbonated
water, preferably between 0700 and 1100 hours (7:00-11:00 AM).

Subjects who participate will visit the site approximately 32 times. Every
month for the first 3 months, at months 8,9,10 and 12, and then every 3 months
afterwards. The subject will return to the study clinic for a follow-up exam
1-4 weeks after the last dose of study drug, or the end of the treatment period
in the study.
After the end of the study, the subject will be contacted by the study team of
the site by telephone approximately every 6 months for up to 5 years.

The screening phase consists of 4 primary screening steps as shown below. In
addition, part of the
baseline cognitive, functional, and medical resource utilization/health
outcomes measures will be
performed during the screening phase, as described further below. Assessments
for Step III (MRI) and
Step IV (Elevated Amyloid Accumulation) may only be performed after the subject
is determined to be
still eligible for the study after review of results from Step I (General
Health) and Step II (Clinical
Scales).

There may be risks associated with taking investigational product (for adverse
events see section E9) which have (not) been identified in the studies
completed to date. Participation in this study does not guarantee that the
patient will receive any medical benefit. During the investigation, his / her
condition may remain the same or deteriorate, regardless of the treatment group
to which he / she has been assigned. It is possible that the patient has been
allocated to the placebo arm and may receive no active investigational product.