31P-MRS Imaging to Assess the Effects of CNM-Au8 on Impaired Neuronal Redox State in Parkinson's Disease

This is a single-center open label pilot, sequential group, investigator blinded study of the CNS metabolic effects, safety, pharmacokinetics, and pharmacodynamics of CNM-Au8 in patients who have been diagnosed with Parkinson's Disease within three years of Screening. The Sponsor will select a starting treatment dose of CNM-Au8 for the initial treatment. Investigators and patients will be blinded to each cohort's study dose. Upon completion of the first treatment cohort, the Sponsor will select a single dose or two different doses for the subsequent second cohort from a pre-specified dosing selection plan based on the evaluation of the 31P-Magnetic Resonance Spectroscopy (31P-MRS) changes versus baseline in the first cohort. Up to a total of two treatment cohorts may be studied (n=15 patients/cohort, total n=30 patients). All patients will receive daily oral treatment over twelve consecutive weeks during each cohort's Treatment Period.

There will be three study periods per treatment cohort:

• A six-week screening period (Screening Period);
• A twelve-week treatment period (Treatment Period);
• A four-week follow-up period (End-of-Study Assessment).

The primary study outcome, CNS metabolic changes, will be assessed based upon each patient's Week 12 study visit versus the pre-treatment baseline. The primary endpoint is the brain metabolic effects of treatment with CNM-Au8 as assessed by an improvement of 31P-MRS assessment of Brain Tissue Cellular Redox Potential defined by the measured tissue ratio of NAD+:NADH concentrations following 12 weeks of once daily treatment.

Inclusion criteria

• Able to understand and give written informed consent and follow study procedures.
• Male or female, aged 30 - 80 years or age (inclusive) at the time of PD diagnosis.
• PD subjects will be recruited in accordance with the MDS Clinical Diagnostic Criteria for

PD:

• Parkinsonism present (bradykinesia + either rest tremor or rigidity)
• 2 of the following 4 supportive criteria:

i. Clear and dramatic beneficial response to dopaminergic medication

ii. Presence of levodopa-induced dyskinesias

iii. Rest tremor of a limb

iv. Olfactory loss or cardiac sympathetic denervation seen on prior MIBG SPECT

• Duration of PD since diagnosis is </= 3 years (inclusive)
• Modified Hoehn and Yahr stage </= 3
• Treatment with dopaminergic therapy for at least 12-weeks and with no change in current medications within the prior 6-weeks

Exclusion criteria

• Atypical parkinsonism, including that due to drugs, metabolic disorders, encephalitis, cerebrovascular disease, normal pressure hydrocephalus, or other neurodegenerative disease.
• The presence of any of the following:

• Unequivocal cerebellar abnormalities
• Downward vertical gaze limitation or slowing of downward saccades
• Diagnosis of behavioral variant frontotemporal dementia or primary progressive aphasia
• Parkinsonian features restricted to the lower limbs for > 3 years
• Treatment with dopamine blockers or depleters in a time course consistent with drug-induced parkinsonism
• Absence of an observable response to high dose levodopa despite moderate disease severity
• Expert considers a diagnosis of alternative syndrome more likely than PD
• Rapid progression of gait impairment requiring wheelchair within 5 years of onset
• Complete absence of progression of motor symptoms over 3 years unless due to treatment
• Early bulbar dysfunction within the first 5 years since diagnosis
• Inspiratory respiratory dysfunction (stridor or frequent sighs)
• Severe autonomic failure in the first 5 years
• Recurrent falls (>1 per year) because of impaired balance in the first 3 years
• Disproportionate dystonic anterocollis or hand contractures of hands or feet within 10 years
• Absence of any of the common non-motor features of PD despite 5 years of disease
• Otherwise unexplained pyramidal tract signs (weakness, hyperreflexia, or extensor toe signs)
• Bilateral symmetric parkinsonism
• Mini-Mental State Exammination (MMSE) score of less than 19.
• Patient with a history of any clinically significant or unstable medical condition based on the Investigator's judgment.
• History of human immunodeficiency virus (HIV), hepatitis C (HepC) virus antibody, or hepatitis B (HepB) virus antibody.
• Based on the investigator's judgment, patients who may have difficulty complying with the protocol and/or study procedures.
• Patient with clinically significant abnormalities in hematology, blood chemistry, ECG, or physical examination not resolved by the Baseline visit which according to Investigator may interfere with study participation.
• Patients with clinically significant hepatic or renal dysfunction or clinical laboratory findings that would limit the interpretability of change in liver or kidney function, or those with low platelet counts (<150 x 109 per liter) or eosinophilia (absolute eosinophil count of ≥500 eosinophils per microliter) at Screening.
• Patient participating in any other investigational drug trial or using investigational drug (within 12 weeks prior to screening and thereafter)
• Positive screen for drugs of abuse or known history of alcohol abuse.
• Women of child-bearing potential, or men, who are unwilling or unable to use accepted methods of birth control for up to 6 months following study participation.
• Women with a positive pregnancy test, are lactating, or are planning to become pregnant during the study or within 6 months of the end of this trial.
• Patients with implanted metal objects in their body that may be affected by an MRI procedure.
• Patients who are claustrophobic or otherwise unlikely to be able to complete the MRI scanning procedures.
• History of allergy to gold in any form.
• Patient is considered a suicide risk in the opinion of the Investigator, has previously made a suicide attempt, or is currently demonstrating active suicidal ideation. Subjects with intermittent passive suicidal ideation are not necessarily excluded based on the assessment of the Investigator.