A Pilot Clinical Trial of Exendin-4 in Alzheimer's Disease

Objective: Exendin-4 (or exenatide) is a medication currently used in the treatment of
diabetes mellitus (DM). Exendin-4 has generated promising results as an agent protecting
neurons from a number of assaults both in the laboratory and in studies on animals.
Specifically, there is pre-clinical evidence that Exendin-4 may be a treatment for
Alzheimer's disease (AD). Based on these facts, we conducted a pilot Phase II double blind
randomized placebo-controlled clinical study to assess the safety and provide proof of
concept for exendin-4 treatment in early Alzheimer's disease (AD), by demonstrating a
response of disease biomarkers to the intervention. Our main hypothesis is that long-term
administration of Exendin-4 in participants with amnestic MCI/early AD in FDA-approved doses
is safe and will induce a change over time in AD biomarkers. Subject population: We intend to
screen up to 100 potential participants in order to ensure that at least 40 participants
(enrolled based on a clinical diagnosis of amnestic MCI/early AD and Cerebrospinal Fluid
(CSF) biomarker evidence of AD) will be enrolled into treatment and complete the study.
Design: Enrolled participants will be randomly assigned into one of two groups (Exendin-4 vs.
Placebo) and will be followed at regular intervals for 18 months. Outcome measures: Safety
and tolerability will be the primary outcomes. In addition, we will measure and assess the
change over time of a number of exploratory outcomes with the intervention, including CSF and
plasma biomarkers (such as CSF A42, tau, p181-tau and plasma A42/A40), cognitive performance
measures (such as the Alzheimer's Disease Assessment scale, cognitive sub-scale, and other
tests), clinical progression of dementia measures (such as the Clinical Dementia Rating scale
sum-of-boxes), volumetric changes on structural brain MRI and changes in resting fMRI. All
research will be performed on the National Institute on Aging (NIA) Clinical Research Unit
located on the 5th floor of Harbor Hospital.

- INCLUSION CRITERIA:

- Age > 60

- Clinical Dementia Rating (global CDR) of 0.5 or 1. Memory box score must be at least
0.5.

- Mini Mental Status Exam (MMSE) > 20

- Clinical diagnosis of (amnestic or mixed) MCI or early AD and Memory deficit on
neuropsychological or clinical testing.

- Hamilton Depression Scale score of less than or equal to 12 on the 17-item scale

- CSF A beta 42 < 192 (+- 10%) pg/ml (given an intra-subject laboratory variability ~
10%)

- Medications stable for at least 4 weeks prior to screening. In particular:

- Participants may take stable doses of antidepressants, chronic anxiolytics or
sedative hypnotics, if started at least 4 weeks or longer prior to screening

- Cholinesterase inhibitors and/or memantine are allowable, if started at least 4
weeks prior to screening

- Participants will not be asked to discontinue medications without permission from
their primary care provider (PCP) or specialist.

- Fluency in English

- At the time of enrollment, participants must have the ability to provide informed
consent and make health care decisions.

- An informant or caregiver who has frequent contact with the participant (e.g. an
average of 10 hours per week or more) must be appointed to serve as Durable Power of
Attorney (DPA) for research and medical care at NIA, accompany the participant to
clinic visits and provide historical information regarding the participant s cognitive
status, and assist participants with/administer injections of the investigational
medication.

- Good general health with no additional disease states that could interfere with the
study.

EXCLUSION CRITERIA:

- Other significant neurological disease of the Central Nervous System (such as
Parkinson s disease, atypical Parkinsons disease, Multi-infarct Dementia,
Frontotemporal Dementia, Huntington s disease, Normal Pressure Hydrocephalus, brain
tumor, Progressive Supranuclear Palsy, Epilepsy, Subdural Hematoma or Multiple
Sclerosis)

- A history of significant head trauma followed by persistent neurologic defaults or
known structural brain abnormalities

- Positive RPR or HIV

- Abnormal PT/PTT and INR (1.5 standard deviation over the upper normal limit)
increasing the risk for LP related bleeding/hematoma; platelet count
<100,000/microliters.

- Anti-coagulant therapy (such as coumadin). Aspirin up to 325 is allowed.

- Investigators unable to obtain CSF, failure of Lumbar Puncture after a limited number
of unsuccessful attempts).

- History of psychiatric disease with significant impairment in thought processes (e.g.
schizophrenia, bipolar disease, psychosis). Participants who develop psychiatric
conditions necessitating treatment after their enrollment will not be dropped from the
study. The high incidence of late-onset depression and anxiety among individuals with
MCI and AD requires that participants with depression, and/or anxiety should not be
excluded from the cohort to maintain the ecological validity of the results.

- Current abuse of alcoholic beverages (> 7 in women and >14 in men) or substance abuse.

- Known diagnosis of diabetes at the time of enrollment or new diagnosis of diabetes
based on the findings of elevated fasting blood glucose (= or >126 mg/dl) and/or the
oral glucose tolerance test at screening (>200 mg/dl at two hours).

- Severe renal impairment (creatinine clearance <30 ml/min) or end-stage renal disease.
Individuals with moderate renal impairment (creatinine clearance 30 to 50 ml/min) may
be enrolled in the study, but their BUN and Creatinine will be monitored during each
visit after drug initiation and extra safety visits will be conducted at 3, 9, and 15
months.

- Current or previous treatment with Exendin-4 (Exenatide, trade name Byetta.)

- History of pancreatitis, active upper GI, hepatic or gallbladder disease

- Personal or family history of medullary thyroid carcinoma or Multiple Endocrine
Neoplasia syndrome type 2

- History of repeated hypoglycemia

- Body mass index (BMI) < 18 on enrollment (given the expected weight loss caused by
Exendin-4 and dementia). In the BLSA, participants with age > 65 had a mean BMI of
25.8 with SD of 3.9 Exendin-4 has been shown to cause an average 5.3 kg weight loss,
with 95% CI: 6 to 4.5 kg (126).

- Allergy to Exendin-4 or to substances in the injection pen (metacresol, mannitol,
glacial acetic acid, sodium acetate trihydrate, water for injection).

- Participation in other studies of investigational treatments for Alzheimer s disease
in the last year.