Impact of Nilotinib on Safety, Tolerability, Pharmacokinetics and Biomarkers in Parkinson's Disease

Based on strong pre-clinical evidence of the effects of Nilotinib on neurodegenerative
pathologies, including autophagic clearance of neurotoxic proteins, neurotransmitters
(dopamine and glutamate), immunity and behavior, the investigators conducted an open label
pilot clinical trial in advanced PD with dementia (PDD) and Dementia with Lewy Body (DLB)
(stage 3-4) patients. Participants (N=12) were randomized 1:1 to once daily oral dose of
150mg and 300mg Nilotinib for 6 months. The investigators' data suggest that Nilotinib
penetrates the brain and inhibits CSF Abelson (Abl) activity via reduction of phosphorylated
Abl in agreement with pre-clinical data. Several studies show that CSF alpha-Synuclein and
Abeta42 are decreased and CSF total Tau and p-Tau are increased in PD and DLB. The
investigators' data show attenuation of loss of CSF alpha-Synuclein and Abeta40/42 with 300mg
(50% of the CML dose) compared to 150mg Nilotinib after 6 months treatment. CSF homovanillic
acid (HVA), which is an end by-product of dopamine, is significantly increased; and CSF total
Tau and p-Tau are significantly reduced (N=5, P<0.05) with 300mg Nilotinib between baseline
and 6 months treatment. Despite the reduction of L-Dopa replacement therapies in our study,
UDPRS I-IV scores improved with 150mg (3.5 points) and 300mg (11 points) from baseline to 6
months and worsened (13.7 points and 11.4 points) after 3 months withdrawal of 150mg and
300mg, respectively. Other non-motor functions e.g. constipation was resolved in all patients
and cognition was also improved (3.5 points) using both the Mini-Mental Status Exam (MMSE) or
the Scales for Outcomes in Parkinson's Disease-Cognition (SCOPA-Cog) between baseline and 6
months. MMSE scores returned to baseline after 3 months of Nilotinib withdrawal. These data
are very compelling to evaluate the effects of Nilotinib in a phase II, randomized,
double-blind, placebo-controlled trial in patients with PD.

Inclusion Criteria:

1. Written informed consent

2. Capable of providing informed consent and complying with study procedures. Subjects
who are unable to provide consent may use a Legally Authorized Representative (LAR).

3. Patients between the age of 40-90 years, medically stable

4. Diagnosis of PD according to the UK Brain Bank Diagnostic Criteria

5. PD subjects with MoCA ≥ 22

6. 2.5 ≥Hoehn and Yahr stage ≤3

7. No mono-amine oxidase (MAO)-B inhibitors (Selegeline or rasagiline) are allowed at
least 6 weeks before enrollment

8. Must be medically stable on 800mg Levodopa daily for at least 4 weeks

9. QTc interval 350-460 ms, inclusive

10. Participants must be willing to undergo LP at baseline and 12 months after treatment

Exclusion Criteria:

1. Patients with hypokalemia, hypomagnesaemia, or long QT syndrome- QTc≥461 ms

2. Concomitant drugs known to prolong the QTc interval and history of any cardiovascular
disease, including myocardial infraction or cardiac failure, angina, arrhythmia

3. History or presence of cardiac conditions including:

- Cardiovascular or cerebrovascular event (e.g. myocardial infarction, unstable
angina, or stroke)

- Congestive heart failure

- First, second- or third-degree atrioventricular block, sick sinus syndrome, or
other serious cardiac rhythm disturbances

- Any history of Torsade de Pointes

4. Treatment with any of the following drugs at the time of screening or the preceding 30
days, and/or planned use over the course of the trial:

- Treatment with Class IA or III antiarrhythmic drugs (e.g. quinidine)

- Treatment with QT prolonging drugs (www.crediblemeds.org)- excluding Selective
Serotonin Reuptake Inhibitors (SSRIs) (e.g. Citalopram, Paxil, Zoloft, Cymbalta,
Sertraline, etc...)

- Strong CYP3A4 inhibitors (including grapefruit juice). The concomitant use of
strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin,
atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir,
telithromycin, voriconazole) must be avoided. Grapefruit products may also
increase serum concentrations of Nilotinib. Should treatment with any of these
agents be required, therapy with Nilotinib should be interrupted.

- Anticoagulants, including Coumadin (warfarin), heparin, enoxaparin, daltiparin,
xarelto, etc.

- St. John's Wort and the concomitant use of strong other CYP3A4 inducers (e.g.,
dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine,
phenobarbital) must be avoided since these agents may reduce the concentration of
Nilotinib.

5. Abnormal liver function defined as AST and/or ALT > 100% the upper limit of the normal

6. Renal insufficiency as defined by a serum creatinine > 1.5 times the upper limit of
normal

7. History of HIV, clinically significant chronic hepatitis, or other active infection

8. Females must not be lactating, pregnant or with possible pregnancy

9. Medical history of liver or pancreatic disease

10. Clinical signs indicating syndromes other than idiopathic PD, including corticobasal
degeneration, supranuclear gaze palsy, multiple system atrophy, chronic traumatic
encephalopathy, signs of frontal dementia, history of stroke, head injury or
encephalitis, cerebellar signs, early severe autonomic involvement, Babinski sign

11. 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

12. 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

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

14. 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

15. Must not be on any immunosuppressant medications (e.g. IVig)

16. Must not be enrolled as an active participant in another clinical study

17. Diagnosis of DLB