A Single Site, Randomized, Double-blind, Placebo Controlled Trial of NIC5-15 in Subjects With Alzheimer's Disease

Recent epidemiologic evidence, has suggested that diabetes mellitus significantly increases
risk for the development of Alzheimer's disease, independent of vascular risk factors.
Moreover, even patients who are simply insulin resistant, without frank diabetes, have been
shown to share this elevated risk for the development of AD. As insulin's role as a
neuromodulator in the brain has been revealed, several potential mechanisms for the
interaction of diabetes or insulin resistance with AD have been suggested such as decreased
cortical glucose utilization particularly in the hippocampus and entorhinal cortex;
increased oxidative stress through the formation of advanced glycation end products;
increased Tau phosphorylation and neurofibrillary tangle formation; and increased
beta-amyloid aggregation through inhibition of insulin-degrading enzyme. The future
treatment of AD might involve pharmacologic and dietary manipulations of insulin and glucose
regulation

NIC5-15 is a single, small, naturally occurring molecule. Animal studies and some human
trials have shown NIC5-15 to be safe and a potent insulin sensitizer at doses equivalent to
800-2000mg per day. In preclinical studies at doses higher than those previously studied in
clinical trials, we found that NIC5-15 interferes with the accumulation of beta amyloid, an
important step in the development of Alzheimer's pathology. These data suggest that NIC5-15
may be a reasonable therapeutic agent for the treatment of Alzheimer Disease for two
reasons:

It is a -secretase inhibitor that is Notch-sparing. It is potentially an insulin-sensitizer.

However critical safety and human efficacy studies must be conducted. This application
proposes to conduct these early critical human studies. The goal of the studies contained in
this proposal is to establish safety and efficacy of NIC5-15 for the treatment of AD. The
specific objectives of this study are to:

Specific Objective #1) Conduct a multiple dose safety study of NIC5-15 to establish safety
in the doses that appear to block amyloid accumulation. These studies will characterize the
safety profile, pharmacokinetics, and tolerability

This objective was met with completion of the initial study ID#NCT00470418.

The current study continues investigations of NIC5-15 in Alzheimer's disease with the
following objective:

Specific Objective #2) Conduct a double blind placebo controlled pilot efficacy study of
NIC5-15 in patients with AD. The goals of this study are to:

A) Demonstrate feasibility for a multi-site trial that will be used to guide the design of a
future larger effort. Demonstration of feasibility will include examination of accrual rate,
overall recruitment, adherence to protocol, compliance with medication and willingness to
complete a randomized trial, and lack of short term toxicity.

B) Collect preliminary evidence of efficacy in terms of cognitive and global measures as
well as secondary efficacy outcomes of activities of daily living, behavioral disturbances
and AD biomarkers.

Inclusion Criteria:

- NINCDS/ADRDA criteria for probable AD

- MMSE between 12-27

- Treatment with a cholinesterase inhibitor or an NMDA (N-methyl-D-asparate) antagonist
with stable dose for at least 12 weeks

- Home monitoring available for supervision of medications

- Caregiver available to accompany patient to all visits and willing to participate in
study as informant

- Fluent in English or Spanish

- Medical stability for this study as confirmed by review of records, internist's
physical exam, neurological exam, and laboratory tests

- Stable doses of non-excluded medication

- No evidence of hepatic insufficiency

- Able to swallow oral medications

- Ability to participate in the informed consent process

Exclusion Criteria:

- History of Diabetes Mellitus (OGTT criteria) requiring treatment with an excluded
antidiabetic medication (see below) or history of hypoglycemia

- Active hepatic or renal disease

- Cardiac disease including history of congestive heart failure or current treatment
for CHF; history of recent myocardial infarction

- Use of another investigational drug within the past two months

- History of clinically significant stroke

- History of seizure or head trauma with disturbance of consciousness within the past
two years

- Major mental illness including psychotic disorders, bipolar disorder, or major
depressive episode within the past two years Medication Exclusion

- Current use of oral hypoglycemic agents including sulfonylureas and meglintinides

- Current or past treatment with insulin for longer than two weeks

- Current use of drugs with significant anticholinergic or antihistaminic properties