The FDA recognized CSF HS-NRE as a surrogate biomarker reasonably likely to predict clinical benefit. How significant is this validation for accelerating approval pathways in ultra-rare neurological diseases like MPS IIIB, and what does it mean for future biomarker-driven drug development?

Spruce reported rapid and durable normalization of CSF HS-NRE levels in children treated with TA-ERT. From a neuropathological perspective, how closely is the clearance of heparan sulfate linked to slowing or preventing neurodegeneration in MPS IIIB?

The integrated data show stabilization of cortical grey matter volume and cognitive function. Given the progressive nature of Sanfilippo Type B, how clinically meaningful is this stabilization, and what benchmarks exist for interpreting these neurological outcomes in pediatric MPS trials?

Tralesinidase Alfa uses an insulin-like growth factor 2 (IGF2) fusion to enhance cellular uptake via the cation-independent mannose-6-phosphate receptor. How does this mechanism compare to traditional enzyme replacement approaches, and why is it particularly advantageous for CNS-targeted therapy?”

TA-ERT has been administered in 22 individuals across five years of integrated clinical data. What key safety signals or tolerability trends have emerged from these studies, and how do they inform the risk-benefit profile for chronic intracerebroventricular administration?

Conducting clinical trials in children with rapidly progressive neurodegenerative conditions is extremely challenging. What are the most difficult aspects of trial design and endpoint selection in MPS IIIB, and how has Spruce’s approach addressed these ethical and scientific hurdles?”

With the BLA submission planned for Q1 2026, how do you anticipate the FDA will evaluate TA-ERT given the strength of biomarker and clinical data to date? Could this set a precedent for other CNS-targeted enzyme therapies in the MPS spectrum?

Assuming approval, how might TA-ERT fit into the broader therapeutic landscape for MPS IIIB, particularly as gene therapy and next-generation delivery platforms emerge? Do you see potential for synergistic or sequential treatment strategies to maximize clinical benefit?”