Discussion
sleep behavior, hepatomegaly, MPS, MPS IIIB, hepatosplenomegaly, PD, cognitive and communication skills, LSDs, cognitive decline
BRAIN ATROPHY, DISEASE
In the present study, we show that, within weeks of weekly i.c.v. administration, 300 mg tralesinidase alfa could effectively compensate for NAGLU enzymatic activity as demonstrated by the normalization of HS and HS-NRE levels in both the CSF and plasma. Consequently, we observed resolution of hepatomegaly in most of the patients with MPS IIIB within 24 weeks of tralesinidase alfa administration. The presence of ADAs had no effect on HS normalization, hepatomegaly resolution, or the rate of cognitive decline. A longer treatment duration will be needed to fully evaluate the capacity of tralesinidase alfa to positively affect the lives of patients with MPS IIIB. The safety data for tralesinidase alfa (300 mg) administered weekly via i.c.v. infusion are in line with those for other ERTs, especially agents such as cerliponase alfa administered via i.c.v. dosing (Our study of 22 patients with MPS IIIB, aged 25–118 months at baseline, established an effective dose of 300 mg tralesinidase alfa administered i.c.v. as necessary to achieve and sustain normalization of both total HS and disease-specific HS-NRE levels. The normalization of total HS and HS-NRE levels in the CSF provides evidence that tralesinidase alfa can be potentially beneficial to patients with MPS IIIB. While HS-NRE normalization in CSF is critical and a prerequisite for potential efficacy, the concentration of both tralesinidase alfa and the greater dynamic range of measurement of HS-NRE levels in plasma might be indicative of the efficacy of tralesinidase alfa in the CNS (It is classically assumed that CSF flow is unidirectional and, therefore, that proteins directly administered in the CSF should be rapidly transported out of the brain and into the periphery (Our data favor an alternate explanation based on a recently identified pathway regarding the exchange of fluids and solutes from the CSF to the brain; the existence of the glymphatic system has now been established in human brain (The use of both a sedative and a flushing solution could facilitate tralesinidase alfa distribution into the brain, possibly through the perivascular Virchow-Robin spaces (Advances in MRI procedures are enabling new and exciting opportunities to understand the exchange of fluids and solutes from the CSF to the periphery in patients (Our data show that ADAs had no impact on the PK and PD of tralesinidase alfa, unlike what has been reported by others (We believe that the initial accelerated loss of CGMV in the first 24 weeks of Study 250-201 Part 2, i.e., 58 mL on average, versus 22 mL for the same patients in natural history Study 250-901 (The data presented here and in our natural history study (The present analysis has focused on the PK of tralesinidase alfa, the normalization of HS in the CSF and plasma following tralesinidase alfa administration, and its impact on hepatosplenomegaly and stabilization of brain atrophy. In addition, our data show a positive effect of tralesinidase alfa on cognitive function in patients with the highest plasma drug exposure and the lowest levels of HS in plasma. Yet, we recognize the limitations of the current study. In particular, the number of enrolled patients was limited because of the ultra-rare nature of the disease. The treatment duration was only 48 weeks for the great majority of the patients; however, our ongoing clinical study seems to confirm a long-term effect of tralesinidase alfa on cognitive and communication skills. Other long-term effects on sleep behavior and hearing and other quality-of-life measures are being monitored and will be reported in a future publication. Nonetheless, the analyses described in the current study can be applied to other forms of MPS and more broadly to other LSDs with neurological manifestations.In conclusion, the present study demonstrates the ability of 300 mg tralesinidase alfa to normalize HS and HS-NRE levels in CSF, resolve hepatomegaly, and stabilize brain atrophy in patients with MPS IIIB. ADAs did not interfere with tralesinidase alfa efficacy. The safety profile of tralesinidase alfa is consistent with what is expected of a drug administered i.c.v. Plasma drug exposure and plasma HS-NRE levels may indirectly indicate glymphatic function, which may play a role in improved efficacy. Considering the severity of MPS IIIB, it would be unexpected for tralesinidase alfa to provide clinical benefits to every patient, at least in terms of cognitive function. However, the early effect observed in a few patients within only 48 weeks of treatment is very encouraging and warrants further evaluation. In light of the poor and eventually fatal prognosis and the absence of disease-modifying therapies, tralesinidase alfa has the potential to change the course of the disease in children with MPS IIIB.