From May 11-14, 2021, the American Society of Gene and Cell Therapy (ASGCT) held its 24^th Annual Meeting. Due to COVID-19, the meeting was held virtually – but that didn’t stop industry leaders from coming together to share research insights. In a news release, biotechnology company REGENXBIO Inc. shared that safety and positive interim data from its Phase 1/2 clinical trial evaluating RGX-121 for pediatric patients with mucopolysaccharidosis type II (MPS II / Hunter syndrome) was presented during the meeting.

RGX-121

To begin, what is RGX-121? This investigational therapeutic candidate delivers the iduronate-2-sulfatase (IDS) gene to the central nervous system. According to REGENXBIO:

MPS II is a rare, X-linked recessive disease caused by a deficiency in the lysosomal enzyme IDS. Specific treatment to address the neurological manifestations of MPS II and prevent or stabilize cognitive decline remains a significant unmet medical need.

The therapy is administered intracisternally using an AAV9 vector. REGENXBIO believes that the administration method, and treatment, offer an opportunity to provide permanent IDS secretion beyond the blood-brain barrier (BBB). Thus far, the treatment has received Orphan Drug, Fast Track, and Rare Pediatric Disease designations.

RGX-121 Clinical Trial Data

Thus far, two cohorts have participated in the clinical trial. In both cohorts, patients were 5 years old or under. During the trial, patients received either 1.3×10¹⁰ genome copies per gram (GC/g) of brain mass or 6.5×10¹⁰ GC/g of brain mass of RGX-121. Altogether, REGENXBIO followed up with patients between 24 weeks (5.5 months) and 2 years. Some findings include:

• In both cohorts, RGX-121 was shown to be relatively safe and well-tolerated. No patients experienced serious adverse reactions, including patients recently dosed in Cohort 3 at 2.0×10¹¹ GC/g of brain mass.
• Two patients, who had been receiving weekly enzyme replacement therapy (ERT) at the onset of the trial, were able to discontinue ERT. Five patients finished a 48-week immunosuppressive regimen.
• Following a singular RGX-121 treatment, patients had lower heparin sulfate levels in their cerebrospinal fluid. Since these levels correlate with I2S activity, which RGX-121 is attempting to address, this is an extremely positive response. Additionally, all patients in Cohort 2 had detectable I2S levels following dosing.
• RGX-121 treatment also enhanced neurological and cognitive development for up to 2 years, showing a sustained response.

Mucopolysaccharidosis Type II (MPS II / Hunter Syndrome)

Mucopolysaccharidosis type II, also known as MPS II or Hunter syndrome, is a rare, inherited genetic disorder. Because it is an X-linked recessive disorder, it primarily affects males. While it is not impossible for females to have Hunter syndrome, it is extremely rare. The defective chromosome causes I2S deficiency, which prevents the body from breaking down mucopolysaccharides (complex chains of sugar molecules) called heparan sulphate and dermatan. As a result, these molecules remain in the body, causing progressive organ and tissue damage.

In around 75% of diagnoses, symptoms and physical characteristics appear between ages 18 months (1.5 years) and 4 years. Often, this form is also associated with developmental delay and early mortality (10-20 years old). In the more mild form, comprising 25% of diagnoses, patients may live into adulthood.

Symptoms and characteristics of MPS II include:

• Enlarged tongue, liver, and spleen
• Full lips, a broad nose, and large rounded cheeks
• Joint stiffness
• Carpal tunnel syndrome
• Developmental delays
• Skeletal irregularities
• A deep, hoarse voice
• Macrocephaly (an overly large head)
• Inguinal hernia
• Chronic diarrhea
• Abdominal distention
• Hydrocephalus (excess fluid around the brain)
• Reduced vision
• Spinal stenosis
• Frequent upper respiratory infections
• Chronic runny nose