Objective:

To announce the FDA approval of Fayuvi, the first gene therapy for Sanfilippo syndrome type A.

Approach:

• Treatment Description: Fayuvi (rebisufligene etisparvovec-hopf) is a one-time AAV9 gene therapy indicated for neurological manifestations of mucopolysaccharidosis type IIIA (MPS IIIA) in pediatric patients with preserved neurodevelopmental function.
• Mechanism of Action: The therapy delivers a functional copy of the SGSH gene via a single intravenous infusion to restore sulfamidase production and support the breakdown of accumulated heparan sulfate.
• Study Design: Approval was based on an open-label, single-arm study comparing 17 treated children with 27 untreated patients from an external natural history cohort.

Key Findings:

• Treated patients showed a mean 16-point increase in Bayley-III Cognitive Scale raw score, while untreated patients had a 7.6-point decline. The adjusted between-group difference was 23.5 points. Cerebrospinal fluid heparan sulfate concentrations decreased, with 15 of 16 evaluated patients maintaining at least a 50% reduction at 24 months. Median follow-up in the primary efficacy population was 4.2 years.

Interpretation:

The comparison with an external natural history cohort introduces greater uncertainty than a controlled trial.

Limitations:

• The study lacked a randomized control group due to the rarity and severity of the disease, which may affect the robustness of the findings. The most common adverse reaction was elevated liver enzymes, reported in 85% of patients.

Conclusion:

Fayuvi represents a significant advancement in the treatment of Sanfilippo syndrome type A, although it requires careful monitoring for adverse effects.

Sources:

• FDA Announcement