RGX-121 Gene Therapy in Patients With MPS II (Hunter Syndrome)

MPS II is a rare X-linked recessive genetic disease caused by mutations in the
iduronate-2-sulfatase (IDS) gene . 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) is then expected to be secreted by transduced cells which are
then expected to cross-correct non-transduced cells by taking up the functional enzyme. This
is a Phase I/II, first-in-human, multicenter, open-label, dose escalation study of RGX-121.
Two, one time doses of RGX-121 will be studied in approximately 6 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.

Inclusion Criteria:

- Must meet any of the following criteria:

- a. Has a documented diagnosis of MPS II and a has a neurocognitive testing score > 55
and ≤ 77 (Bayley or Kaufman), OR

- b. Has a documented diagnosis of MPS II AND has a decline of ≥ 1 standard deviation on
serial neurocognitive testing (Bayley or Kaufman) and a testing score > 55, OR

- c. Has a relative 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

- 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 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

- Received ELAPRASE® via intrathecal (IT) administration within 4 months of signing the
ICF or experienced a serious hypersensitivity reaction to ELAPRASE®

- 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