BACKGROUND. Sanfilippo type B is a mucopolysaccharidosis (MPS) with a major neuronopathic component characterized by heparan sulfate (HS) accumulation due to mutations in the NAGLU gene encoding for alfa-N-acetyl-glucosaminidase. Enzyme replacement therapy for neuronopathic MPS requires efficient enzyme delivery throughout the brain in order to normalize HS, prevent brain atrophy and potentially delay cognitive decline. METHODS. In this phase 1/2, open-label study, subjects (n=22) affected with MPS IIIB were treated with tralesinidase alfa administered intracerebroventricularly (ICV). Subjects were monitored for drug exposure, total HS and HS non-reducing end (HS-NRE) levels in both cerebrospinal fluid (CSF) and plasma, anti-drug antibody response, brain, spleen and liver volumes as measured by magnetic resonance imaging and cognitive development as measured by age-equivalent (AEq) scores. RESULTS. In the Part 1 dose escalation (30, 100, and 300 mg) phase, tralesinidase alfa 300 mg was necessary to achieve normalization of HS and HS-NRE in CSF and plasma. In Part 2, tralesinidase alfa 300 mg sustained HS and HS-NRE normalization in the CSF and stabilized cortical grey matter volume (CGMV) over 48 weeks of treatment. Resolution of hepatomegaly and reduction in spleen volume were observed in most subjects. Significant correlations were also established between change in cognitive AEq and plasma drug exposure, plasma HS-NRE level and change in CGMV. CONCLUSION. ICV administration of tralesinidase alfa effectively normalized HS and HS-NRE as a prerequisite for clinical efficacy. Peripheral drug exposure data suggests a role for the glymphatic system in altering tralesinidase alfa efficacy. TRIAL REGISTRATION. Clinicaltrials.gov: NCT02754076.
Nicole Muschol, Anja Koehn, Katharina von Cossel, Ilyas Okur, Fatih Ezgu, Paul Harmatz, Maria Jose de Castro Lopez, Maria Luz Couce, Shuan-Pei Lin, Spyros Batzios, Maureen Cleary, Martha Solano, Igor Nestrasil, Brian D. Kaufman, Adam J. Shaywitz, Stephen M. Maricich, Bernice Kuca, Joseph Kovalchin, Eric H. Zanelli