DIAN-TU-001 A Phase II/III Randomized, Double-Blind, Placebo-Controlled, Cognitive Endpoint, Multicenter Study of Potential Disease Modifying Therapies in Individuals at Risk for and with Dominantly Inherited Alzheimer*s Disease

This study will recruit subjects from the Dominantly Inherited Alzheimer
Network (DIAN) observational study, a multicenter international study supported
by the National Institutes of Health (Grant Number U01-AG032438; RJ Bateman),
Dominantly Inherited Alzheimer Network Trial Units (DIAN-TU) sites, DIAN-TU
partner sites, DIAN Expanded Registry, and families identified by the sites.
As part of the DIAN-TU-001 protocol, subjects undergo longitudinal assessments
that include clinical assessment, cognitive testing, MRI and amyloid imaging,
and analysis of cerebrospinal fluid.
There are DIAN observational study sites located in multiple countries
including the USA, Argentina, Australia, Germany, Japan, and the United
Kingdom. Subjects in DIAN are recruited from families that have at least one
member who has been identified as having a mutation linked to dominantly
inherited Alzheimer*s disease (DIAD). The mutations in presenilin 1 (PSEN1),
presenilin 2 (PSEN2) and amyloid precursor protein (APP) that are associated
with dominantly inherited Alzheimer*s disease have very high penetrance (near
100%). This study will target individuals who are either known to have a
disease-causing mutation or who are at risk for such a mutation (the child or
sibling of a proband with a known mutation) and unaware of their genetic
status. Because the age at onset of cognitive changes is relatively consistent
within each family and with each mutation (Ryman, Acosta-Baena et al. 2014), an
age at onset is determined for each affected parent or mutation as part of the
DIAN observational study protocol. This study will enroll subjects who are
either asymptomatic and are within a specific window of time of expected age at
onset for their family and/or mutation or who have symptoms of mild Alzheimer*s
disease.
Gantenerumab (RO4909832): is a recombinant human anti-amyloid beta peptide (A*)
monoclonal antibody of the immunoglobulin subclass G1 (IgG1) that binds
specifically to aggregated forms of A* peptide. In a Phase 1 multiple
ascending dose (MAD) study, subjects treated with gantenerumab for up to 6
months had a dose dependent reduction in brain amyloid, as measured by a
reduction in [11C]-Pittsburgh Compound B ([11C]PiB) binding, using a
volume-weighted average from 6 cortical areas (Ostrowitzki, Deptula et al.
2012).
Solanezumab (LY2062430): is humanized anti-A* peptide immunoglobulin G-1
(IgG1); solanezumab recognizes an epitope in the middle of the A* peptide and
binds to soluble A*. In a Phase 2 trial, treatment with solanezumab resulted
in a dose-dependent increase in levels of A*40 and A*42 in both CSF and plasma
(Siemers, Friedrich et al. 2010).
Drugs that target amyloid beta peptide may be associated with amyloid-related
imaging abnormalities (ARIA), including both vasogenic edema (ARIA-E) and
hemorrhages (ARIA-H), which are typically microhemorrhages, but larger
hemorrhages and frank infarction have also been reported (Sperling, Salloway et
al. 2012). Subjects will undergo MRI scans to monitor for ARIA. The schedule
is drug arm specific and the frequency reflects the likely risk, based on
available safety studies and the mechanism of action of the treatment.
BACE Inhibitor (JNJ-54861911): is a *-site amyloid precursor protein cleaving
enzyme (*-secretase, BACE) inhibitor being developed for the treatment of
Alzheimer*s disease (AD). The hallmark pathologic features of AD patients are
neurofibrillary tangles, which consist of hyperphosphorylated tau protein and
amyloid plaques (AP), the main constituent of which is beta-amyloid (A*). BACE
Inhibitor reduces production of A* fragments by inhibiting BACE-1 processing of
amyloid precursor protein (APP) with the aim of reducing AP formation.

To assess the safety, tolerability, biomarker and cognitive efficacy of
investigational products in subjects who are known to have an Alzheimer*s
disease-causing mutation by determining if treatment with the study drug slows
the rate of progression of cognitive impairment and improves disease related
biomarkers.

This study is an adaptive platform based study which allows flexibility to add
a new compound to the same protocol, allowing new subjects to be randomized to
study drug arms open to enrollment. This study has 3 study drug arms
(gantenerumab, solanezumab and JNJ-54861911), each enrolling subject is to
receive active drug or the corresponding placebo. All subjects will be treated
with active drug or placebo with biomarker (e.g., PET imaging, volumetric brain
MRI, CSF, and plasma measures), cognitive, and safety assessments (including
safety MRI scans, vital signs, ECG, clinical chemistry, and hematology)
throughout the study period.
The primary efficacy hypothesis is that the active drug group will have a
slower rate of progression on the cognitive composite endpoint compared to the
mutation-carrier placebo group after treatment for a minimum of 4 years. The
biomarker and cognitive endpoints may be used to conduct interim analyses in
any of the study drug arms; a study drug arm may be stopped early or revised
(e.g., dose adjustment or treatment duration) based upon the results of the
interim analyses or information from other clinical trials for the same drug,
as outlined in each drug-specific appendix.

Mutation positive subjects will be randomized in a 3:1 ratio for active
drug:placebo. Groups enrolled simultaneously will be balanced by a minimization
algorithm including clinical state and stage of disease measures (CDR-SB, years
from onset) and other factors (gene type [APP, PSEN1, PSEN2), years of
education, age, presence of an APOE *4 allele, region, study site and gender).
Subjects who are mutation negative will be assigned to one of the placebo
groups.
Mutation negative subjects are included to maintain blinding as to genetic
status for those who do not wish to know their genetic status. Mutation
negative subjects will not be included in the primary efficacy or futility
analyses.
At the request of participants, mutation negative subjects participate in the
trial to maintain blinding of their genetic status. Data from mutation negative
subjects will be used to develop models for longitudinal changes in biomarkers
and cognition in healthy adult controls.

- PET scan and a lumbar puncture * at four visits.
- MRI * at eight visits
- ECG - at eighteen visits
- Vital signs (blood pressure, breathing rate, temperature and heartbeat) * at
each in-person visit
- Body weight * approximately every three months
- Blood draw - at most visits.
- Urine samples * at all visits.
- Physical and neurological examination * at 8 visits
- Dermatologic evaluation (eye and skin examination) * at two visits.

Plaque removal effect was demonstrated in the prodromal study WN25203 with the
higher 225 mg dose showing a stronger effect of removal. These results for the
first time showed the effect of immunotherapies against A* in early (prodromal)
AD. In dominantly inherited Alzheimer*s disease (DIAD), amyloid deposition is
present at early stages of the disease when no memory impairment is present
(Bateman et al., 2012). Thus, the current dose and the higher doses to be
administered are expected to be effective in DIAD.
The mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2) and amyloid
precursor protein (APP) that are associated with DIAD and which subjects in
this study who receive active study drug will have tested positive for, have
very high penetrance (near 100%). AD is a progressive and ultimately fatal
disease and no disease modifying treatment is available to date.
Besides injection site reactions which, however appear of mild intensity in
most subjects and not limiting the maintenance of subjects in the long-term
treatment trial, ARIAs represent a side effect of concern in the development of
immune-therapeutics targeting A* in the brain (Sperling et al., 2012). These
changes may include micro-hemorrhage, vasogenic edema/effusion and infarction;
they are most often asymptomatic, but symptoms have been reported in some cases.
Therefore, dedicated monitoring and action plans for ARIAs are implemented in
respective multiple dose clinical trials of gantenerumab including the
DIAN-TU-001 study. Given the experiences made with gantenerumab thus far, the
proposed risk minimization plan including frequent MRI monitoring and reads by
independent experts together with an ARIA based dose intervention algorithm
appears to be effective in preventing clinical sequelae to the subjects treated
with gantenerumab.