Nilotinib in Huntington's Disease

The investigators performed an open label phase I clinical trial using two commercially
available doses of Nilotinib (150 and 300mg capsules) in patients with advanced PDD and DLB.
These indications have some overlapping pathologies and clinical symptoms and share common
plasma and CSF biomarkers, including alpha-Synuclein, Abeta42/40, total Tau and p-Tau. The
investigators obtained preliminary data showing that Nilotinib crosses the BBB and is
detected in the CSF, suggesting Abl inhibition and downstream target engagement
(alpha-Synuclein, Tau and Abeta) in the CNS (pharmacodynamics). Nilotinib increased CSF HVA
levels as a downstream biomarker of dopamine metabolism. These data provide feasibility to
test Nilotinib in a phase Ib clinical trial to demonstrate safety, tolerability and changes
in disease biomarkers in patients with HD. The Huntingtin gene provides the genetic
information for a protein that is also called "huntingtin" (Htt). Expansion of CAG
(cytosineadenine-guanine) triplet repeats in the gene coding for the Huntingtin protein
results in an abnormal protein, mutant Htt (mHTT), which gradually leads to protein
accumulation within neurons and neuronal cell damage. Based on preclinical and clinical
studies, the investigators hypothesize that Nilotinib will be safe and tolerable in
individuals with HD. The level of HVA is significantly reduced in HD patients compared to
controls (22), and the investigators expect Nilotinib to increase HVA levels. Nilotinib may
also affect CSF level of total Huntingtin proteins and cell death markers, including NSE and
S100B. The investigators further hypothesize that the investigators may see evidence of
change in cognitive, motor or behavioral outcomes that will help us to build a better
clinical development program going forward.

Neurodegenerative diseases, including HD, are a group of genetic and sporadic disorders
associated with neuronal death and progressive nervous system dysfunction. Cancer is also a
collection of related genetic diseases, in which cells begin to divide without stopping and
spread into surrounding tissues. Unlike neurodegeneration, in which no regeneration happens
when damaged or aging postmitotic neurons die, damaged cells survive when they should die in
cancer, resulting in uncontrolled mitotic cell division to form tumors. Cancerous tumors are
malignant as they spread or invade nearby tissues by cellular contiguity or metastasize via
blood and/or humoral transport. In neurodegeneration, the spread of disease by contiguity is
supported by the hypotheses that toxic or "prion-like" proteins propagate along
neuroanatomical pathways leading to progressive spread of disease and cell death. In
neurodegeneration, failure of cellular quality control mechanisms leads to inadequate protein
degradation via the proteasome or autophagy, resulting in intracellular accumulation of
neurotoxic proteins. Consequently, these proteins are secreted from a pre-synaptic neuron and
can traverse the synaptic cleft and enter a contiguous post-synaptic neuron. Secreted
proteins may not penetrate an adjacent cell via the synapse but they may be re-routed into
the cell and recycled via the endosomal system to fuse with autophagic vacuoles like the
autophagosome or the lysosome. Microglia, the brain resident immune cells may also
phagocytose and destroy toxic proteins. Accumulation of neurotoxic proteins, including
alpha-Synuclein (Lewy bodies), beta-amyloid plaques, Tau tangles, Huntingtin, prions and
TDP-43 are major culprits in neurodegeneration. These toxic proteins trigger progressive
apoptotic cell death leading to loss of many central nervous system (CNS) functions,
including mentation, cognition, language, movement, gastrointestinal motility, sleep and many
others. The discoveries of toxic protein propagation from cell to cell, leading to
progression of neurodegeneration triggered a series of pre-clinical and clinical studies to
limit protein propagation via antibodies (active and passive immune therapies) that can
capture the protein and destroy it en route to healthy neurons. This approach is fraught with
difficulties, including failure to arrest neurocognitive decline and brain
edema/inflammation. Manipulation of autophagy is a novel therapeutic approach that focuses on
degradation of neurotoxic proteins at the manufacturing site in order to prevent their
secretion and propagation. This novel strategy leads to unclogging the cell's disposal
machine and degradation of toxic proteins, thus preserving neuronal survival via bulk
digestion of abnormal proteins. Preservation of neuronal survival maintains the level of
neurotransmitters that are necessary for cognitive, motor and other CNS functions, leading to
alleviation of symptoms as well as arrest of neurodegeneration. As neurons are post-mitotic
cells, pulsatile autophagy may promote protein degradation and provide an effective
disease-modifying therapy for neurodegenerative diseases. Autophagy is a double-edged sword
in cancer, either preventing accumulation of damaged proteins and organelles to suppress
tumors, or promoting cell survival mechanisms that lead to tumor growth and proliferation.
Leukemia and many other cancer treatments have been revolutionized by manipulation of
autophagy, which leads to bulk degradation of unwanted or toxic molecules. For example in
leukemia, genetic mutations and DNA damage can lead to large numbers of abnormal white blood
cells (leukemia cells and leukemic blast cells) to accumulate in the blood and bone marrow,
crowding out normal blood cells. Autophagy can lead to the degradation of the products of
cancer-causing genes (oncogenes), tumor suppressor genes, damaged DNA and essential
components of the cytosol, thereby controlling abnormal mitotic division and limiting tumor
growth. Autophagy can also lead to self-cannibalization via promotion of programmed cell
death, or apoptosis. Activation of the tumor suppressor p53 in response to DNA damage leads
the cell to arrest proliferation, initiate DNA repair, and promote survival. However, if the
DNA damage cannot be resolved by p53, it can trigger apoptotic death. Cell division and
apoptosis are mediated by signaling mechanisms via the endosomal (early and recycling)
system. Tyrosine kinases are activated via auto phosphorylation, triggering various signaling
mechanisms that mediate cell division and/or apoptosis. Tyrosine kinase inhibition via
de-phosphorylation leads to signaling via the late endosomal-lysosomal pathway, thus
increasing autophagic degradation and tumor growth. TKIs have significantly improved the life
quality and expectancies in many cancers, including CML. CML is characterized by the
translocation of chromosomes 9 and 22 to form the "Philadelphia" chromosome resulting in the
expression of a constitutively active Breakpoint Cluster Region-Abelson (BCR-Abl) tyrosine
kinase. This oncogenic protein activates intracellular signaling pathways and induces cell
proliferation. Our laboratory investigated TKIs that activate autophagy and are FDA-approved
for CML, thus significantly reducing research and development efforts and cost by
re-purposing for new indications. Abl is activated in neurodegeneration. A fraction of
Nilotinib crosses the blood-brain-barrier (BBB), inhibits Abl and facilitates autophagic
amyloid clearance, leading to neuroprotection and improved cognition and motor behavior. Mice
treated with a much lower dose of these drugs (<25% of the typical CML dose) show significant
motor and cognitive improvement and degradation of alpha-Synuclein, beta-amyloid, Tau and
TDP-43 without evidence of increased inflammation. There was also significant reversal of
neurotransmitter alterations, including dopamine and glutamate in several models of
neurodegeneration. As a modulator of myeloid cells, Nilotinib may also positively regulate
neuronal death and produce neuro-restorative effects via increased production of necessary
growth factors and proliferation of myeloid-derived glia. Autophagic toxic protein clearance
and production of growth factors may restore loss of neurotransmitters, leading to improved
motor and cognitive functions. Nilotinib provides a double-edge sword via manipulation of
autophagy to inhibit cell division and tumor growth in CML on one hand, and promote toxic
protein degradation and neuronal survival in neurodegeneration on the other hand. The
investigators propose to perform an open label, Phase Ib, proof of concept study to evaluate
the impact of low doses of Nilotinib treatment on safety, tolerability and biomarkers in
participants with HD. The investigators propose an adaptive design based on safety and
tolerability of 150mg Nilotinib treatment for 3 months. The investigators will first enroll
10 participants who will receive an oral dose of 150mg Nilotinib once daily (group 1) for 3
months. If these participants tolerate 150mg dose of Nilotinib, i.e. with no exacerbation of
chorea and behavioral symptoms and no other AEs (i.e. myelosuppression, QTc prolongation,
liver/pancreatic toxicity, etc ), an additional 10 new HD participants (group 2) will be
enrolled to evaluate the effects of 300 mg dose of Nilotinib for 3 months. The investigators
will then compare baseline with the effects of 3-months Nilotinib treatment within each group
and between groups (1 and 2). Participants (group 1 and 2) will return for a follow up visit
one month after the termination of 3-months treatment with Nilotinib and results will
compared to baseline visits and end of study visits. Ten (10) participants will receive an
oral dose of 150mg Nilotinib once daily for 3 months (group 1). If this dose is tolerated
another 10 participants will receive an oral dose of 300mg Nilotinib once daily (group 2) for
3 months.

Inclusion Criteria:

- Written informed consent

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

- Patients between the age of 25-90 years, medically stable

- Clinical diagnosis of HD with either a confirmed family history or positive CAG repeat
(CAG≥35)

- MoCA ≥ 22

- Able to perform the TMT-B in ≤240 seconds

- Total Functional Capacity 7-12

- Stable concomitant medical and/or psychiatric illnesses, in the judgement of the PI.

- QTc interval 350-460 ms, inclusive

- Participants must be willing to undergo LP at baseline and 3 months after treatment

Exclusion Criteria:

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

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

- History or presence of cardiac conditions including:

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

2. Congestive heart failure

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

4. Any history of Torsade de Pointes

- 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:

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

2. Treatment with QT prolonging drugs (www.crediblemeds.org)- excluding Selective
Serotonin Reuptake Inhibitors (SSRIs) (e.g. Citalopram, Escitalopram, Paroxetine,
Sertraline, Duloxetine, Trazodone, etc.)

3. 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.

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

5. 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.

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

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

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

- Females must not be lactating, pregnant or with possible pregnancy

- Medical history of liver or pancreatic disease

- 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

.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 active major psychiatric
disorder including psychosis, major depression, bipolar disorder, alcohol or substance
abuse

- 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

- 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)

- 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

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

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