AMX0035 in Patients With Amyotrophic Lateral Sclerosis (ALS) (CENTAUR)

Evaluation of the Safety, Tolerability, Efficacy and Activity of AMX0035, a Fixed Combination of Phenylbutyrate (PB) and Tauroursodeoxycholic Acid (TUDCA), for the Treatment of ALS

The CENTAUR trial was a 2:1 (active:placebo) randomized, double-blind, placebo-controlled Phase II trial to evaluate the safety and efficacy of AMX0035 for the treatment of ALS.

Study Overview

• Status: Completed
• Conditions: Central Nervous System Diseases; Nervous System Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Spinal Cord Diseases; TDP-43 Proteinopathies
• Intervention / Treatment: Other: Placebo; Drug: AMX0035

Detailed Description

AMX0035 is a combination therapy designed to reduce neuronal death through blockade of key cellular death pathways originating in the mitochondria and endoplasmic reticulum (ER). This clinical trial is designed to demonstrate that treatment is safe, tolerable, and able to slow decline in function as measured by the ALSFRS-R. The trial will also assess the effects of AMX0035 on muscle strength, vital capacity, and biomarkers of ALS including markers of neuronal death and neuroinflammation.

• Study Type: Interventional
• Enrollment (Actual): 137
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • Barrow Neurological Institute
  • California
    • Orange, California, United States, 92868
      • UC Irvine Medical Center
    • San Francisco, California, United States, 94114
      • Forbes Norris MDA/ALS Research Center - California Pacific Medical Center
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida Medical Center
    • Tampa, Florida, United States, 33612
      • Carol and Frank Morsini Center for Advanced Health Care - University of South Florida
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University Hospital
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky Medical Center
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Neuroscience Institute
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Worcester, Massachusetts, United States, 01655
      • University of Massachusetts Memorial Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Medical Center
  • Minnesota
    • Minneapolis, Minnesota, United States, 55415
      • Hennepin County Medical Center
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University Medical Center
  • Nebraska
    • Lincoln, Nebraska, United States, 68506
      • Neurology Associates P.C.
  • New York
    • New York, New York, United States, 10003
      • Mount Sinai Beth Israel
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest Baptist Medical Center
  • Ohio
    • Columbus, Ohio, United States, 43221
      • The Ohio State University Wexner Medical Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple University Hospital
    • Philadelphia, Pennsylvania, United States, 19107
      • The Penn Comprehensive ALS Center
  • Texas
    • Dallas, Texas, United States, 75214
      • Texas Neurology, P.A.
    • San Antonio, Texas, United States, 78229
      • University of Texas Health Science Center at San Antonio
  • Washington
    • Seattle, Washington, United States, 98122
      • ALS Center at the Swedish Neuroscience Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

1. Male or female, aged 18-80 years of age
2. Sporadic or familial ALS diagnosed as definite as defined by the World Federation of Neurology revised El Escorial criteria
3. Less than or equal to 18 months since ALS symptom onset
4. Capable of providing informed consent and following trial procedures
5. Slow Vital Capacity (SVC) >60% of predicted value for gender, height, and age at the Screening Visit
6. Subjects must either not take riluzole or be on a stable dose of riluzole for at least 30 days prior to the Screening Visit. Riluzole-naïve subjects are permitted in the study.
7. Women of child bearing potential (e.g. not post-menopausal for at least one year or surgically sterile) must agree to use adequate birth control for the duration of the study and 3 months after last dose of study drug. Women must not be planning to become pregnant for the duration of the study and 3 months after last dose of study drug
8. Men must agree to practice contraception for the duration of the study and 3 months after last dose of study drug. Men must not plan to father a child or provide for sperm donation for the duration of the study and 3 months after last dose of study drug

Key Exclusion Criteria:

1. Presence of tracheostomy
2. Exposure to PB, Taurursodiol or UDCA within 3 months prior to the Screening Visit or planning to use these medications during the course of the study
3. History of known allergy to PB or bile salts
4. Abnormal liver function defined as aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 3 times the upper limit of the normal
5. Renal insufficiency as defined by a serum creatinine > 1.5 times the upper limit of normal
6. Poorly controlled arterial hypertension (systolic blood pressure (SBP)>160mmHg or diastolic blood pressure (DBP)>100mmHg) at the Screening Visit
7. Pregnant women or women currently breastfeeding
8. History of cholecystectomy
9. Biliary disease which impedes biliary flow including active cholecystitis, primary biliary cirrhosis, sclerosing cholangitis, gallbladder cancer, gallbladder polyps, gangrene of the gallbladder, abscess of the gallbladder.
10. History of Class III/IV heart failure (per New York Heart Association - NYHA)
11. Severe pancreatic or intestinal disorders that may alter the enterohepatic circulation and absorption of TUDCA including biliary infections, pancreatitis and ileal resection
12. The presence of unstable psychiatric disease, cognitive impairment, dementia or substance abuse that would impair ability of the subject to provide informed consent, according to Site Investigator judgment
13. Clinically significant unstable medical condition (other than ALS) that would pose a risk to the subject if they were to participate in the study
14. Active participation in an ALS clinical trial evaluating a small molecule within 30 days of the Screening Visit
15. Exposure at any time to any biologic under investigation for the treatment of subjects with ALS (off-label use or investigational) including cell therapies, gene therapies, and monoclonal antibodies.
16. Implantation of Diaphragm Pacing System (DPS)

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; Placebo administered by mouth or via feeding tube for 24 weeks: once daily for first 3 weeks and then twice daily for remainder of study if participant tolerating	Other: Placebo; Matching Placebo Comparator
Experimental: AMX0035; AMX0035 administered by mouth or via feeding tube for 24 weeks: once daily for first 3 weeks and then twice daily for remainder of study if participant tolerating	Drug: AMX0035; AMX0035; Other Names: Proprietary formulation of taurursodiol and sodium phenylbutyrate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) Slope Change	Change in slope of Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) over treatment duration. The ALSFRS-R consists of 12 items across 4 subdomains of function (bulbar, fine motor, gross motor, and breathing) with each item scored on a scale from 0 (total loss of function) to 4 (no loss of function). Total scores range from 0 to 48, with higher scores indicating better function.	24 Weeks
Number of Participants With Adverse Events	Comparison Between Groups of Number of Participants With Adverse Events Until Planned Completion	24 Weeks
Number of Participants in Each Group Able to Remain on Study Drug Until Planned Discontinuation	A comparison of the number of participants in each group able to remain on study drug until planned discontinuation between groups	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Accurate Testing of Limb Isometric Strength (ATLIS) Total Score Change	The ATLIS device assess the isometric muscle strength of six upper-limb and six lower-limb muscle groups. At least two trials are performed for each muscle group to assess change in rate of decline of isometric muscle strength over treatment duration. Values are standardized to the percentage of predicted normal strength based on sex, age, weight, and height. Results are presented as percent of predicted normal.	24 Weeks
Change in Plasma Levels of Phosphorylated Axonal Neurofilament H Subunit (pNF-H)	Neuronal degeneration releases phosphorylated axonal neurofilament H subunit (pNF-H) into the cerebrospinal fluid and subsequently the blood and is thought to be a potential biomarker of motor neuron degeneration; elevated plasma levels of pNF-H are presumed to correlate with neuronal injury. Change in levels of plasma pNF-H were measured from baseline to week 24	24 Weeks
Rate of Decline in Slow Vital Capacity (SVC)	Respiratory muscle function was assessed according to slow vital capacity (SVC). SVC was measured in an upright position for at least three trials per assessment. SVC volumes were standardized to the percentage of predicted normal value based on age, sex, and height.	24 Weeks
Death, Tracheostomy, and Hospitalization	The composite outcome was defined as death, a death-equivalent event (which consisted of only tracheostomy in one participant in this trial), or hospitalization, whichever occurred first; there were no instances of permanent ventilation delivered by noninvasive means in the study.	24 Weeks

Collaborators and Investigators

• Sponsor: Amylyx Pharmaceuticals Inc.
• Collaborators: ALS Association; ALS Finding a Cure; Northeast ALS Consortium; Neurological Clinical Research Institute at Massachusetts General Hospital; Leandro P. Rizzuto Foundation
• Investigators: Principal Investigator: Sabrina Paganoni, MD, Massachusetts General Hospital; Study Director: Patrick Yeramian, MD, Amylyx Pharmaceuticals Inc.

Publications and helpful links

General Publications

• Cudkowicz ME, Andres PL, Macdonald SA, Bedlack RS, Choudry R, Brown RH Jr, Zhang H, Schoenfeld DA, Shefner J, Matson S, Matson WR, Ferrante RJ; Northeast ALS and National VA ALS Research Consortiums. Phase 2 study of sodium phenylbutyrate in ALS. Amyotroph Lateral Scler. 2009 Apr;10(2):99-106. doi: 10.1080/17482960802320487.
• Elia AE, Lalli S, Monsurro MR, Sagnelli A, Taiello AC, Reggiori B, La Bella V, Tedeschi G, Albanese A. Tauroursodeoxycholic acid in the treatment of patients with amyotrophic lateral sclerosis. Eur J Neurol. 2016 Jan;23(1):45-52. doi: 10.1111/ene.12664. Epub 2015 Feb 9. Erratum In: Eur J Neurol. 2017 Apr;24(4):659.
• Paganoni S, Hendrix S, Dickson SP, Knowlton N, Berry JD, Elliott MA, Maiser S, Karam C, Caress JB, Owegi MA, Quick A, Wymer J, Goutman SA, Heitzman D, Heiman-Patterson TD, Jackson C, Quinn C, Rothstein JD, Kasarskis EJ, Katz J, Jenkins L, Ladha SS, Miller TM, Scelsa SN, Vu TH, Fournier C, Johnson KM, Swenson A, Goyal N, Pattee GL, Babu S, Chase M, Dagostino D, Hall M, Kittle G, Eydinov M, Ostrow J, Pothier L, Randall R, Shefner JM, Sherman AV, Tustison E, Vigneswaran P, Yu H, Cohen J, Klee J, Tanzi R, Gilbert W, Yeramian P, Cudkowicz M. Effect of sodium phenylbutyrate/taurursodiol on tracheostomy/ventilation-free survival and hospitalisation in amyotrophic lateral sclerosis: long-term results from the CENTAUR trial. J Neurol Neurosurg Psychiatry. 2022 May 16;93(8):871-5. doi: 10.1136/jnnp-2022-329024. Online ahead of print.
• Paganoni S, Macklin EA, Hendrix S, Berry JD, Elliott MA, Maiser S, Karam C, Caress JB, Owegi MA, Quick A, Wymer J, Goutman SA, Heitzman D, Heiman-Patterson T, Jackson CE, Quinn C, Rothstein JD, Kasarskis EJ, Katz J, Jenkins L, Ladha S, Miller TM, Scelsa SN, Vu TH, Fournier CN, Glass JD, Johnson KM, Swenson A, Goyal NA, Pattee GL, Andres PL, Babu S, Chase M, Dagostino D, Dickson SP, Ellison N, Hall M, Hendrix K, Kittle G, McGovern M, Ostrow J, Pothier L, Randall R, Shefner JM, Sherman AV, Tustison E, Vigneswaran P, Walker J, Yu H, Chan J, Wittes J, Cohen J, Klee J, Leslie K, Tanzi RE, Gilbert W, Yeramian PD, Schoenfeld D, Cudkowicz ME. Trial of Sodium Phenylbutyrate-Taurursodiol for Amyotrophic Lateral Sclerosis. N Engl J Med. 2020 Sep 3;383(10):919-930. doi: 10.1056/NEJMoa1916945.

Helpful Links

• TUDCA in patients with ALS

Study record dates

Study Major Dates

• Study Start (Actual): June 22, 2017
• Primary Completion (Actual): September 25, 2019
• Study Completion (Actual): November 24, 2019

Study Registration Dates

• First Submitted: April 12, 2017
• First Submitted That Met QC Criteria: April 20, 2017
• First Posted (Actual): April 25, 2017

Study Record Updates

• Last Update Posted (Actual): August 11, 2021
• Last Update Submitted That Met QC Criteria: July 20, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: Amyotrophic Lateral Sclerosis; Placebo-controlled; Randomized; Double-blind; Sodium Phenylbutyrate; Tauroursodeoxycholic Acid
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Proteostasis Deficiencies; Sclerosis; Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Nervous System Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; Central Nervous System Diseases; Neuromuscular Diseases; TDP-43 Proteinopathies; Antineoplastic Agents; 4-phenylbutyric acid
• Other Study ID Numbers: AMX-3500

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Amylyx Pharmaceuticals, Inc., is in the process of developing a formal data sharing plan; requests for future data sharing can be sent to medinfo@amylyx.com

Drug and device information, study documents

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