RGX-111 Gene Therapy in Patients With MPS I

• ClinicalTrials.gov Identifier: NCT03580083
• Recruitment Status: Active, not recruiting
• First Posted: July 9, 2018
• Last Update Posted: January 10, 2023
• Sponsor: REGENXBIO Inc.
• Information provided by (Responsible Party): REGENXBIO Inc.

Study Description

Brief Summary:

RGX-111 is a gene therapy which is intended to deliver a functional copy of the α-L-iduronidase (IDUA) gene to the central nervous system. This is a safety and dose ranging study to determine whether RGX-111 is safe and tolerated by patients with MPS I.

Condition or disease	Intervention/treatment	Phase
Mucopolysaccharidosis Type I (MPS I); Hurler Syndrome; Hurler-Scheie Syndrome	Genetic: RGX-111	Phase 1; Phase 2

Detailed Description:

Mucopolysaccharidosis type I (MPS I) is a rare recessive genetic disease caused by a deficiency of α-L-iduronidase (IDUA) leading to an accumulation of glycosaminoglycans (GAGs) in tissues of patients with MPS I. While currently available therapies, enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT), provide clinical benefit over untreated disease progression, they still possess significant limitations. ERT does not cross the blood-brain barrier and, therefore, does not treat the central nervous system (CNS) effects of the disease, and HSCT has clinically relevant morbidity and mortality and is not able to completely treat the CNS effects. RGX-111 is designed to deliver a functioning gene enabling the production of IDUA in the brain. This is a Phase I/II, first-in-human, multicenter, open-label, dose escalation study of RGX-111. Up to 11 subjects with MPS I will be treated in 2 dose cohorts and will receive a single dose of RGX-111. Safety will be the primary focus for the initial 24 weeks after treatment (primary study period) whereupon, subjects will continue to be assessed (safety and efficacy) for up to a total of 104 weeks following treatment with RGX-111.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 8 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Intervention Model Description: Sequential Assignment Dose escalation
• Masking: None (Open Label)
• Masking Description: Open-Label
• Primary Purpose: Treatment
• Official Title: A Phase I/II Multicenter, Open-Label Study to Evaluate the Safety, Tolerability, and Pharmacodynamics of Intracisternal RGX-111 in Subjects With Mucopolysaccharidosis Type I
• Actual Study Start Date: April 3, 2019
• Estimated Primary Completion Date: April 2023
• Estimated Study Completion Date: October 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Dose 1; 1x10^10 GC/g brain mass of RGX-111	Genetic: RGX-111; Recombinant adeno-associated virus serotype 9 capsid containing α-L-iduronidase expression cassette
Experimental: Dose 2; 5x10^10 GC/g brain mass of RGX-111	Genetic: RGX-111; Recombinant adeno-associated virus serotype 9 capsid containing α-L-iduronidase expression cassette

Outcome Measures

Primary Outcome Measures :

1. Safety: Number of participants with treatment-related adverse events and serious adverse events [ Time Frame: 24 Weeks ]
   Number of participants with treatment-related adverse events and serious adverse events

Secondary Outcome Measures :

1. Safety: Number of participants with treatment-related adverse events [ Time Frame: 104 Weeks ]
   Number of participants with treatment-related adverse events as assessed by CTCAE (Version 4.03)
2. Change in neurodevelopmental parameters [ Time Frame: Baseline, Week 24, Week 52, Week 78, Week 104 ]
   As measured by the Wechsler Abbreviated Scale of Intelligence, 2nd Edition (WASI-II).Based on their mean age equivalence score on the Vineland Adaptive Behavior Scales (#7) the subject will be assessed using the WASI-II ( for scores of >/= 72 months).
3. Change in neurodevelopmental parameters [ Time Frame: Baseline, Week 24, Week 52, Week 78, Week 104 ]
   As measured by the Bayley Scale of Infant and Toddler Development, Third Edition (Bayley-III). Based on their mean age equivalence score on the Vineland Adaptive Behavior Scales (#7) the subject will be assessed using the BSID-III (for scores of </ = 36 months or >36 months to <42 months) .
4. Change in neurodevelopmental parameters [ Time Frame: Baseline, Week 24, Week 52, Week 78, Week 104 ]
   As measured by the Wechsler Preschool and Primary Scales of Intelligence, Fourth Edition (WPPSI-IV). Based on their mean age equivalence score on the Vineland Adaptive Behavior Scales (#7) the subject will be assessed using the WPPSI-IV (for scores >36 months to < 42 months OR for scores of >/= 42 months and <72 months or >36 months to <42 months and unable to complete BSID-III (#4)) .
5. Change in neurodevelopmental parameters [ Time Frame: Baseline, Week 24, Week 52, Week 78, Week 104 ]
   Change from baseline in neurodevelopment parameters of attention as measured by the Tests of Variables of Attention, Version 9 (TOVA) if able to complete the WASI-II (as defined in #3).
6. Change in adaptive behavior [ Time Frame: Baseline, Week 12, Week 24, Week 36, Week 52, Week 78, Week 104 ]
   Change in baseline in adaptive behavior as measured by the Vineland Adaptive Behavior Scales, Third Edition (VABS-III)
7. Vector shedding [ Time Frame: Baseline, Week 1, Week 4, Week 8, Week 16, Week 24 ]
   As measured by vector concentration (quantitative polymerase chain reaction [qPCR] to RGX-111 deoxyribonucleic acid [DNA]) in CSF, serum, and urine

Eligibility Criteria

• Ages Eligible for Study: 4 Months and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Has documented evidence of CNS involvement due to MPS I or documented diagnosis of severe MPS I
2. Subjects who have had HSCT may be enrolled in the study if the PI, medical monitor, and sponsor agree that he/she can participate in the study.

Exclusion Criteria:

1. Has contraindications for intracisternal and intracerebroventricular injection or lumbar puncture.
2. Has contraindications for immunosuppressive therapy.
3. Has neurocognitive deficit not attributable to MPS I or diagnosis of a neuropsychiatric condition.
4. Received intrathecal (IT) laronidase at any time and experienced a significant AE considered related to IT administration
5. Has received intravenous (IV) laronidase at any time and experienced a significant AE considered related to IV administration.
6. Received any investigational product within 30 days of Day 1 or 5 half-lives before signing of the Informed Consent Form (ICF), whichever is longer.
7. Has alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 × upper limit of normal (ULN) or total bilirubin >1.5 × ULN at screening unless the subject has a previously known history of Gilbert's syndrome and a fractionated bilirubin that shows conjugated bilirubin <35% of total bilirubin.

Contacts and Locations

Locations

United States, California

Children's Hospital of Orange County

Orange, California, United States, 92868

United States, Pennsylvania

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States, 19104

Brazil

Hospital de Clinicas de Porto Alegre

Porto Alegre, RS, Brazil, 90035-903

Israel

Sheba Medical Center

Tel HaShomer, Israel, 5265601

Sponsors and Collaborators

REGENXBIO Inc.

More Information

• Responsible Party: REGENXBIO Inc.
• ClinicalTrials.gov Identifier: NCT03580083
• Other Study ID Numbers: RGX-111-002
• First Posted: July 9, 2018
• Last Update Posted: January 10, 2023
• Last Verified: January 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by REGENXBIO Inc.:

MPS I , gene therapy, Hurler, Hurler- Scheie

Additional relevant MeSH terms:

Mucopolysaccharidoses; Mucopolysaccharidosis I; Syndrome; Disease; Pathologic Processes; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Lysosomal Storage Diseases; Mucinoses; Connective Tissue Diseases; Metabolic Diseases