Impact of Nilotinib on Safety, Biomarkers and Clinical Outcomes in Mild to Moderate Alzheimer's Disease

The investigators propose a novel treatment strategy that involves Abl inhibition to alter
Abeta40/42, total Tau and p-Tau231/181 in subjects with mild to moderate dementia due to AD.
The investigators pre-clinical studies show that Nilotinib inhibits brain Abl, decreases
Abeta and p-Tau, modulates brain and peripheral immune profiles and reverses cognitive
decline in AD models. Taken together, these data support the hypothesis that Nilotinib is a
viable therapeutic candidate - via Abl inhibition - in subjects with AD. Based on strong
pre-clinical evidence about the effects of Nilotinib on neurodegenerative pathologies,
including autophagic clearance of neurotoxic proteins, immunity and behavior, the
investigators conducted an open label pilot clinical trial in advanced (stage 3-5) PD with
dementia (PDD) and Lewy Body Dementia (LBD) patients. Participants (N=12) were randomized 1:1
to once daily oral dose of 150mg and 300mg Nilotinib for 6 months. The investigators showed
that Nilotinib penetrates the blood brain barrier (BBB), in agreement with pre-clinical data.
Several studies show that Abeta42 is decreased and CSF total Tau and p-Tau are increased in
PD and LBD. Investigators data show that Nilotinib reverses loss of CSF Abeta40/42 and
significantly reduces (N=5, P<0.05) CSF total Tau and p-Tau between baseline and 6 months
treatment. These biomarker changes are consistent with cognitive improvement (3.5-3.85
points) using Mini-Mental Status Exam (MMSE) and the Scales for Outcomes in Parkinson's
Disease-Cognition (SCOPA-Cog) between baseline and 6 months. These data are very compelling
to evaluate the effects of Nilotinib in a phase II, randomized, double-blind,
placebo-controlled trial in patients with mild to moderate AD.

Inclusion Criteria:

1. Age ≥ 50

2. Fluent in English

3. Biomarker confirmed AD with CSF level of Abeta42 <600ng/mL

4. Able to ingest oral medications

5. Diagnosis of mild to moderate AD according to dementia criteria outlined by McKhann et
al.

6. Neuroimaging (MRI or CT) consistent with the diagnosis of AD within the past year

7. MMSE between 17 and 24 (inclusive) at screening

8. Modified Hachinski score ≤ 4

9. QTc interval 350-460ms, inclusive

10. Caregiver/study partner to accompany participant to all visits and have direct contact
with the participant > 2 days/week

11. Written informed consent

12. Capability and willingness to comply with all study criteria

13. Supervision available for study medication

14. Stable medical conditions for 3 months prior to screening visit

15. Stable medications for 4 weeks prior to screening visit

16. Able to complete baseline assessments

17. Minimum of 6 years of education, or work history sufficient to exclude mental
retardation

18. Stable use of cholinesterase inhibitors and memantine (U.S. FDA-approved medications
for patients with probable AD), vitamin E (up to 400 IU daily), estrogens, aspirin
(81-300 mg daily), and cholesterol-lowering agents for 3 months prior to screening is
allowed.

19. Clinical laboratory values within normal limits or, if abnormal, must be judged to be
clinically insignificant by the investigator

Exclusion Criteria:

1. Non-AD dementia, probable AD with Down syndrome, APP, PS-1, or PS-2 mutations (known
familial AD), LBD and Fronto-temporal dementia (FTD)

2. History of clinically significant stroke

3. Current evidence or history in past two years of epilepsy, focal brain lesion, head
injury with loss of consciousness or DSM-IV criteria for any major psychiatric
disorder including psychosis, major depression, bipolar disorder, alcohol or substance
abuse

4. Sensory impairment that would preclude participation/cooperation with the protocol

5. Patients with hypokalemia, hypomagnesaemia, or long QTc syndrome.

6. Concomitant drugs known to prolong the QTc interval (>461ms) and history of
cardiovascular disease, including myocardial infarction or cardiac failure, angina,
arrhythmia

7. Prescribed strong CYP3A4 inhibitors or a medical history of liver or pancreatic
disease

8. Evidence of any significant clinical disorder or laboratory finding that renders the
participant unsuitable for receiving an investigational drug including clinically
significant or unstable hematologic, hepatic, cardiovascular, pulmonary,
gastrointestinal, endocrine, metabolic, renal or other systemic disease or laboratory
abnormality

9. Active neoplastic disease, history of cancer five years prior to screening, including
breast cancer (history of treated basal or squamous skin cancer, or stable prostate
cancer are not exclusionary)

10. Pregnancy or possible pregnancy

11. Contraindications to LP: prior lumbosacral spine surgery, severe degenerative joint
disease or deformity of the spine, platelets < 100,000, use of Coumadin/warfarin, or
history of a bleeding disorder

12. Contraindication to MRI

13. Evidence of more than 4 micro hemorrhages and/or hemosiderosis by a recent (12 months)
and/or the screening MRI.

14. A low B12 is exclusionary, unless follow-up labs (homocysteine (HC) and methylmalonic
acid (MMA)) indicate that it is not physiologically significant.

15. Enrolled in another active trial investigating an experimental drug or therapy for AD

16. HIV positive