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

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

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).

Study Overview

• Status: Completed
• Conditions: Alzheimer Disease
• Intervention / Treatment: Drug: Placebo; Drug: AMX0035

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 95
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Florida
    • Jacksonville, Florida, United States, 32256
      • CNS Healthcare - Jacksonville
    • Orlando, Florida, United States, 32801
      • CNS Healthcare - Orlando
    • Palmetto Bay, Florida, United States, 33157
      • International Medical Investigational Centers (IMIC)
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
  • Kansas
    • Fairway, Kansas, United States, 66205
      • University of Kansas Clinical Research Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • New Jersey
    • Stratford, New Jersey, United States, 08084
      • Rowan University
  • New York
    • New York, New York, United States, 10032
      • Columbia University
    • New York, New York, United States, 10029
      • Mount Sinai Alzheimer's Disease Research Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Penn Memory Center
  • Tennessee
    • Knoxville, Tennessee, United States, 37909
      • Center for Biomedical Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 53 years to 87 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Ages 55-89, inclusive, male or female
2. 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
3. MoCA 8 - 26 inclusive
4. Able to read and write in English sufficiently to complete all study procedures
5. Geriatric Depression Scale <7
6. Willing and able to complete all assessments and study procedures
7. Not pregnant, lactating or of child-bearing potential (women must be >2 years post-menopausal or surgically sterile)
8. Study partner with at least two days per week with contact with patient willing to accompany patient to visits and complete partner study forms
9. No known hypersensitivity to Tauroursodeoxycholic acid or Phenylbutyrate
10. 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
11. If on cholinesterase inhibitor and/or memantine, doses are stable for 3 months prior to baseline

Exclusion Criteria:

1. 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
2. Abnormal liver function defined as AST and/or ALT > 3 times the upper limit of normal
3. Renal insufficiency as defined by a serum creatinine > 1.5 times the upper limit of normal
4. History of cholecystectomy or biliary disease
5. 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

6. Any contraindication to undergo MRI studies such as:

   1. History of a cardiac pacemaker or pacemaker wires
   2. Metallic particles in the body
   3. Vascular clips in the head
   4. Prosthetic heart valves
   5. Severe claustrophobia impeding ability to participate in an imaging study
7. Major active or chronic psychiatric illness (e.g. depression, bipolar disorder, obsessive compulsive disorder, schizophrenia) within the previous year prior to baseline
8. Any significant neurodevelopmental disability
9. 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
10. History of alcohol or other substance abuse or dependence within the past two years
11. Any significant systemic illness or medical condition that could affect safety or compliance with study at the discretion of the Site Investigator
12. Laboratory abnormalities in B12, TSH, or other common laboratory parameters that might contribute to cognitive dysfunction
13. Current use of medications with psychoactive properties that may deleteriously affect cognition (e.g., anticholinergics, centrally-acting antihistamines, antipsychotics, sedative hypnotics, anxiolytics)
14. 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.
15. Use of any immunotherapy investigational therapy is prohibited beginning one year (365 days) prior to the Baseline Visit and throughout the study.
16. Use of other investigational agents one month (28 days) prior to the Baseline Visit and for the duration of the trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
CSF Biomarkers	Impact of AMX0035 on CSF biomarkers	6 Months
Plasma Biomarkers	Impact of AMX0035 on plasma biomarkers	6 Months

Collaborators and Investigators

• Sponsor: Amylyx Pharmaceuticals Inc.
• Collaborators: Alzheimer's Association; Alzheimer's Drug Discovery Foundation

Study record dates

Study Major Dates

• Study Start (Actual): August 27, 2018
• Primary Completion (Actual): April 15, 2021
• Study Completion (Actual): August 15, 2021

Study Registration Dates

• First Submitted: April 30, 2018
• First Submitted That Met QC Criteria: May 10, 2018
• First Posted (Actual): May 23, 2018

Study Record Updates

• Last Update Posted (Actual): November 11, 2021
• Last Update Submitted That Met QC Criteria: November 10, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Alzheimer Disease; Anti-Infective Agents; Antiviral Agents; Antineoplastic Agents; Gastrointestinal Agents; Cholagogues and Choleretics; 4-phenylbutyric acid; Ursodoxicoltaurine
• Other Study ID Numbers: AMX-8000

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No