An Open Label Phase 2 Study of ManNAc in Subjects With GNE Myopathy

NCT02346461 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: 15006815-HG-0068
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief Summary

Background: Patients with GNE myopathy have progressive muscle weakness and can have difficulty walking and decreased mobility. The disease is a rare genetic disorder that results from a gene mutation in a key step in the body's production of a sugar called sialic acid, (also called N-acetylneuraminic acid, Neu5Ac). Researchers think decreased sialic acid bound to muscle proteins may be the cause of muscle wasting in GNE myopathy. Researchers are testing the drug ManNAc which is a precursor in the production of sialic acid within cells. ManNAc is provided as a powder dissolved in water to be administered orally.

Conditions

GNE Myopathy

Keywords

Hereditary Inclusion Body Myopathy (HIBM); Sialic Acid (N-acetylneuraminic acid, Neu5Ac); GNE Myopathy; N-Acetyl-D-mannosamine (ManNAc); GNE Gene

Outcome Measures

Primary Outcomes (7)

• Mean Area Under the Curve (AUClast) of Plasma ManNAc (Baseline-adjusted)

  The mean area under the plasma ManNAc concentration-versus time curve from time 0 (dosing) to the time of last quantifiable concentration.

  Day 7

• Maximum Observed Plasma Concentration (Cmax) of ManNAc (Baseline-adjusted)

  The maximum (or peak) plasma ManNAc concentration that the drug achieves in the body after the drug has been administrated.

  Day 7

• The Time to Cmax (Tmax) for ManNAc

  The time taken to achieve the maximum observed plasma concentration for ManNAc .

  Day 7

• Half-life (t ½) for ManNAc

  The amount of time it takes for plasma ManNAc concentration to decline by half.

  Day 7

• Mean Area Under the Curve (AUClast) of Plasma Neu5Ac (Baseline-adjusted)

  The mean area under the plasma Neu5Ac concentration-versus time curve from time 0 (dosing) to the time of last quantifiable concentration.

  Day 7

• Maximum Observed Plasma Concentration (Cmax) of Neu5Ac (Baseline-adjusted)

  The maximum (or peak) plasma Neu5Ac concentration that the drug achieves in the body after the drug has been administrated.

  Day 7

• The Time to Cmax (Tmax) for Neu5Ac

  The time taken to achieve the maximum observed plasma concentration for Neu5Ac.

  Day 7

Study Arms (2)

Cohort A

ACTIVE COMPARATOR

6 subjects on Cohort A will receive oral ManNAc 3 g twice daily (6 g/day) for 7 days and, if safe, continue on 6 g twice daily (12 g/day) for the remainder of the study.

Drug: ManNAc

Cohort B

ACTIVE COMPARATOR

6 subjects on Cohort B will receive oral ManNAc 6 g twice daily (12 g/day) for the duration of the study.

Drug: ManNAc

Interventions

ManNAc DRUG

At doses of 3 g and 6 g twice daily for a total dose of 6 and 12 g per day.

Cohort A

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Subject is age 18-60 years, inclusive, and of either gender.
• Subject has a diagnosis of GNE myopathy based upon a consistent clinical course and identification of two GNE gene mutations.
• Subject must be willing to stop any treatment with ManNAc, sialic acid, intravenous immunoglobulin (IVIG), and/or other supplements containing sialic acid (e.g. St. John s wort, sialyllactose) 90 days prior to dosing and remain off such treatment for the duration of the trial.
• Subjects must have a body mass index (BMI) between 18 and 30 kg/m2, with a bodyweight of \>50 kg.
• Subjects must have 20-75% of predicted strength measured by QMA at baseline on at least one of the following: 1) ankle dorsiflexion, 2) knee flexion, 3) hip extension, 4) grip, 5) elbow flexion, shoulder abduction
• % of predicted strength measures by OMA at baseline, or
• If predicted muscle strength above 75%, a documented change of at least 10% per year.
• Subject has the ability to travel to the NIH Clinical Center for admissions.
• Subject has an INR less than or equal to 1.5 and must have stopped warfarin and other anticoagulants 2 weeks prior and after muscle biopsy procedures. Aspirin and clopidogrel should be stopped 3 days and 5 days before the procedure, respectively.
• Subject must be able to comply with requirements of the protocol, including blood collection, drug administration, muscle MRI/MRS, muscle biopsy and muscle strength assessments.
• If a woman of reproductive age, subject must be willing to use an effective method of contraception for the duration of the trial.
• Subject must be able to provide informed consent.

You may not qualify if:

• Subject had a clinical significant infection or medical illness 30 days prior to the first protocol visit.
• Subject has a psychiatric illness or neurological disease that would interfere with the ability to comply with the requirements of this protocol. This includes, but is not limited to, uncontrolled/untreated psychotic depression, bipolar disorder, schizophrenia, substance abuse or dependence, antisocial personality disorder, panic disorder, or behavioral problems, which interfere with effective communication.
• Subject has hepatic laboratory parameters (AST, ALT, GGTP) or renal laboratory parameters (creatinine, BUN) greater than 3 times the upper limit of normal.
• Subject has known adverse reactions to anesthetic or sedatives utilized for muscle biopsy.
• Subject is anemic (defined as Hematocrit \<30%) or has platelets \<100,000 or white blood cell count less than 3,000.
• Subject shows evidence of clinically significant cardiovascular, pulmonary, hepatic, renal, hematological, metabolic, or gastrointestinal disease, or has a condition that requires immediate surgical intervention.
• Subject is pregnant or breastfeeding at any time during the study.
• Subject has received treatment with another investigational drug, investigational device, or approved therapy for investigational use less than 90 days prior to the first protocol visit.
• Subject has hypersensitivity to ManNAc or in the judgment of the investigator, has a condition that places the subject at increased risk for adverse effects.
• Subject has received ManNAc, sialic acid, intravenous immunoglobulin (IVIG), and/or other supplements containing sialic acid (e.g. St. John s wort, sialyllactose) less than 90 days prior to the first protocol visit.
• The presence of persistent diarrhea or malabsorption that could interfere with the subject s ability to absorb drugs or to tolerate ManNAc therapy.

Sponsors & Collaborators

• National Human Genome Research Institute (NHGRI): lead
• National Center for Advancing Translational Sciences (NCATS): collaborator

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (2)

• Carrillo N, Malicdan MC, Leoyklang P, Shrader JA, Joe G, Slota C, Perreault J, Heiss JD, Class B, Liu CY, Bradley K, Jodarski C, Ciccone C, Driscoll C, Parks R, Van Wart S, Bayman L, Coffey CS, Quintana M, Berry SM, Huizing M, Gahl WA. Safety and efficacy of N-acetylmannosamine (ManNAc) in patients with GNE myopathy: an open-label phase 2 study. Genet Med. 2021 Nov;23(11):2067-2075. doi: 10.1038/s41436-021-01259-x. Epub 2021 Jul 13.

  PMID: 34257421 DERIVED

• Van Wart S, Mager DE, Bednasz CJ, Huizing M, Carrillo N. Population Pharmacokinetic Model of N-acetylmannosamine (ManNAc) and N-acetylneuraminic acid (Neu5Ac) in Subjects with GNE Myopathy. Drugs R D. 2021 Jun;21(2):189-202. doi: 10.1007/s40268-021-00343-6. Epub 2021 Apr 24.

  PMID: 33893973 DERIVED

MeSH Terms

Conditions

Distal myopathy, Nonaka type

Interventions

N-acetylmannosamine

Results Point of Contact

• Title: Carrillo, Nuria
• Organization: National Human Genome Research Institute

nuria.carrillo@nih.gov

+1 301 402 2324

Study Officials

• Nuria Carrillo, M.D.

  National Human Genome Research Institute (NHGRI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 24, 2015
• First Posted: January 27, 2015
• Study Start: February 5, 2015
• Primary Completion: December 30, 2017
• Study Completion: November 15, 2018
• Last Updated: April 16, 2019
• Results First Posted: April 16, 2019

Record last verified: 2019-03

Locations

US (1)