Insulin-Sensitizing Anti-Inflammatory Small Molecule for Investigative Treatment of Dementia

Study Overview
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Brief Summary
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This study seeks to measure changes in cognition through verbal and visual test procedures and changes in biomarkers of Alzheimer's disease and inflammatory and metabolic parameters that can be measure in the central nervous system (CNS) with advanced neuroimaging techniques in patients treated with NE3107 (17a-ethynyl-androst-5-3b,7b,17b-triol).

Detailed Description
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Considering how many people are in a state of mild cognitive impairment (MCI) and frank dementia, there is a substantial cost to society in terms of financial burden and suffering. Degenerative conditions that result in cognitive change in middle and late life are frequently associated with abnormal deposits of protein material (e.g., amyloid, phospho-tau) which interfere with neuronal function and viability. Inflammation and insulin resistance in the CNS and abnormal protein deposition and resultant physiological impairment characterize conditions of the Alzheimer's dementia (AD) type. Neuroinflammation prompts AD progression, impaired cholesterol efflux and reduced insulin signaling (insulin resistance). Insulin resistance has been considered a risk factor as well as a feature of AD, and has also been associated with increased aß-42 secretion, neuritic plaque burden, abnormal insulin receptor performance, decreased glucose metabolism, and consequently decreased cognitive performance. No therapy exists that has been proven to halt or reverse the progressive deposition of abnormal proteins or the attendant neurophysiological deterioration. Various investigational therapies aim to target the pathophysiological processes of AD; from combating abnormal protein deposition, to targeting sources of systemic and neuroinflammation, to providing cholinergic, hormonal, and metabolic support. A promising area of research is the ongoing use of insulin synthesizers as a therapeutic option for AD. Several Phase 3 studies have been initiated and/or completed with compounds such as Semaglutide, a hormone that stimulates insulin signaling, Metformin, an insulin synthesizer, and NE3107, an anti-inflammatory insulin-sensitizing agent. This study seeks to measure changes in cognition through verbal and visual test procedures and changes in biomarkers of Alzheimer's disease and inflammatory and metabolic parameters that can be measured in the CNS with advanced neuroimaging techniques in patients treated with NE3107 (17a-ethynyl-androst-5-ene-3b,7b,17b-triol). Investigational Product The drug under investigation is NE3107 (17a-ethynyl-androst-5-ene-3b,7b,17b-triol). NE3107 is formulated with common excipients used in oral medications in #2 hard gelatin capsules. The capsules are designed for oral administration. NE3107 capsules are stable at room temperature for at least 18 months. Stability of the capsules used in this study will be monitored by a concurrent stability study conducted by the capsule manufacturer and the holder of the primary IND, Biovie, Inc (Santa Monica, CA).

Official Title
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Anti-Inflammatory, Insulin-Sensitizing Agent for Treatment of Cognitive Decline Due to Degenerative Dementias

Conditions
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Alzheimer Disease

Intervention / Treatment
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* Drug: NE3107


Participation Criteria
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Eligibility Criteria
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In order for a subject to be considered for this study, the following criterion is required: Inclusion Criteria: Cognitive decline with Clinical Dementia Rating (CDR) score of 0.5 to 1, suggesting mild cognitive impairment to mild dementia. Participants must be between the ages of 50-89 Primary cognitive complaint must be memory Impairment without movement or psychiatric explanation/diagnosis Participants must show at least one abnormal imaging biomarker and none of the exclusion criteria below. Exclusion Criteria: In order for a subject to be considered for this study, he/she may NOT have any of the following: Subjects with contraindications for lumbar puncture, such as bleeding abnormalities, use of anticoagulant medications, and local skin or spine abnormalities Reversible causes of cognitive impairment that explains the clinical status entirely, such as hypothyroidism, depression Advanced stages of any terminal illness or any active cancer that requires chemotherapy History of breast cancer Women with child-bearing potential who are not willing to use a double-barrier birth control method Males not willing to use a double-barrier birth control method with female sex partners with child-bearing potential

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 89 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental Arm: NE3107<br>All participants will take 200mg BID (12 hours apart) of NE3107 for 3 months. | Drug: NE3107<br>* Participants will take 20mg twice daily (BID) approximately 12 hours apart. The dose will be stable the duration of the study intervention (3 months)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| fMRI MRS Change | Change in MRS from baseline to completion on advanced functional magnetic resonance imaging (fMRI). Specifically the change in glutathione levels will be analyzed (as measured by Magnetic Resonance Spectroscopy (MRS) | 3 months | 
| fMRI DTI-NODDI Change | Change in Diffusion Tensor Imaging - Neurite Orientation Dispersion Density Imaging (DTI-NODDI) from baseline to completion on advanced functional magnetic resonance imaging (fMRI). Specifically the stabilization and or improvement in dendritic density will be analyzed from baseline to completion | 3 months | 
| fMRI ASL Change | Change in Arterial Spin Labeling (ASL) compared to baseline | 3 Months | 
| fMRI resting BOLD Seed Change | Change in functional connectivity of the nucleus basalis of meynert (NBM) with both hippocampi as well as between both hippocampi compared to baseline as visualized by seed analysis of blood-oxygen level depended (BOLD) imaging | 3 Months | 
| fMRI NVR Change | Change in Neurovascular Coupling (NVR) as measured on BOLD imaging compared to baseline | 3 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Dementia Rating Change as calculated from the Quick Dementia Rating Scale Change | Quick Dementia Rating Scale (QDRS) The Quick Dementia Rating Scale (QDRS) is an interview-based tool administered by study officials to participants' caregivers used to obtain observations from a consistent source. The QDRS form consists of 10 categorical questions (5 cognitive, 5 functional), each with 5 detailed options depicting the level of impairment as either 0 (normal), 0.5 (mild/inconsistent impairment), 1 (mild/consistent impairment), 2 (moderate impairment), or 3 (severe impairment). Based on the conversion table outlined in Dr. James Galvin's research (2015), total QDRS scores were converted to Clinical Dementia Rating (CDR) scale levels ranging from 0 (normal aging), 0.5 (mild cognitive impairment), 1 (mild dementia), 2 (moderate dementia), and 3 (severe dementia). | 3 Months | 
| Montreal Cognitive Assessment (MoCA) Change | The MoCA evaluates frontal-executive functions (e.g., verbal abstraction and mental calculation), language (e.g., confrontation naming, phonemic fluency), orientation (e.g., person, place, date, day of the week, and time), visuospatial construction (e.g., simple figure copy), divided visual attention, and immediate and delayed memory of unstructured information. MoCA scores range from 0-30 possible points; 26 or greater is considered to reflect normal cognitive status. | 3 Months | 
| Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) Change | The ADAS-Cog evaluates participants' cognitive ability. It is composed of 11 parts that measure word recall, object/figure naming, command following, constructional praxis, ideational praxis, orientation, word recognition, test direction recall, spoken language, comprehension, and word-finding difficulty. The ADAS-Cog is scored from 0-70 by measuring the errors made in each task, with a score of 70 representing the most severe impairment. A point reduction of 3.1 to 3.8 has been found to be the minimal clinically important difference (Schrag & Schott, 2012). A change will be evaluated from baseline to completion. | 3 Months | 
| Mini-Mental State Examination (MMSE) Change | The MMSE is a 30-point questionnaire that evaluates cognition. The MMSE includes specific tasks that assess orientation, attention, memory, language, and visual-spatial skills. MMSE scores range from 0 - 30 possible points; 0-17: severe cognitive impairment, 18-23: mild cognitive impairment, 24-30: no cognitive impairment. A point decrease >/= to 3 on the MMSE has been identified as the minimally clinically important difference (Andres, 2019). A change will be evaluated from baseline to completion. | 3 Months | 
| Glucose Serology/Metabolic Level Change | Fasting Glucose will be measured in baseline and post blood work and measured based on reference range 75 - 99 mg/dL. | 3 Months |