RGX-111 Gene Therapy in Patients With MPS I
Study Details
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 |
|---|---|---|
|
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
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
- Safety: Number of participants with treatment-related adverse events and serious adverse events [24 Weeks]
Number of participants with treatment-related adverse events and serious adverse events
Secondary Outcome Measures
- Safety: Number of participants with treatment-related adverse events [104 Weeks]
Number of participants with treatment-related adverse events as assessed by CTCAE (Version 4.03)
- Change in neurodevelopmental parameters [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).
- Change in neurodevelopmental parameters [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) .
- Change in neurodevelopmental parameters [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)) .
- Change in neurodevelopmental parameters [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).
- Change in adaptive behavior [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)
- Vector shedding [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
Criteria
Inclusion Criteria:
-
Has documented evidence of CNS involvement due to MPS I or documented diagnosis of severe MPS I
-
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:
-
Has contraindications for intracisternal and intracerebroventricular injection or lumbar puncture.
-
Has contraindications for immunosuppressive therapy.
-
Has neurocognitive deficit not attributable to MPS I or diagnosis of a neuropsychiatric condition.
-
Received intrathecal (IT) laronidase at any time and experienced a significant AE considered related to IT administration
-
Has received intravenous (IV) laronidase at any time and experienced a significant AE considered related to IV administration.
-
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.
-
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
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Children's Hospital of Orange County | Orange | California | United States | 92868 |
| 2 | Children's Hospital of Philadelphia | Philadelphia | Pennsylvania | United States | 19104 |
| 3 | University of Pennsylvania | Philadelphia | Pennsylvania | United States | 19104 |
| 4 | Hospital de Clinicas de Porto Alegre | Porto Alegre | RS | Brazil | 90035-903 |
Sponsors and Collaborators
- REGENXBIO, Inc.
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- RGX-111-002