Study to Assess the Safety and Biological Activity of AMX0035 for the Treatment of Alzheimer's Disease

Study Overview
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Brief Summary
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The proposed study will be a 24-week, randomized, double-blind, multi-site, placebo-controlled study in volunteers with late mild cognitive impairment (MCI) or early dementia due to Alzheimer's disease (AD).

Detailed Description
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The study is a 24-week, randomized, double-blind, multi-site, placebo-controlled study in volunteers with late mild cognitive impairment (MCI) or early dementia due to Alzheimer's disease (AD). The study is designed to evaluate the safety, tolerability, drug target engagement and neurobiological effects of treatment with AMX0035 over 24 weeks. The study is designed to yield deep phenotyping insight for the purposes of demonstrating the effects of AMX0035 on mechanistic targets of engagement and disease biology. The study will evaluate diverse disease-relevant markers and produce an informative dataset that will allow for evaluation and correlation of imaging-based markers, neurobiological changes, functional measures, and cognitive outcomes.

Official Title
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Phase II Study to Assess the Safety, Tolerability, and Target Engagement of AMX0035, a Fixed Combination of Sodium Phenylbutyrate and Tauroursodeoxycholic Acid for the Treatment of Alzheimer's Disease

Conditions
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Alzheimer Disease

Intervention / Treatment
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* Drug: AMX0035
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ages 55-89, inclusive, male or female Diagnosis of Probable Alzheimer's Disease or Mild Cognitive Impairment (amnestic or amnestic plus other) with biomarkers that suggest intermediate or high likelihood that the syndrome is due to AD, according to 2011 NIA-AA Workgroup criteria MoCA 8 - 26 inclusive Able to read and write in English sufficiently to complete all study procedures Geriatric Depression Scale <7 Willing and able to complete all assessments and study procedures Not pregnant, lactating or of child-bearing potential (women must be >2 years post-menopausal or surgically sterile) Study partner with at least two days per week with contact with patient willing to accompany patient to visits and complete partner study forms No known hypersensitivity to Tauroursodeoxycholic acid or Phenylbutyrate Must have a previous biomarker supportive of AD as the underlying pathology of cognitive decline, which could include amyloid PET, CSF AD biomarkers, FDG-PET, or vMRI scan If on cholinesterase inhibitor and/or memantine, doses are stable for 3 months prior to baseline Exclusion Criteria: Any CNS disease other than suspected AD, such as clinical stroke, brain tumor, normal pressure hydrocephalus, multiple sclerosis, significant head trauma with persistent neurological cognitive deficits or complaints, Parkinson's disease, frontotemporal dementia, or other neurodegenerative diseases Abnormal liver function defined as AST and/or ALT > 3 times the upper limit of normal Renal insufficiency as defined by a serum creatinine > 1.5 times the upper limit of normal History of cholecystectomy or biliary disease Clinically significant unstable medical condition (other than AD) that in the Site Investigator opinion would pose a risk to the participant if they were to participate in the study Any contraindication to undergo MRI studies such as: History of a cardiac pacemaker or pacemaker wires Metallic particles in the body Vascular clips in the head Prosthetic heart valves Severe claustrophobia impeding ability to participate in an imaging study Major active or chronic psychiatric illness (e.g. depression, bipolar disorder, obsessive compulsive disorder, schizophrenia) within the previous year prior to baseline Any significant neurodevelopmental disability Current suicidal ideation or history of suicide attempt within five years of baseline or significant change from the screening and baseline C-SSRS at the discretion of the Site Investigator History of alcohol or other substance abuse or dependence within the past two years Any significant systemic illness or medical condition that could affect safety or compliance with study at the discretion of the Site Investigator Laboratory abnormalities in B12, TSH, or other common laboratory parameters that might contribute to cognitive dysfunction Current use of medications with psychoactive properties that may deleteriously affect cognition (e.g., anticholinergics, centrally-acting antihistamines, antipsychotics, sedative hypnotics, anxiolytics) Use of any small molecule investigational therapy being used or evaluated for the treatment of AD is prohibited beginning three months (84 days) prior to the Baseline Visit and throughout the study. Use of any immunotherapy investigational therapy is prohibited beginning one year (365 days) prior to the Baseline Visit and throughout the study. Use of other investigational agents one month (28 days) prior to the Baseline Visit and for the duration of the trial.

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Placebo-Controlled, Double-Blind, Parallel-Group
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active (AMX0035)<br>AMX0035--a combination of TUDCA and Phenylbutyrate | Drug: AMX0035<br>* Combination Therapy of TUDCA and Sodium Phenylbutyrate<br>* Other names: Tauroursodeoxycholic Acid and Sodium Phenylbutyrate;|
| Placebo Comparator: Placebo<br>Taste-matched Placebo | Drug: Placebo<br>* Placebo<br>* Other names: Comparator;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quantity of Adverse Events Observed in the Study | Rate of Adverse Events between Placebo and Active Groups | 6 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MRI Volumetric Imaging | Impact of AMX0035 on levels of whole brain atrophy, as assessed by volumetric Magnetic Resonance Imaging (vMRI) | 6 Months | 
| Cognition | Impact of AMX0035 on clinical symptoms as measured by ADAS-Cog | 6 Months | 
| Psychiatric Symptoms | Impact of AMX0035 on measures of neuropsychiatric symptoms as assessed by the Neuropsychiatric Inventory (NPI) | 6 Months | 
| MRI Hippocampal Imaging | Impact of AMX0035 on levels of hippocampal atrophy, as assessed by volumetric Magnetic Resonance Imaging (vMRI) | 6 Months | 
| Functional MRI Imaging | Impact of AMX0035 on rsfMRI | 6 Months |