Feasibility Study in Subjects With Mild to Moderate Alzheimer's Disease

T3D-959 is an orally-delivered, once-a-day administered, small molecule dual nuclear receptor
agonist that has been shown in animal and Phase 1 studies in normal human subjects to be safe
and well tolerated. The purpose of this clinical study in AD patients is to demonstrate
mechanistic proof of concept that T3D-959, can produce desired changes in cerebral glucose
metabolism and functional connectivity that may indicate potential for cognitive improvement.
The therapeutic approach to be tested is based on two suppositions; (A) ameliorating multiple
pathologies in the disease with a single therapy may provide a superior clinical benefit than
therapeutic approaches which target a single pathology and (B) correcting insulin resistance
in the brain, (highly correlated with AD and potential key driver of AD pathophysiology) and
peripherally may be disease remedial.

The brain requires integral insulin signaling for metabolic homeostasis and neuronal
plasticity. Insulin resistance disrupts energy balance and signaling networks needed for a
broad range of functions. Impaired insulin signaling in neurons enhances apoptosis, promotes
oxidative cell death induced by Abeta1-42, increases secretion of Abeta1-42, blocks removal
of extracellular Abeta oligomers and increases plaque loads. A growing body of evidence
suggests that brain insulin resistance promotes or possibly is the trigger of key pathologies
in AD and is supported by observed changes in levels of insulin signaling molecules in AD
forebrains and associated changes in memory. Pre-clinical studies in animals have
demonstrated the insulin sensitizing activity of T3D-959 and ability to improve multiple
pathologies of AD in a rat model of disease.

This non-placebo controlled trial will be conducted in one to three clinical centers. Thirty
six (36) patients with mild-to-moderate Alzheimer's disease will be randomly assigned to once
daily, orally administered treatment with 3mg, 10mg, 30mg or 90mg doses of T3D-959.
Participants will be treated for two weeks and will undergo at baseline and at two weeks;
FDG-PET scans to measure brain glucose metabolism, BOLD fMRI scans to measure functional
connectivity of the hippocampus, venous blood draws for biomarker analysis and ApoE
genotyping, and ADAS-Cog11 and DSST cognitive testing. For monitoring potential toxicities of
the drug subjects will undergo physical examination, neurological examination, adverse event
review, blood chemistries, and pharmacokinetic (PK) analyses for T3D-959 plasma levels.

BOLD fMRI definition of terms:

GoF (Goodness of Fit): The degree to which the spatial extent and magnitude of one subject's
default mode network (DMN) regions matches the one of an elderly control group.

Hippo-PreC Link (Hippocampus - Precuneus Link): The resting-state BOLD signal correlation
strength between hippocampus and precuneus regions of interest.

GlobEff_DMN: (Global Efficiency from DMN Regions): The global efficiency among 11 pre-defined
default mode network regions.

GlobEff_AAL: (Global Efficiency from AAL Regions): The global efficiency among 90 pre-defined
cerebral regions based on automated anatomical labeling.

ALFF_lPCC_PreC: Amplitude of Low Frequency Fluctuations (ALFF) from left posterior cingulate
cortex (PCC) and precuneus (PreC).

ALFF_rPCC_PreC: ALFF from right PCC and precuneus. fALFF_lPCC_PreC: Ratio ALFF from left PCC
and precuneus. fALFF_rPCC_PreC: Ratio ALFF from right PCC and precuneus. ReHo_lPCC_PreC:
Regional Homogeneity in left PCC and PreC. ReHo_rPCC_PreC: Regional Homogeneity in right PCC
and PreC. ALFF_lIPL: ALFF from left inferior parietal lobule (IPL). ALFF_rIPL: ALFF from
right IPL. fALFF_lIPL: Ratio ALFF from left IPL. fALFF_rIPL : Ratio ALFF from right IPL.
ReHo_lIPL: Regional Homogeneity in left IPL. ReHo_rIPL: Regional Homogeneity in right IPL.

Expanded Access Extension: This is an open label 10 visit extension for up to 5 subjects who
have completed the T3D959-201 protocol and whose caregivers and physician requested their
continued treatment in an expanded access protocol. All subjects enrolled in this study will
be treated with a 15mg q.d. dose of T3D959 for six months, regardless of their assigned dose
level from the main study. A continued risk/benefit assessment by the investigator will be
conducted at each visit to determine the need for treatment continuation. Subjects will be
assessed for safety and tolerability to T3D-959 and evaluated for changes from baseline
cognitive function via ADAS-Cog11 and DSST testing and global change via CIBIC-plus testing.

Inclusion Criteria:

- Meets criteria for mild-to-moderate AD with Mini-Mental State Examination (MMSE) score
of 14 through 26

- Clinical Dementia Rating = 0.5 to 2.0

- Modified Hachinski less than or equal to 4

- A clinical diagnosis of AD per NINCDS-ADRDA criteria

- Washout of psychoactive medication (other than anti-depressants): at least 4 weeks
prior to baseline

- Stability of all permitted medications for 4-12 weeks prior to baseline

- Visual and auditory acuity adequate for neuropsychological testing

- Home monitoring available for supervision of medications

Exclusion Criteria:

- Unstable diabetes or insulin use

- Unable to participate in FDG-PET scanning

- Inability to undergo a clinical MRI of the brain

- Diagnosis of significant neurological/psychiatric disease other than AD

- History of moderate or severe congestive heart failure, NYHA class III or IV, within
12 months prior to baseline.

- Previous cardiovascular event within the past 6 months prior to baseline

- Subject is pregnant, or lactating.

- ALT and/or AST levels that are twice the upper limit of normal; bilirubin levels that
exceed 2 mg/dL; serum creatinine >1.5 mg/dL in men or > 1.4 mg/dL in women.

- Current or history of severe or unstable disorder (medical or psychiatric) requiring
treatment that may make the subject unlikely to complete the study.

- Current use of fluvoxamine.

- Current unstable use of warfarin.

- Current use (within 30 days of baseline, visit 2) of certain highly protein-bound
medications

- Malignancy within the last 5 years (other than non-melanoma skin cancer, stable,
non-progressive prostate cancer not requiring treatment or in situ cervical cancer).

- Known history of HIV, hepatitis B, or hepatitis C.

- Blood pressure greater than 160/100 mmHg.

- Known or suspected intolerance or hypersensitivity to the study drugs, closely related
compounds, or any of their stated ingredients.

- History of alcohol, drug abuse or dependence (except nicotine dependence) within 2
years.

- Investigational amyloid lowering therapies use within two months prior to baseline

- Have participated in any other investigational study or received an investigational
drug within 30 days or 5 half-lives (whichever is longer) prior to baseline

- Any surgical or medical condition which may significantly alter the absorption of any
drug substance

- Resides in hospital or moderate to high dependency continuous care facility.

- Non ambulatory, or wheelchair-bound

- History of swallowing difficulties.

- Evidence of clinically relevant pathology that in the investigator's opinion could
interfere with the study results or put the subject's safety at risk.

Expanded Access Extension :

Subjects must continue to meet the main study inclusion/exclusion criteria to insure
continued safety to continue on a 6 months study extension