Spruce Biosciences has announced compelling long-term clinical data demonstrating that tralesinidase alfa enzyme replacement therapy (TA-ERT) provides profound and durable benefits for patients with Sanfilippo Syndrome Type B (MPS IIIB), a fatal ultra-rare genetic disease affecting fewer than 1 in 200,000 people in the United States.
The integrated analysis encompassed five years of data from clinical studies 201, 202, and 401, comparing outcomes in 22 treated patients with untreated patients from natural history studies 901 and 902. The results show TA-ERT's ability to normalize pathogenic biomarkers while stabilizing cognitive function and brain structure in this devastating neurological condition.
Dramatic Biomarker Reduction Supports Accelerated Approval Pathway
The most striking finding involved cerebrospinal fluid heparan-sulfate non-reducing end (CSF HS-NRE), the toxic factor responsible for neurodegeneration in MPS IIIB. TA-ERT therapy reduced CSF HS-NRE levels by 91.5 ng/mL from baseline at 240 weeks (95% CI: -102.10, -80.90; p<0.0001), achieving normal or near-normal levels. Most participants experienced normalization within eight weeks of initiating therapy.
"These data demonstrate a rapid, profound, and durable effect of ICV-administered TA-ERT on normalizing CSF HS-NRE, the pathogenic factor leading to neurodegeneration, and in stabilizing CGMV and cognitive function, relative to the declines observed in untreated children," said Paul Harmatz, M.D., Principal Investigator and Professor in Residence at UCSF and UCSF Benioff Children's Hospital Oakland.
Critically, the FDA confirmed in a 2024 meeting that CSF HS-NRE is a surrogate biomarker reasonably likely to predict clinical benefit and could serve as basis for accelerated approval, potentially expediting the path to market for this orphan indication.
Cognitive Stabilization Contrasts with Natural Disease Progression
The cognitive outcomes revealed a stark contrast between treated and untreated patients. While untreated children showed declining cognition beginning around five years of age that progressively worsened, TA-ERT-treated patients maintained stable cognitive function over time.
Using model-based analysis, the mean Bayley-III Cognitive Raw Score (BSID-C) over six to 10 years of age was significantly higher in TA-ERT-treated patients compared to untreated, age-matched children. Differences emerged at six years of age (group difference: 10.67, 95% CI: 3.23, 18.11; p=0.005) and increased substantially by age 10 (group difference: 34.66, 95% CI: 24.38, 44.93; p<0.0001).
The data suggest that earlier treatment initiation in patients with higher baseline cognitive function and less established neurodegeneration may yield greater benefits, with some subjects showing actual improvements in BSID-C scores.
Brain Structure Preservation Demonstrates Neuroprotective Effects
Cortical grey matter volume (CGMV) analysis provided additional evidence of TA-ERT's neuroprotective effects. While untreated children with MPS IIIB experienced an average loss of approximately 32 mL over 48 weeks, treated patients showed stabilization of CGMV from weeks 48 to 240.
The initial 24-week period showed decreases in CGMV in treated patients, likely reflecting intracellular clearance of pathogenic substances consistent with TA-ERT's mechanism of action. This was followed by stabilization, contrasting with the continued decline observed in the natural disease course.
Safety Profile Supports Long-Term Treatment
TA-ERT demonstrated an adequate safety profile over exposures up to 7.3 years, with a mean exposure of 4.2 years. No deaths occurred throughout the studies. The most frequent treatment-emergent adverse events included vomiting (100% of participants), pyrexia (90.9%), upper respiratory tract infection (77.3%), pleocytosis (50.0%), COVID-19 infection (45.5%), and diarrhea (40.9%).
Four patients (18%) discontinued treatment, though three discontinuations were attributed to hydrocephalus, a known complication of MPS IIIB itself rather than treatment-related toxicity. Adverse events related to the intracerebroventricular delivery device were consistent with other therapies administered via this route.
Addressing Critical Unmet Medical Need
MPS IIIB is characterized by deficiency in N-Acetyl-Alpha-Glycosaminidase (NAGLU), an enzyme required for heparan sulfate catabolism in lysosomes. The resulting accumulation of toxic levels of cerebrospinal fluid heparan sulfate drives progressive neurodegeneration, leading to brain atrophy, cognitive impairment, behavioral changes, and ultimately death typically between ages 15-19.
"Currently, there is no U.S. FDA-approved therapy for the treatment of MPS IIIB, and disease management consists of limited palliative care," said Cara O'Neill, M.D., Co-Founder and Chief Science Officer of Cure Sanfilippo Foundation. "We are eager to see TA-ERT advance under the accelerated approval pathway."
Innovative Therapeutic Approach
TA-ERT represents a sophisticated approach to enzyme replacement therapy, comprising recombinant human alpha-N-acetylglucosaminidase (rhNAGLU) fused to an insulin-like growth factor 2 peptide. This fusion design addresses the challenge that naked rhNAGLU lacks mannose-6-phosphate residues essential for efficient cellular uptake.
The fusion protein binds to cation-independent mannose-6-phosphate receptors on cell surfaces, enabling internalization and lysosomal delivery. By restoring NAGLU enzymatic activity and promoting clearance of accumulated substrates in the brain, TA-ERT aims to preserve neuronal health and halt or slow neurological decline.
The therapy is administered via intracerebroventricular injection to ensure direct delivery to the central nervous system, where the pathogenic accumulation occurs. The BSID-C cognitive assessment is anticipated to serve as the primary endpoint for post-marketing clinical trials.
