MPSII Gene Therapy Shows Some Signs of Durable Efficacy


Interim data from the phase 1/2 CAMPSIITE trial were presented at WORLDSymposium 2023.

REGENXBIO’s gene therapy RGX-121 has demonstrated safety and efficacy in improving development in children with mucopolysaccharidosis type 2 (MPSII), according to interim data from the phase 1/2 CAMPSIITE trial (NCT03566043).1

The data were presented at the WORLDSymposium 2023, held February 22-26, in Orlando, Florida, by first author Can Ficicioglu, MD, PhD, Director, Newborn Metabolic Screening Program and Lysosomal Storage Diseases Program, and Clinical Director, Metabolic Disease Program, Children's Hospital of Philadelphia.

“MPS II, also known as Hunter syndrome, is a rare X-linked recessive genetic disease caused by a deficiency of duronate-2-sulfate (I2S), an enzyme required for the degradation of the glycosaminoglycans (GAGS) which results in GAG accumulation. [This] causes systemic symptoms, neurodegeneration, and leads to early death,”Ficiciogluand colleagues wrote in their poster.1 “Standard of care includes intravenous enzyme replacement therapy (ERT), which does not address central nervous system involvement.”

The CAMPSIITE trial has dosed 15 participants as of January 3, 2023, with 3 in cohort 1, 7 in cohort 2, and 5 in cohort 3. These participants had ages ranging from 5 months to 59 months and IDS mutations that included deletion, frameshift, gene inversion, insertion, missense, splicing, and substitution. The study lasted 104 weeks, after which participants were invited to participate in a long-term follow-up study for a total of 260 weeks or 5 years.

READ MORE: MPS-IH HSC Gene Therapy Gets IND Clearance

"These new results demonstrate sustained reductions in cerebrospinal fluid (CSF) GAGs and an encouraging, long-term clinical profile of RGX-121 up to 3 years," Steve Pakola, MD, chief medical officer, REGENXBIO, said in a statement.2 "GAGs measured in CSF, specifically heparan sulfate, reflect disease manifestations in the CNS and are a direct cause of disease pathophysiology. Our data provide additional evidence to support the finding that meaningful changes in CSF heparan sulfate is an appropriate and reliable surrogate endpoint reasonably likely to predict the clinical benefit of CNS-targeted therapies for MPS II. We are excited to have taken RGX-121 into a pivotal program and plan to file a Biologics License Application in 2024 using the accelerated approval pathway."

Investigators found that RGX-121 therapy was well-tolerated, with no serious adverse events (AEs) related to the therapy, although there were 12 serious unrelated AE, which included herpes simplex virus (HSV) gingivostomatitis, fever requiring hospitalization, infection of ventriculoperitoneal shunt, viral meningitis, hydrocephalus, laryngospasm. Seizures, and cerebellar/cerebral infarction, as well as tonsilitis, pharyngitis, viral upper respiratory infection (URI) and URI during long-term follow-up.1 Treatment-emergent AEs were mild, and investigators identified AEs of special interest related to immunosuppression which all resolved. The most common was HSV gingivostomatitis.

Ficicioglu and colleagues observed promising signs of efficacy in the treated patients, with most participants (n = 14) having dose-dependent reductions in CSF heperpan sulfate (HS) from baseline at week 48. Furthermore, HS D2S6 was also decreased from baseline at week 48 in 13 participants, with 3 partiicpants approaching normal levels. In cohorts 2 and 3, 10 of 11 participants had measurable CSF I2S protein concentration after treatment and the majority had increased plasma I2S protein concentration.

ERT use decreased in study participants. Seven participants maintained GAG concentration after ERT withdrawal, 3 ERT-naïve patients had a decrease in urine GAGS, and 12 of 13 participants that had previously used ERT had a decrease in total urine GAGS at the last ERT treated time point available.

"Treatment options to address the neurological manifestations of MPS II remain a significant unmet medical need for patients," Ficicioglu added to the statement.2 "The data presented today are encouraging and continue to show the potential of a one- time gene therapy to provide meaningful, durable clinical benefits to the MPS II community. I look forward to continuing to follow RGX-121 as it progresses through the pivotal program."

Investigators assessed neurodevelopment using the Bayley Scales of Infant and Toddler Development, 3rd edition (BSID-3) and found that most participants with a baseline function at least 2 standard deviations (SDs) below normal maintained in that range in at least 2 domains, and the majority of participants that were less than 2 SDs from normal stabilized or had an increase of over 3 months on cognitive, expressive, language or fine motor subtests.1 Seven of 9 participants with elevated maladaptive behavior at baseline had a reduction in Vineland Adaptive Behavior Scales Second Edition Maladaptive Behavior Index and 4 of 5 participants with average scores at baseline maintained these scores.

“[There were] dose-dependent, durable reductions in GAGS demonstrated across cohorts... [and] neurodevelopmental and daily activity skill acquisition was observed up to 3 years after RGX-121 administration,” Ficicioglu and colleagues wrote.1

Click here to read more coverage of WORLDSymposium 2023.

1. Ficicioglu C, Giugliani R, Harmatz P, et al. RGX-121 gene therapy for the treatment of neuronopathic mucopolysaccharidosis type II (MPS II): interim analysis of data from the first in human study. Presented at: WORLDSymposium 2023, February 22-26; Orlando, Florida. Abstract #LB-21
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