CAMPSIITE™ RGX-121 Gene Therapy in Subjects With MPS II (Hunter Syndrome)

MPS II (Hunter Syndrome) 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 central nervous system (CNS) (neurocognition and behavior) involvement. RGX-121 is designed to deliver a functional gene to cells in the CNS. Iduronate-2-sulfatase (I2S) may then be secreted by transduced cells, which may then cross-correct non-transduced cells by taking up the functional enzyme.

This is a Phase I/II/III study enrolling in two sequential parts. Part 1 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 up to 16 pediatric subjects who have neuronopathic 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. Part 2 is a pivotal expansion, multicenter, open-label, single arm study of RGX-121. A single dose of RGX-121 will be studied in up to 30 pediatric patients who have been diagnosed with neuronopathic MPS II. Subjects will be assessed at various timepoints for 24 months after receiving RGX-121. Subjects will be given the opportunity to enroll in a separate 3-year long-term follow-up study in accordance with the US federal government guidelines for the safety follow-up of patients receiving gene therapy.

Part 1 Inclusion Criteria:

• The subject's legal guardian(s) is (are) willing and able to provide written, signed informed consent after the nature of the study has been explained, and prior to any research-related procedures
• Is a male ≥4 months to < 5 years of age on Day 1
• Must meet any of the following criteria:

• Has a documented diagnosis of MPS II and a 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

Part 2 Inclusion Criteria:

• The subject's legal guardian(s) is (are) willing and able to provide written, signed informed consent after the nature of the study has been explained, and prior to any research-related procedures
• Is a male ≥4 months to < 5 years of age on Day 1
• Has a documented diagnosis of neuronopathic MPS II. Neuronopathic MPS II can be documented with any of the following methods:

• Has a BSID-III Cognitive Composite score at or below -1 SD (85) from normative mean
• Has two consecutive neurodevelopmental assessments that support a decline on MSEL visual receptive, expressive language, or fine motor, or BSID-III cognition, expressive language, or fine motor ≥ 1 SD on serial neurocognitive testing administered between 3 to 36 months apart
• Has a relative clinically diagnosed with neuronopathic MPS II who has the same IDS mutation as the subject AND the subject, in the opinion of a geneticist, has inherited a neuronopathic form of MPS II
• Has documented mutation(s) in IDS known to result in a neuronopathic phenotype

Part 1 Exclusion Criteria:

• Has contraindications for intracisternal (IC) injection, intracerebroventricular (ICV) 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

Part 2 Exclusion Criteria:

• Has a contraindication for an IC injection, ICV 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
• Is receiving idursulfase (ELAPRASE®) via intrathecal (IT) administration, or a blood brain barrier-crossing enzyme replacement therapy. Subjects receiving IT ELAPRASE® or a blood brain barrier-crossing ERT may enroll if they agree to discontinue these therapies starting at least 3 months prior to dosing with RGX-121, and for the 24 months of follow-up
• Has received any investigational product within 30 days of Day 1 or 5 half-lives before signing the ICF, whichever is longer