RGX-121 Gene Therapy in Patients With MPS II (Hunter Syndrome)
Study Details
Study Description
Brief Summary
RGX-121 is a gene therapy which is intended to deliver a functional copy of the iduronate-2-sulfatase (IDS) gene to the central nervous system. This study is a safety and dose ranging study to determine whether RGX-121 is safe and tolerated by patients with MPS II.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1/Phase 2 |
Detailed Description
MPS II is a rare X-linked recessive genetic disease caused by mutations in the iduronate-2-sulfatase gene (IDS). Enzyme replacement therapy (ERT) with recombinant idursulfase (ELAPRASE®) is the only approved product for the treatment of Hunter syndrome, however, ERT as currently administered does not cross the Blood Brain Barrier and is therefore unable to address the unmet need in MPS II patients with CNS (neurocognition and behavior) involvement. RGX-121 is designed to deliver a healthy gene to cells in the CNS and iduronate-2-sulfatase (I2S) where it may be secreted by transduced cells which may cross-correct non-transduced cells by taking up the functional enzyme. This is a Phase I/II, first-in-human, multicenter, open-label, single arm dose escalation study of RGX-121. Three, one time doses of RGX-121 will be studied in approximately 18 pediatric subjects who have severe MPS II. 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-121.-121.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: RGX-121 Dose 1 1.3x10^10 GC/g brain mass of RGX-121 |
Genetic: RGX-121
Recombinant adeno-associated virus serotype 9 capsid containing human iduronate-2-sulfatase expression cassette
|
| Experimental: RGX-121 Dose 2 6.5x10^10 GC/g brain mass of RGX-121 |
Genetic: RGX-121
Recombinant adeno-associated virus serotype 9 capsid containing human iduronate-2-sulfatase expression cassette
|
| Experimental: RGX-121 Dose 2 Expanded Cohort 6.5x10^10 GC/g brain mass of RGX-121 |
Genetic: RGX-121
Recombinant adeno-associated virus serotype 9 capsid containing human iduronate-2-sulfatase expression cassette
|
| Experimental: RGX-121 Dose 3 2.0x10^11 GC/g brain mass of RGX-121 |
Genetic: RGX-121
Recombinant adeno-associated virus serotype 9 capsid containing human iduronate-2-sulfatase expression cassette
|
| Experimental: RGX-121 Dose 3 Expanded Cohort 2.0x10^11 GC/g brain mass of RGX-121 (Poly-A-specific PCR assay) equivalent to, 2.9x10^11 GC/g brain mass of RGX-121 (transgene-specific PCR assay) |
Genetic: RGX-121
Recombinant adeno-associated virus serotype 9 capsid containing human iduronate-2-sulfatase 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 as assessed by CTCAE (Version 4.03).
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).
- Biomarkers [Baseline, Week 2, Week 4, Week 8, Week 24, Week 48, Week 56, Week 104]
Change from baseline in Glycosaminoglycan levels (ng/mL)
- Biomarkers [Baseline, Week 1, Week 2, Week 4, Week 8, Week 24, Week 32, Week 48, Week 56, Week 104]
Change from baseline in iduronate-2-sulfatase activity
- Change in neurodevelopmental parameters [Baseline, Week 48, Week 78, Week 104]
Change from baseline in neurodevelopment parameters of cognitive, behavioral and adaptive function as measured by the Bayley Scales of Infant and Toddler Development, 3rd Edition (BSID-III) or Kaufman Assessment Battery for Children, 2nd Edition (KABC-II). Based on their mean age equivalence score on the Vineland Adaptive Behavior Scales (outcome #7) , the child will be assessed using either the BSID-III (for scores of <36 months or </=42 months and unable to complete the KABC-II) OR the KABC-II (for scores of >/= 36 months).
- Change in neurodevelopmental parameters [Baseline, Week 48, Week 78, Week 104]
Change from baseline in neurodevelopment parameters of cognitive, behavioral and adaptive function as measured by the Mullen Scales of Early Learning (MSEL)
- Change in neurodevelopmental parameters [Baseline, Week 48, Week 78, Week 104]
Change from baseline in neurodevelopment parameters of cognitive, behavioral and adaptive function as measured by the Vineland Adaptive Behavior Scales, 2nd Edition (VABS-II), Comprehensive Interview Form
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Must meet any of the following criteria:
-
- Has a documented diagnosis of MPS II AND has a neurocognitive testing score ≤ 77 (Bayley or Kaufman), OR
-
- Has a documented diagnosis of MPS II AND has a decline of ≥ 1 standard deviation on serial neurocognitive testing administered between 3 to 36 months apart (Bayley or Kaufman) OR
-
- Has a relative clinically diagnosed with severe MPS II who has the same IDS mutation as the subject AND in the opinion of a geneticist has inherited a severe form of MPS II OR
-
- Has documented mutation(s) in IDS that in the opinion of a geneticist is always known to result in a neuronopathic phenotype AND in the opinion of a clinician has a severe form of MPS II
-
Patient's legal guardian must be willing and able to provide written, signed informed consent.
-
Is ≥4 months to <5 years of age.
Exclusion Criteria:
-
Has contraindications for intracisternal injection, intracerebroventricular injection, or lumbar puncture
-
Has contraindications for immunosuppressive therapy
-
Has neurocognitive deficit not attributable to MPS II or diagnosis of a neuropsychiatric condition
-
Has a (cerebral) ventricular shunt that may impact the proper dosing of the subject
-
Received hematopoietic stem cell transplantation
-
Has had prior treatment with an AAV-based gene therapy product
-
Received ELAPRASE® via intrathecal (IT) administration within 4 months of signing the ICF or experienced a serious hypersensitivity reaction to ELAPRASE®
-
Has received any investigational product within 30 days of Day 1 or 5 half-lives before signing the ICF, whichever is longer
-
Has a platelet count <100,000 per microliter (µL), absolute neutrophil count <1.3 × 103/µL, or 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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of California San Francisco, Benioff Children's Hospital | Oakland | California | United States | 94609 |
| 2 | Children's Hospital of Philadelphia | Philadelphia | Pennsylvania | United States | 19104 |
| 3 | Children's Hospital of Pittsburgh - UPMC: Program for Neurodevelopment in Rare Disorders | Pittsburgh | Pennsylvania | United States | 15224 |
| 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-121-101