K0706 for Patients Diagnosed With Dementia With Lewy Bodies
K0706 for Patients Diagnosed With Dementia With Lewy Bodies
This study evaluates the safety and tolerability of treatment with K0706 in Dementia with
 Lewy Bodies (DLB).

 The hypothesis is that K0706 will be safe and tolerable and that this drug will alter CSF and
 plasma biomarkers in DLB. Clinical assessments of cognitive, behavioral and motor functioning
 will also be evaluated. A total of 45 participants will be randomized 1:1:1 into 3 groups
 (n=15/per group) to be treated with oral daily doses of 96 mg K0706 (group 1), 192mg K0706
 (group 2) or matching placebo (group 3) for 12 weeks, followed by 4-week wash-out period.
Dementia with Lewy Bodies (DLB) is an alpha-synucleinopathy and the second most common form
 of dementia in the elderly. DLB shares striking neuropathological and clinical similarities
 with both Parkinson's disease (PD) and Alzheimer's disease (AD). DLB and PD are characterized
 by death of dopaminergic (DA) neurons in the nigro-striatal system and formation of
 intra-neuronal alpha-synuclein inclusions known as Lewy bodies (LBs). Misfolded
 alpha-synuclein aggregates within LBs and apha-synuclein (SYN) is the highest genetic risk
 factor for PD and DLB followed by the microtubule associated protein tau (MAPT) . At autopsy
 alpha-synuclein, hyper-phosphorylated tau (p-tau) and amyloid plaques are all detected in the
 brains of individuals with DLB. Therefore, the neuropathology of DLB overlaps with both PD
 and AD, and includes alpha-synuclein accumulation in LBs, p-tau and beta-amyloid deposition .
 Potential cerebrospinal fluid (CSF) biomarkers, including alpha-synuclein, dopamine
 metabolites homovanillic acid (HVA) and 3,4-Dihydroxyphenylacetic acid (DOPAC) , total tau
 and p-tau and amyloid beta peptides (Abeta 40/42) may be commonly shared in AD, PD and DLB.
 The core clinical features of DLB, include dementia and Parkinsonism in addition to
 hallucinations, cognitive fluctuations and rapid eye movement (REM) sleep behavior disorders
 (RBD) . L-Dopa replacement therapies and acetylcholinesterase inhibitors may partially
 control motor and cognitive symptoms, respectively in DLB. Selective Serotonin Re-uptake
 Inhibitors (SSRIs) and antipsychotics manage the behavioral but worsen motor symptoms in DLB.
 There is a major unmet medical need for further research into DLB to identify potential
 therapies for this disease and provide significant insights into the treatment of other
 Parkinsonian and memory disorders. A major challenge facing DLB is to develop a therapy that
 can halt neuronal death and alleviate cognitive, motor and behavioral symptoms. No
 therapeutic approach exists to alter the levels of neurotoxic proteins such as
 alpha-synuclein and halt DA and other neuronal death in DLB. One mechanism to degrade
 neurotoxic proteins is autophagy , which is a process by which the cell can degrade its own
 contents. There is evidence that autophagy is impaired in neurodegeneration , leading to
 failure of degradation of protein aggregates, including misfolded alpha-synuclein.
 Importantly, autophagy is exploited therapeutically in several diseases, including adult
 chronic myeloid leukemia (CML). Tyrosine kinase inhibitors (TKIs) induce autophagy, leading
 to destruction of rapidly dividing tumor cells in CML and degradation of neurotoxic proteins,
 including alpha-synuclein, beta-amyloid and p-tau in PD and AD models. Sun Pharma Advanced
 Research Company Limited (SPARC Ltd.) is developing K0706, for the treatment of adult
 patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML)
 that is resistant or intolerant to prior TKI therapy or Philadelphia positive acute
 lymphoblastic leukemia (Ph+ ALL) that is resistant or intolerant to prior TKI therapy; and
 its ability to slow down progression of PD. Using allometric scaling and an average human
 body weight of 70kg an oral dose of 15-30mg/kg once daily in mice corresponds to an oral
 human equivalent dose (HED) of 85-160 mg which is within the tolerated dose in both CML and
 PD. Therefore, the effects of 96 mg K0706 and 192 mg K0706 versus matching placebo taken
 daily by mouth for 12 weeks, followed by a 4 week wash-out period will be evaluated in
 individuals diagnosed with DLB. The data obtained from this study will serve as a proof of
 concept for future placebo-controlled, double-blind studies in patients diagnosed with DLB,
 AD, or 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. Age of 25-90 years, medically stable

 4. Clinical diagnosis of DLB according to McKeith et al
 (https://www.ncbi.nlm.nih.gov/pubmed/28592453) with both dementia MoCA≥14 and
 Parkinsonian defined as bradykinesia in combination with rest tremor, rigidity or both
 UPDRS I-III ≤ 50 and UPDRS-III between 20-40.

 5. Dementia and Parkinsonism must be present with at least one other symptom such as
 fluctuation, visual hallucinations or REM sleep behavioral disorder (RBD)

 6. Stable on Levodopa no more than 800mg daily, acetylcholinesterase inhibitors, dopamine
 agonists for at least 6 weeks

 7. Stable on monoamine oxidase inhibitors (MOA-B) for at least 4 weeks before enrollment
 and during the trial

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

 9. Corrected QT interval (QTc) 350-470 ms, inclusive

 10. Participants must be willing to undergo Lumbar puncture (LP) at baseline and 3 months
 after treatment.

 Exclusion Criteria:

 1. Medical history of liver or pancreatic disease, GI ulcers and Chron's disease, kidney,
 GI, or blood problems

 2. Abnormal liver function defined as Aspartate aminotransferase ( AST) and/or Alanine
 aminotransferase (ALT) > 100% the upper limit of the normal

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

 4. History of Human immunodeficiency virus (HIV), clinically significant chronic
 hepatitis, or other active infection

 5. Hypokalemia, hypomagnesaemia, or long QT syndrome- QTc≥471 ms or concomitant drugs
 known to prolong the QTc interval and history of any cardiovascular disease, including
 myocardial infarction or cardiac failure, angina, arrhythmia

 6. History or presence of significant 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.

 7. 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 SSRIs (e.g. Citalopram, Escitalopram, Paroxetine,
 Sertraline, Duloxetine, Trazodone, etc.). Should treatment with any of these agents be
 required, therapy with K0706 should be interrupted.

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

 9. Clinical signs indicating syndromes other than DLB including, AD idiopathic PD,
 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

 10. Current evidence or history in past two years of epilepsy, focal brain lesion, head
 injury with loss of consciousness or Diagnostic and Statistical Manual of Mental
 Disorders 4th Edition ( DSM-IV) criteria for any active major psychiatric disorder
 including psychosis, major depression, bipolar disorder, alcohol or substance abuse

 11. 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.

 12. 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)

 13. 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.

 14. Must not be on any immunosuppressant medications

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