Multi-Center Study of ManNAc for GNE Myopathy (MAGiNE)

A Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study to Evaluate the Efficacy of ManNAc in Subjects With GNE Myopathy

GNE myopathy is a rare genetic muscle disease characterized by progressive muscle atrophy and weakness. The disease is caused by mutations in the gene that encodes the enzyme that initiates and regulates N-acetylneuraminic acid (Neu5Ac) biosynthesis and glycan sialylation. Currently, there is no therapy available for this disease. N-Acetylmannosamine (ManNAc), an orphan drug in development for GNE myopathy, is an uncharged monosaccharide and the first committed precursor in Neu5Ac biosynthesis. In this randomized, double-blind, placebo-controlled trial the efficacy and long-term safety of ManNAc will be evaluated in subjects with GNE myopathy.

Study Overview

• Status: Active, not recruiting
• Conditions: GNE Myopathy
• Intervention / Treatment: Other: Placebo; Drug: ManNAc

Detailed Description

This is a randomized, placebo-controlled, double-blind, multi-center study to evaluate the long-term safety and clinical efficacy of ManNAc in subjects with GNE myopathy.

A total of 51 eligible subjects will be randomized in a 2:1 ratio to receive either ManNAc at 4 g three times daily (total of 12 g/day) or placebo. Subjects will have follow-up visits every 6 months (±7 days) and take study drug for a minimum of 24 months, until their final study visit . The final on-site study visit for a subject is the last expected 6-month follow-up visit that occurs prior to the time the last randomized subject is expected to reach 24 months (extended follow-up).

Subjects will undergo screening and baseline evaluations that include clinical laboratory tests, Quantitative Muscle Assessment (QMA), the Inclusion Body Functional Myositis Rating Scale (IBMFRS), and other patient-reported outcomes (PROs), and rehabilitation medicine functional assessments. Follow-up evaluations will occur every six months following baseline, until 24 months after randomization of the last subject. Phone follow-up will occur every month without a clinic visit for the duration of the trial, and the last visit for each subject will be followed by phone follow-up 1 month after the final study visit.

• Study Type: Interventional
• Enrollment (Actual): 54
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095
      • UCLA
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas, Medical Center
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • NIH Clinical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • Rochester, New York, United States, 14642
      • University of Rochester
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University, Wexner Medical Center
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Subject should be 18-70 years of age at the time of enrollment, inclusive, and of either gender.
2. Subject has a diagnosis of GNE myopathy based upon a consistent clinical course and biallelic GNE gene mutations that classify as pathogenic or likely pathogenic according to American College of Medical Genetics and Genomics (ACMG) guidelines.
3. Subjects must have 10.00-65.99% of predicted muscle strength measured by QMA at screening in at least one of the selected muscle groups (ankle dorsiflexion, knee flexion, grip, shoulder abduction and elbow flexion).
4. Subject has the ability to travel to the Clinical Trial Site for visits.
5. Subjects must be able to communicate effectively with study staff and understand the requirements of the protocol without translators.
6. Subject must be able to comply with requirements of the protocol, including blood collection, drug administration, and muscle strength assessments.
7. Women of childbearing potential must be willing to use an effective method of contraception for the duration of the trial. It is recommended that male subjects follow birth control measures for the duration of the trial.
8. Subject must be able to provide informed consent.

Exclusion Criteria:

1. Subject had an infection or medical illness requiring intravenous antibiotics or hospitalization within 30 days prior to the baseline/randomization visit.
2. Subject has another comorbid condition which may affect physical function.
3. Subject has a psychiatric illness or neurological disease that would interfere with the ability to comply with the requirements of this protocol.
4. Subject with hepatic laboratory parameters (AST, ALT, GGTP), equal to or greater than 3 times the upper limit of normal at screening.
5. Subject with existing renal dysfunction, as defined by glomerular filtration rate (GFR) less than 60 mL/min/1.73 m2 at screening.
6. Subject is anemic (defined as Hematocrit <30%) or has platelets <75 x 10^3/µL or white blood cell count less than 3 x 10^3/µL at screening.
7. Subject shows evidence of clinically significant cardiovascular, pulmonary, hepatic, renal, hematological, metabolic, or gastrointestinal disease, or has a condition that requires immediate surgical intervention.
8. Subject is pregnant or breastfeeding at any time during the study.
9. Subject has received treatment with another investigational drug, investigational device, or approved therapy for investigational use less than 90 days prior to screening.
10. Subject has received any dose of ManNAc, sialic acid, intravenous immunoglobulin (IVIG), and/or other compounds containing, or that can be metabolized into sialic acid, within 6 months prior to enrollment as reported by subject at the time of screening.
11. Subject has received stem cell therapy or gene therapy within 1 year prior to screening.
12. Subject has hypersensitivity to ManNAc or erythritol or in the judgment of the investigator, has a condition that places the subject at increased risk for adverse effects.
13. The presence of persistent diarrhea or malabsorption that could interfere with the subject's ability to absorb drugs or to tolerate ManNAc therapy.

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: ManNAc; Oral ManNAc will be administered at a dose of 4 grams three times daily (total of 12 grams daily).	Drug: ManNAc; Oral N-acetyl-D-mannosamine monohydrate (ManNAc); Other Names: N-acetyl-D-mannosamine monohydrate
Placebo Comparator: Placebo; Oral Placebo will be administered three times daily.	Other: Placebo; Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Muscle strength of ankle dorsiflexion, knee flexion, knee extension, shoulder abduction, elbow flexion and grip measured by fixed-frame Quantitative Muscle Assessment (QMA)	The primary endpoint is the change in muscle strength decline under treatment compared to placebo. The primary analysis is based on the disease progression ratio (γ) comparing the rate of progression from baseline until last visit, under placebo to that under treatment.	Minimum 2 years, until 24 months from randomization of last subject

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Inclusion Body Myositis Functional Rating Scale (IBMFRS)	Change in patient-reported function as measured by the Inclusion Body Myositis Functional Rating Scale (IBMFRS).	Minimum 2 years, until 24 months from randomization of last subject

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Events	Safety and tolerability will be evaluated by comparing the frequency of adverse events (AEs) across groups, collected using information from in-person assessments, clinical laboratory tests, vital signs, electronic diary reports, and physical examinations.	Minimum 2 years, until 24 months from randomization of last subject
Correlation muscle strength measured Exploratory GNEM Functional Questions (ExGNEM)	Evaluate the effect of ManNAc on patient-reported physical functioning assessed by ExGNEM, a six-question rating scale that assesses lower body function.	Minimum 2 years, until 24 months from randomization of last subject
Adult Myopathy Assessment Tool	Evaluate the effect of ManNAc on physical function as measured by the Adult Myopathy Assessment Tool (AMAT), a 13-item standardized test that assesses physical performance, to be performed at baseline and every 6 months thereafter until completion of the study.	Minimum 2 years, until 24 months from randomization of last subject
Six-Minute Walk Test	Evaluate the effect of ManNAc on physical function as measured by the Six-Minute Walk Test (whenever possible) to be performed at baseline and every 6 months thereafter until completion of the study.	Minimum 2 years, until 24 months from randomization of last subject
Timed Up and Go Test	Evaluate the effect of ManNAc on physical function as measured by the Timed Up and Go, performance test to evaluate functional mobility, to be performed at baseline and every 6 months thereafter until completion of the study.	Minimum 2 years, until 24 months from randomization of last subject
Functional Reach Test	Evaluate the effect of ManNAc on physical function as measured by the Functional Reach, a measure of stability, to be performed at baseline and every 6 months thereafter until completion of the study.	Minimum 2 years, until 24 months from randomization of last subject
Jebsen Hand Function Test	Evaluate the effect of ManNAc on physical function as measured by the Jebsen Hand Function Test, a performance measure which assesses unilateral hand function, to be performed at baseline and every 6 months thereafter until completion of the study.	Baseline and every 12 months thereafter
Inclusion Body Myositis Functional Rating Scale	Evaluate effect of ManNAc on activities of daily living (ADLs) compared to placebo as measured by the Inclusion Body Myositis Functional Rating Scale (IBMFRS), a patient-reported outcome completed at baseline, and every 6 months thereafter until completion of the study.	Minimum 2 years, until 24 months from randomization of last subject
Human Activity Profile	Evaluate effect of ManNAc on activities of daily living (ADLs) compared to placebo as measured by the Human Activity Profile, a patient-reported outcome completed at baseline, and every 6 months thereafter until completion of the study.	Minimum 2 years, until 24 months from randomization of last subject
Activities-specific Balance Confidence (ABC) scale	Evaluate effect of ManNAc on activities of daily living (ADLs) compared to placebo as measured by the Activities-specific Balance Confidence (ABC) scale, a patient-reported outcome completed at baseline, and every 6 months thereafter until completion of the study.	Minimum 2 years, until 24 months from randomization of last subject

Collaborators and Investigators

• Sponsor: Leadiant Biosciences, Inc.
• Collaborators: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); National Institute of Neurological Disorders and Stroke (NINDS); Brigham and Women's Hospital; National Human Genome Research Institute (NHGRI)
• Investigators: Principal Investigator: Anthony A. Amato, MD, Brigham and Women's Hospital; Principal Investigator: Francis Rossignol, MD, National Institutes of Health (NIH)

Publications and helpful links

General Publications

• Quintana M, Shrader J, Slota C, Joe G, McKew JC, Fitzgerald M, Gahl WA, Berry S, Carrillo N. Bayesian model of disease progression in GNE myopathy. Stat Med. 2019 Apr 15;38(8):1459-1474. doi: 10.1002/sim.8050. Epub 2018 Dec 3.
• Carrillo N, Malicdan MC, Huizing M. GNE Myopathy: Etiology, Diagnosis, and Therapeutic Challenges. Neurotherapeutics. 2018 Oct;15(4):900-914. doi: 10.1007/s13311-018-0671-y.
• Xu X, Wang AQ, Latham LL, Celeste F, Ciccone C, Malicdan MC, Goldspiel B, Terse P, Cradock J, Yang N, Yorke S, McKew JC, Gahl WA, Huizing M, Carrillo N. Safety, pharmacokinetics and sialic acid production after oral administration of N-acetylmannosamine (ManNAc) to subjects with GNE myopathy. Mol Genet Metab. 2017 Sep;122(1-2):126-134. doi: 10.1016/j.ymgme.2017.04.010. Epub 2017 Apr 26.

Helpful Links

• Study NN109/MAGiNE website

Study record dates

Study Major Dates

• Study Start (Actual): April 5, 2022
• Primary Completion (Estimated): March 28, 2024
• Study Completion (Estimated): July 15, 2024

Study Registration Dates

• First Submitted: January 8, 2020
• First Submitted That Met QC Criteria: January 13, 2020
• First Posted (Actual): January 18, 2020

Study Record Updates

• Last Update Posted (Estimated): February 7, 2024
• Last Update Submitted That Met QC Criteria: February 6, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: GNE Myopathy; Hereditary Inclusion Body Myopathy (HIBM); Distal Myopathy with Rimmed Vacuoles (DMRV); Nonaka Myopathy; Inclusion Body Myopathy type 2 (IBM-2)
• Additional Relevant MeSH Terms: Nervous System Diseases; Genetic Diseases, Inborn; Musculoskeletal Diseases; Neuromuscular Diseases; Muscular Disorders, Atrophic; Muscular Dystrophies; Muscular Diseases; Distal Myopathies
• Other Study ID Numbers: NN109; 1U01AR070498-01A1 (U.S. NIH Grant/Contract)

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