A PHASE II, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL-GROUP, EFFICACY, AND SAFETY
STUDY OF MTAU9937A IN PATIENTS WITH PRODROMAL TO MILD ALZHEIMER*S DISEASE

Alzheimer*s disease (AD) is the most common cause of dementia, affecting an
estimated 4.5 million individuals in the United States and 26.6 million
worldwide. The disease is characterized pathologically by the accumulation in
the brain neocortex of extracellular *-amyloid (A*) peptide-containing plaques
and intracellular neurofibrillary tangles containing aggregates of the
microtubule associated protein tau. Diagnosis is made through the clinical
assessment of the neurologic and neuropsychiatric signs and symptoms of AD and
the exclusion of other causes of cognitive dysfunction. AD is commonly
classified into preclinical, prodromal, mild, moderate, and severe stages by
the presence and severity of clinically relevant functional and/or cognitive
decline, and categorization is often facilitated by global measures, such as
the Clinical Dementia Rating scale (CDR; Morris 1993) or the Mini-Mental State
Examination (MMSE; Folstein et al. 1975).
The deposition of extracellular amyloid plaques and intracellular tau
aggregates in the
brain are the hallmark pathologic findings in AD, first reported by Alois
Alzheimer in 1906. MTAU9937A is a pan-tau IgG4 monoclonal antibody that has
potential to treat
tauopathies (including AD and primary tauopathies). MTAU9937A is designed to
bind
and intercept all extracellular tau isoforms, in order to stop or slow
cell-to-cell spread and
propagation of tau toxicity and pathology throughout cortical and sub-cortical
networks.
MTAU9937A represents a novel potential therapeutic for the treatment of AD.
Existing therapies for AD provide only modest symptomatic benefit and fail to
slow progression of the underlying neurodegenerative process. Therefore, there
is significant unmet medical need among patients with AD, and MTAU9937A may
fill that gap by targeting a key pathological protein believed to underlie the
degenerative process. Study GN39763 is a proof-of-concept study, using clinical
outcome assessments (COAs), a novel tau imaging technology, and other
biomarkers to test the hypothesis that MTAU9937A administration to patients
with AD improves clinical outcome and stops or slows cell-to-cell spread and
propagation of tau pathology in the brain.

This study will evaluate the efficacy, safety, pharmacokinetics, and
pharmacodynamics of MTAU9937A in patients with prodromal or mild Alzheimer*s
disease (AD), ages 50*80, who are amyloid positive by cerebrospinal fluid (CSF)
or amyloid positron emission tomography (PET). The efficacy objective is to
evaluate the efficacy of MTAU9937A compared with placebo. The safety objective
is to evaluate the safety and tolerability
of MTAU9937A compared with placebo.

This Phase II, randomized, double-blind, placebo-controlled, parallel-group
study will evaluate the efficacy, safety and tolerability, pharmacokinetics,
and pharmacodynamics of MTAU9937A in patients with prodromal AD (pAD) to mild
AD (mAD).
The study consists of a screening period, a double-blind treatment period, an
optional
open-label extension (OLE) period, and a safety follow-up period. An extended
baseline visit (up to 15 days) is included in the double-blind treatment
period, following randomization and prior to the initiation of study drug.
Study drug (MTAU9937A or placebo) will be administered intravenously in the
double-blind treatment period, and MTAU9937A will be administered intravenously
in the optional OLE period. Study drug administration will occur every 2 weeks
(Q2W) for the first three doses of the double-blind treatment period and every
4 weeks (Q4W) thereafter in the double-blind treatment period. MTAU9937A will
be administered Q4W in the OLE period. Study treatment is defined as study drug
plus the PET radioligand used during PET imaging procedures ([18F] Genentech
tau probe 1 [GTP1] for tau PET imaging and the amyloid radioligand for amyloid
PET imaging). Patients will be randomly assigned to one of three active, IV
dose arms (1500 mg, 4500 mg, or 8100 mg MTAU9937A) or to an IV placebo dose arm
in a 2:3:2:3 (1500 mg:4500 mg: 8100 mg:placebo) ratio. All patients
participating in the OLE will receive MTAU9937A 4500 mg IV. To maintain balance
in dementia status and APOE status between treatment arms, randomization will
be stratified by dementia status (pAD vs. mAD) and APOE status (ApoE4+ vs.
ApoE4*). To ensure adequate representations of each diagnostic group, the
Sponsor may operationally manage the proportion of pAD and mAD patients in the
study (e.g., no more than approximately 80% of one category).
Patients will be selected on the basis of clinical diagnosis of probable AD
(according to the National Institute on Aging/Alzheimer*s Association [NIA-AA]
Diagnostic Criteria and Guidelines for AD) or pAD (according to the NIA-AA
Diagnostic Criteria and Guidelines for AD). pAD is defined in this protocol as
a clinical diagnosis of mild cognitive impairment (MCI) due to AD coupled with
evidence of cerebral amyloidosis. Clinical diagnosis for each patient must be
supported by information provided on a Diagnostic Verification Form (DVF),
which must be reviewed and approved by the Sponsor or Sponsor delegate.
Eligible patients must be 50*80 years old at the beginning of screening, meet
diagnostic criteria for MCI or probable AD dementia, and have evidence of
cerebral amyloidosis as indicated by cerebrospinal fluid (CSF) analysis (i.e.,
CSF-enrolled patients) or positive amyloid PET scan by qualitative read (i.e.,
PET-enrolled patients). The choice between CSF versus PET for determination of
cerebral amyloidosis should be made on the basis of the capability of an
individual site and/or the preference of an individual patient. If a patient is
amyloid negative based on one of the two modalities (CSF assessment or amyloid
PET), then the patient may undergo assessment with the other modality during
screening; amyloid positivity by either
modality is sufficient for eligibility.
To monitor patients for safety, the incidence and nature of adverse events,
serious adverse event, adverse events of special interest, responses on the
Columbia-Suicide Severity RatingScale (C-SSRS), and abnormalities in standard
safety blood tests, ECG, and magnetic resonance imaging (MRI) will be assessed
on a regular basis by the Sponsor and an unblinded independent Data Monitoring
Committee (iDMC). Blood samples will be obtained from all patients for the
assessment of pharmacokinetics and for the measurement of antibodies directed
against MTAU9937A and other components of the drug product. At the time of
screening, patients must have a Mini-Mental State Examination (MMSE) score of *
20 points and a Clinical Dementia Rating*Global Score (CDR-GS) of 0.5 or 1.0.
To confirm objective memory impairment, patients must also have a Repeatable
Battery for the Assessment of Neuropsychological Status (RBANS) Delayed Recall
Index of * 85 at the time of screening. All patients must have baseline and
longitudinal tau-related biomarker evaluation. If [18F]GTP1 PET imaging is
available to a patient, based on site availability of [18F]GTP1 PET imaging and
lack of local restriction to such imaging, the patient must undergo [18F]GTP1
PET imaging for tau-related biomarker evaluation. [18F]GTP1 PET imaging will be
performed at the
baseline visit (after randomization), Week 49, and Week 73 during the
double-blind treatment period; those patients continuing into the optional OLE
period must also have [18F]GTP1 PET imaging performed at Week 169. In addition,
for patients undergoing [18F]GTP1 PET imaging, optional CSF collection at
baseline and postbaseline time points is also encouraged. For sites where
[18F]GTP1 PET imaging is not available, or where local restrictions preclude
[18F]GTP1 PET imaging, patients must have CSF collected via lumbar puncture
(LP) at baseline, Week 49, and Week 73 during the double-blind treatment
period; those patients continuing into the optional OLE period are encouraged
to have an LP performed at Week 169. If an LP was performed during screening
for the assessment of amyloid positivity, CSF from this LP will be used for the
baseline measurement; otherwise, an LP must be performed during the baseline
visit (after randomization).

Study drug (MTAU9937A or placebo) will be administered IV in the double-blind
treatment period, and MTAU9937A will be administered IV in the optional OLE
period. Study drug administration will occur Q2W for the first three doses of
the double-blind treatment period and every 4 weeks (Q4W) thereafter in the
double-blind treatment period. Patients will receive 1500 mg, 4500 mg, or 8100
mg MTAU9937A IV or a placebo IV. MTAU9937A will be administered Q4W in the OLE
period. All patients participating in the OLE will receive MTAU9937A 4500 mg IV.
[18F]GTP1 and amyloid radioligands will be used for tau PET and amyloid PET
imaging,
respectively. For each PET imaging procedure, a single dose of the relevant
radioligand will be injected prior to the PET scan.

Existing therapies for AD provide only modest symptomatic benefit and fail to
slow progression of the underlying neurodegenerative process. Therefore, there
is significant unmet medical need among patients with AD, and MTAU9937A may
fill that gap by targeting a key pathological protein believed to underlie the
degenerative process.

Monoclonal antibodies such as MTAU9937A may be associated with a potential
immune
response in clinical trials, such as hypersensitivity or hypersensitivity-like
reactions,
including severe, anaphylactic reactions. Study sites will be prepared to
manage any hypersensitivity or hypersensitivity-like events. The occurrence of
neuroimaging abnormalities believed to represent cerebral vasogenic edema and
microhemorrhage have been reported in association with the investigational use
of immunotherapy targeting the A*peptide, possibly by interacting with
A*deposited in or around blood vessels and eliciting an immune response.
Symptoms, when present in association with such imaging abnormalities, have
been reported to include headache, worsening cognitive function, alteration of
consciousness, seizures, unsteadiness, and vomiting.
Anti-Drug Antibodies (ADA) to MTAU9937A in humans may be associated with
changes in MTAU9937A exposure, reductions in treatment efficacy, or safety
findings such as hypersensitivity reactions. There was no evidence of treatment
emergent ADA in the ongoing Phase I study (GN39058). Immunogenicity in humans
will be evaluated using validated immunoassays and by assessing the incidence
of ADAs after treatment relative to their prevalence at baseline. The study
site will be prepared to manage any hypersensitivity events.