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 study is a 24-week, randomized, double-blind, multi-site, placebo-controlled study in participants with 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 participants with 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. Participants receive orally administered study drug twice daily for a treatment duration of approximately 24 weeks and attend clinic visits at Screening, Baseline, Week 6, Week 12, Week 18, and Week 24.

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

Contacts and Locations

Study Locations

• United States
  • Florida
    • Jacksonville, Florida, United States, 32256
      • Clinical Neuroscience Solutions, Inc. - Jacksonville
    • Orlando, Florida, United States, 32801
      • Clinical Neuroscience Solutions, Inc. - 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 School of Osteopathic Medicine
  • 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
      • Hospital of the University of Pennsylvania, Penn Memory Center
  • Tennessee
    • Knoxville, Tennessee, United States, 37909
      • Genesis Neuroscience Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 51 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

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 score >/=8
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 TURSO or Phenylbutyrate
10. If on cholinesterase inhibitor and/or memantine, treatment must have started for no less than 3 months (84 days) prior to baseline and the dosing regimen must have remained stable for 6 weeks (42 days) prior to baseline. The Investigator anticipated that the dosing regimen at baseline would remain unchanged throughout participation in the study.

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. Recent (less than 1 year) cholecystectomy or the presence of post-cholecystectomy syndrome or biliary obstruction
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, or

   MRI findings that show one or more of the following:

   1. More than 4 incidental microhemorrhages
   2. Incidental lacunar infarct with attributable signs or symptoms and with history of stroke
   3. Incidental meningiomas with attributable signs or symptoms
   4. Newly recognized meningioma
7. Major active or chronic psychiatric illness (e.g. depression, bipolar disorder, obsessive compulsive disorder, schizophrenia) that is not stable or well controlled within the previous year prior to baseline
8. Any significant neurodevelopmental disability
9. Current suicidal ideation or history of suicide attempt within 5 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 2 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 investigational therapy being used or evaluated for the treatment of AD is prohibited beginning 3 months (90 days) prior to the Baseline Visit and throughout the study.
15. Use of other investigational agents 1 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
Placebo Comparator: Placebo; Taste-matched Placebo	Drug: Placebo; Placebo; Other Names: Comparator
Active Comparator: Active (AMX0035); AMX0035 twice daily--a combination of Sodium Phenylbutyrate (3g) and Taurursodiol (1g)	Drug: AMX0035; Combination Therapy of PB and TURSO; Other Names: Sodium Phenylbutyrate (PB) and Taurursodiol (TURSO; also known as Tauroursodeoxycholic Acid [TUDCA])

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-Emergent Adverse Event (TEAEs)	Comparison between the AMX0035 Group and Placebo of the number of participants with TEAEs	From first dose to 24 weeks
Effect of Treatment on a Global Composite Statistical Test of Cognition, Function, and Neuroanatomy (GST)	Change from Baseline in GST (global statistical test combining three measures relevant to disease trajectory (cognition [MADCOMS: Mild/Moderate Alzheimer's Disease Composite Score], function [FAQ: Functional Activities Questionnaire], and total hippocampal volume on magnetic resonance imaging)) for AMX0035 relative to placebo. For MADCOMS and FAQ, a higher score indicates a worse outcome. A larger hippocampal volume is better, so it was reversed before being normalized. Each of the three were normalized against respective baseline means and standard deviations. The mean of the three normalized scores is the final GST. A higher GST score indicates a worse outcome. Standard deviations above the mean are worse; standard deviations below the mean are better. The expected value of the GST at baseline is 0 because it is the mean of three z-scores whose expected values at baseline are 0. AD is multifaceted and the GST was designed to be sensitive to changes in multiple dimensions.	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect of Treatment on Cognition	Impact of AMX0035 on clinical symptoms as measured by Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog). Scoring is in the range of 0 to 90 with a higher score indicating greater cognitive impairment.	24 weeks
Effect of Treatment on Functioning	Impact of AMX0035 on Functional Activities Questionnaire (FAQ) scores. FAQ total score can range from 0 to 30, with higher scores indicating less functional independence.	24 weeks
Effect of Treatment on Dementia Severity	Impact of AMX0035 on Dementia Severity Rating Scale (DSRS) scores. Total score can range from 0 to 54, with higher scores indicating greater severity of dementia.	24 weeks
Effect of Treatment on Cognitive Impairment	Impact of AMX0035 on the Montreal Cognitive Assessment (MoCA) scores. MoCA scores can range from 0 to 30, with lower scores indicating greater cognitive impairment.	24 weeks
Effect of Treatment on Neuropsychiatric Symptoms	Impact of AMX0035 on neuropsychiatric symptoms as assessed by the Neuropsychiatric Inventory (NPI). The total score ranges from 0 to 36, with higher scores indicating a greater severity of symptoms.	24 weeks
Regional Brain Volume	Impact of AMX0035 on levels of hippocampal atrophy, as assessed by volumetric Magnetic Resonance Imaging (vMRI)	24 weeks

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
• Investigators: Study Director: Patrick Yeramian, MD, Amylyx Pharmaceuticals Inc.

Publications and helpful links

General Publications

• Arnold SE, Hendrix S, Nicodemus-Johnson J, Knowlton N, Williams VJ, Burns JM, Crane M, McManus AJ, Vaishnavi SN, Arvanitakis Z, Neugroschl J, Bell K, Trombetta BA, Carlyle BC, Kivisakk P, Dodge HH, Tanzi RE, Yeramian PD, Leslie K. Biological effects of sodium phenylbutyrate and taurursodiol in Alzheimer's disease. Alzheimers Dement (N Y). 2024 Aug 9;10(3):e12487. doi: 10.1002/trc2.12487. eCollection 2024 Jul-Sep.

Helpful Links

• "Biological effects of sodium phenylbutyrate and taurursodiol in Alzheimer's disease"

Study record dates

Study Major Dates

• Study Start (Actual): September 14, 2018
• Primary Completion (Actual): October 22, 2020
• Study Completion (Actual): November 6, 2020

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): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 4, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Neurocognitive Disorders; Dementia; Tauopathies; Neurodegenerative Diseases; Alzheimer Disease; Anti-Infective Agents; Antineoplastic Agents; Gastrointestinal Agents; Antiviral 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)?: NO

Drug and device information, study documents

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