Final results of the phase 1/2, open-label clinical study of intravenous recombinant human N-acetyl-α-d-glucosaminidase (SBC-103) in children with mucopolysaccharidosis IIIB.
Mucopolysaccharidosis IIIB is caused by a marked decrease in N-acetyl-α-d-glucosaminidase (NAGLU) enzyme activity, which leads to the accumulation of heparan sulfate in key organs, progressive brain atrophy, and neurocognitive decline. In this open-label study, 11 eligible patients aged 2 to <12 years (developmental age ≥ 1 year) were sequentially allocated to recombinant human NAGLU enzyme (SBC-103) in 3 staggered- and escalating-dose groups (0.3 mg/kg [n = 3], 1.0 mg/kg [n = 4], or 3.0 mg/kg [n = 4]) by intravenous infusion every 2 weeks for 24 weeks, followed by a 4-week interruption (Part A), treatment at 1.0 and/or 3.0 mg/kg every 2 weeks starting at week 28 (Part B), and treatment at 5.0 or 10.0 mg/kg every 2 weeks (Part C) for approximately 2 total years in the study. The primary objective of the study was safety and tolerability evaluation; secondary objectives included evaluation of SBC-103 effects on total heparan sulfate levels in cerebrospinal fluid (CSF), brain structural magnetic resonance imaging (cortical gray matter volume), and neurocognitive status (age equivalent/developmental quotient). During the study, 13 treatment-emergent serious adverse events (SAEs) occurred in 3 patients; 32 infusion-associated reactions (IARs) occurred in 8 patients. Most AEs were mild and intravenous treatment with SBC-103 was well tolerated. Mean (SD) changes from baseline at 52 weeks in Part C for the 5.0 and 10.0 mg/kg doses, respectively, were: -4.7% (8.3) and - 4.7% (14.7) for heparan sulfate levels in CSF, -8.1% (3.5) and - 10.3% (9.4) for cortical gray matter volume, +2.3 (6.9) points and +1.0 (9.2) points in cognitive age equivalent and -8.9 (10.2) points and -14.4 (9.2) points in developmental quotient. In summary, SBC-103 was generally well tolerated. Changes in heparan sulfate levels in CSF were small and were not maintained from earlier study time points, there was no clear evidence overall of clinically meaningful improvement in neurocognitive function at the higher doses investigated, and no dose-dependent effects were observed.
['Whitley|Chester B|CB|', 'Vijay|Suresh|S|', 'Yao|Bert|B|', 'Pineda|Mercé|M|', 'Parker|Geoff J M|GJM|', 'Rojas-Caro|Sandra|S|', 'Zhang|Xiaoping|X|', 'Dai|Yang|Y|', 'Cinar|Amy|A|', 'Bubb|Gillian|G|', 'Patki|Kiran C|KC|', 'Escolar|Maria L|ML|']
D000118:Acetylglucosaminidase D061605:Administration, Intravenous D001921:Brain D002648:Child D002675:Child, Preschool D064420:Drug-Related Side Effects and Adverse Reactions D005260:Female D006497:Heparitin Sulfate D006801:Humans D008279:Magnetic Resonance Imaging D008297:Male D009084:Mucopolysaccharidosis III D011994:Recombinant Proteins
SBC-103 Mucopolysaccharidosis Heparan sulfate Enzyme replacement therapy Lysosomal storage disease Sanfilippo syndrome