Safety and Efficacy of GS-100 Gene Therapy in Patients With NGLY1 Deficiency

NCT06199531 | Active Not Recruiting Phase 3 DMC FDA Drug

• 1 other identifier: GS-100-A301
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 2

Brief Summary

A non-randomized, open-label, Phase 1/2/3 study of a single intracerebroventricular (ICV) administration of a gene replacement therapy (GS-100) in participants who are 2 to 18 years old with NGLY1 Deficiency.

Conditions

NGLY1 Deficiency

Keywords

Gene Therapy; Intervention study; Infusions, Intraventricular; Enzyme Replacement Therapy

Outcome Measures

Primary Outcomes (2)

• Phase 1/2 (Dose Finding): Safety and Tolerability of GS-100

  Incidence of adverse events (AEs) and serious AEs (SAEs)

  Baseline through Week 52

• Phase 3 (Pivotal): Efficacy of GS-100 at the Selected Dose

  Improvement in one or more domains of the 88-item Gross Motor Function Measure (GMFM-88) from Baseline to Week 52

  Baseline through Week 52

Secondary Outcomes (11)

• Individual domains of the Bayley Scales of Infant and Toddler Development 4th Ed (BSID-4) for the Cognitive, Language, and Motor scales

  Baseline through Week 52

• Clinical Global Impression of Change (CGI-C)

  Baseline through Week 52

• Clinical Global Impression of Severity (CGI-S)

  Baseline through Week 52

• Videotaped movement disorder assessments

  Baseline through Week 52

• Sitting/standing assessment

  Baseline through Week 52

Study Arms (5)

Cohort 1

EXPERIMENTAL

GS-100 Low Dose Level: 4e14 total vector genomes (vg) for 6-18-year-olds (fully enrolled, 2 participants)

Genetic: GS-100

Cohort 2

EXPERIMENTAL

GS-100 Mid Dose Level: 1e15 total vector genomes (vg) for 13-18-year-olds, 8.7e14 total vg for 2-5-year-olds (fully enrolled, 2 participants)

Genetic: GS-100

Cohort 3

EXPERIMENTAL

GS-100 High Dose Level: 3e15 total vector genomes (vg) for 6-18-year-olds, 2.6e15 vg for 2-5-year-olds (fully enrolled, 2 participants)

Genetic: GS-100

Cohort 4

EXPERIMENTAL

GS-100 Intermediate Dose Level: 2e15 total vector genomes (vg) for 6-18-year-olds, 1.75e15 total vg for 2-5-year-olds (fully enrolled, 1 participant)

Genetic: GS-100

Pivotal Cohort

EXPERIMENTAL

GS-100 Selected Dose Level: 1e15 total vector genomes (vg) for 6-18-year-olds, 8.7e14 total vg for 2-5-year-olds (fully enrolled, 3 participants)

Genetic: GS-100

Interventions

GS-100 GENETIC

A single intracerebroventricular (ICV) dose of GS-100

Cohort 1; Cohort 2; Cohort 3; Cohort 4; Pivotal Cohort

Eligibility Criteria

• Age: 2 Years - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Patients must be 2 to 18 years of age, inclusive, at the time of signing the informed consent form (ICF)
• Patients with a documented diagnosis of NGLY1 Deficiency based on detection of biallelic variants in the NGLY1 gene via molecular genetic sequencing
• Elevated GNA levels may be considered alongside genetic sequencing data and other clinical data to assist with diagnosis confirmation
• Patients with two or more of the following clinical features typical of NGLY1 Deficiency:
• Global developmental delay and/or intellectual disability
• Hyperkinetic movement disorder
• Transient elevation of transaminases
• (Hypo)alacrima
• Peripheral neuropathy
• For patients with epilepsy who require anti-seizure medications for seizure control: must be on a stable regimen for 28 days prior to enrollment
• Patients willing and capable per investigator opinion to comply with study procedures and requirements
• Females of childbearing potential must have a negative serum pregnancy test at screening and must agree to use an acceptable method of highly effective contraception from screening through the end of the study
• Patients or parent(s)/guardian(s) must be willing and able to provide written consent after the nature of the study has been explained and prior to performance of any research-related procedures

You may not qualify if:

• For Phase 1/2 only: Patients at Level 5 of both the Gross Motor Function Classification System Expanded and Revised (GMFCS E\&R) and the Communication Function Classification System (CFCS) scales as assessed by the investigator
• Contraindication to use of corticosteroids or history of a condition that could worsen with corticosteroid therapy, as assessed, and determined by the investigator
• Signs / symptoms of increased intracranial pressure (ICP), history of space occupying lesion, or ventricular shunt that would preclude ICV procedures or safety assessments
• a. If clinical signs or symptoms of increased ICP are present (such as headache, vomiting, altered mental status), an ophthalmology examination will be performed to assess for papilledema and/or venous pulsations
• Any comorbid medical or behavioral condition that, in the opinion of the investigator, may adversely affect the safety and well-being of the participant during the study, interfere with completion of the study procedures or follow-up, or compound interpretation of the study results
• Vital signs outside age-based normative values:
• Blood pressure: values \> 99th percentile as cited in the National Heart, Lung and Blood Institute (NHLBI) guidelines for blood pressure levels based on subject's age, height and sex (nhlbi.nih.gov/files/docs/guidelines/child\_tbl.pdf)
• Temperature: evidence of fever such as body temperature (e.g., orally measured) of 38.0°C (100.3°F)
• Respiratory rate in breaths per minute: toddler (1-3 years old): 24-40; preschooler (4-5 years old): 22-34 breaths per minute; school-aged child (6-12 years old): 18-30 breaths per minute; adolescence (13-18 years old): 12-16.
• Oxygen saturation on room air \< 92%
• Any condition that in the opinion of the investigator or the study medical monitor would prevent the patient from fully complying with the requirements of the study (including the corticosteroid treatment outline in the protocol) and/or would impact or interfere with the evaluation and interpretation of patient safety or efficacy results
• Known allergy or hypersensitivity to the GS-100 investigational product formulation
• Prior treatment with gene therapy
• Treatment with any investigational product (IP) within 30 days or 5 half-lives of the IP, whichever is longer, prior to screening period. For patients who have received a prior investigational product, all ongoing AEs experienced while receiving the investigational product must have been resolved prior to screening for this study
• Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study that does not interfere with the requirements of the current protocol and does not have the potential to impact the evaluation of safety and efficacy of GS-100

Sponsors & Collaborators

• Grace Science, LLC: lead

Study Sites (2)

Oakland Children's Hospital (UCSF Benioff)

Oakland, California, 94609, United States

Location

Texas Children's Hospital (Baylor College of Medicine)

Houston, Texas, 77030, United States

Location

Related Publications (4)

• Zhu L, Cook JW, Newton A, Dwight SS, Beahm B, Wilsey M, Mueller WF, Schweighardt B. Preclinical pharmacology and safety studies to support an AAV9 NGLY1 gene therapy clinical trial for the treatment of NGLY1 deficiency. Mol Ther Methods Clin Dev. 2025 Jun 25;33(3):101524. doi: 10.1016/j.omtm.2025.101524. eCollection 2025 Sep 11.

  PMID: 40687377 BACKGROUND

• Tong S, Ventola P, Frater CH, Klotz J, Phillips JM, Muppidi S, Dwight SS, Mueller WF, Beahm BJ, Wilsey M, Lee KJ. NGLY1 deficiency: a prospective natural history study. Hum Mol Genet. 2023 Sep 5;32(18):2787-2796. doi: 10.1093/hmg/ddad106.

  PMID: 37379343 BACKGROUND

• Stanclift CR, Dwight SS, Lee K, Eijkenboom QL, Wilsey M, Wilsey K, Kobayashi ES, Tong S, Bainbridge MN. NGLY1 deficiency: estimated incidence, clinical features, and genotypic spectrum from the NGLY1 Registry. Orphanet J Rare Dis. 2022 Dec 17;17(1):440. doi: 10.1186/s13023-022-02592-3.

  PMID: 36528660 BACKGROUND

• Levy RJ, Frater CH, Gallentine WB, Phillips JM, Ruzhnikov MR. Delineating the epilepsy phenotype of NGLY1 deficiency. J Inherit Metab Dis. 2022 May;45(3):571-583. doi: 10.1002/jimd.12494. Epub 2022 Mar 11.

  PMID: 35243670 BACKGROUND

MeSH Terms

Conditions

NGLY1 deficiency

Interventions

d-limonene-medium-chain monoglyceride

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: The study treatment will be delivered via intracerebroventricular (ICV) infusion.

Study Record Dates

• First Submitted: November 21, 2023
• First Posted: January 10, 2024
• Study Start: February 13, 2024
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): March 1, 2031
• Last Updated: May 4, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)