Restoring the activity of the alpha-N-acetylglucosaminidase (NAGLU) enzyme using enzyme replacement therapy (ERT) is well-tolerated by patients with Mucopolysaccharidosis IIIB (MPS IIIB), but fails to improve clinical outcomes, a Phase 1/2 clinical trial shows.
The findings of the study, “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,” were published in Molecular Genetics and Metabolism.
MPS IIIB, also known as Sanfilippo syndrome type B, is a lysosomal disorder caused by mutations in the NAGLU gene that encodes for the NAGLU enzyme. This enzyme, which usually is found in lysosomes (small cell compartments that digest and recycle several molecules), is essential to break down long complex sugar molecules called heparan sulfate.
When genetic mutations reduce the activity of NAGLU, heparan sulfate starts to accumulate inside lysosomes, causing brain atrophy (shrinkage) and gradual cognitive decline. Although there are no approved treatments for MPS IIIB, recent studies have shown that ERT — a technique in which a faulty enzyme is replaced by a healthy one — could be a promising therapy for MPS IIIB patients.
“SBC-103 is a recombinant human NAGLU enzyme that is produced in hen oviduct [the equivalent of the Fallopian tubes in women] cells and has been studied as a potential enzyme replacement therapy for MPS IIIB. In preclinical studies of NAGLU-deficient mice, SBC-103 was shown to cross the blood-brain barrier and to decrease brain heparan sulfate levels,” researchers wrote.
The blood-brain barrier is a semipermeable membrane that protects the brain against the external environment, and is a major obstacle for the efficient delivery of certain therapeutics that need to reach the brain and central nervous system.
In this study, researchers reported the final results of the NGLU-CL02 study designed to assess the safety, tolerability and effectiveness of ERT with SBC-103 administered intravenously (into the vein) in a group of MPS IIIB patients for two years.
The Phase 1/2 open-label study (NCT02324049; EudraCT number 2013-003400-39) enrolled 11 MPS IIIB patients 2 to 12 years old, who were assigned sequentially to three different dose-escalating groups: three received SBC-103 at 0.3 mg/kg; four at 1.0 mg/kg; and four at 3.0 mg/kg.
After receiving intravenous injections every two weeks for a period of 24 weeks (Part A), patients stopped treatment for a month, and resumed it at 1.0 and/or 3.0 mg/kg every two weeks, starting at week 28 (Part B) and a final dose-escalation of SBC-103 at 5.0 or 10.0 mg/kg every two weeks (Part C) for approximately two years total.
The trial’s primary outcome consisted of evaluating the safety and tolerability of SBC-103. Secondary outcomes included its effects on several clinical outcomes, such as the total levels of heparan sulfate in the cerebrospinal fluid (the liquid that circulates in the brain and spinal cord, or CSF), gray matter volume loss (to assess progressive brain atrophy), and patients’ neurocognitive status (age equivalent/developmental quotient). Gray matter refers to areas of the central nervous system (brain, brainstem and cerebellum) made up of neuron cell bodies.
Overall, SBC-103 was well-tolerated by patients until its highest dose (10.0 mg/kg) administered during the study’s Part C. Most adverse events (side effects) associated with SBC-103 treatment were considered mild and included fever (10%), vomiting (7%) and diarrhea (6%).
On average, the total levels of heparan sulfate in the CSF of patients treated with SBC-103 at 5.0 and 10.0 mg/kg decreased by 4.7% compared to baseline values. Gray matter volume decreased by 8.1% and 10.3% in patients treated with SBC-103 at 5.0 and 10.0 mg/kg respectively, compared to baseline and neurocognitive function showed “continued delay in skill acquisition after approximately 2 years of treatment,” researchers wrote.
“Notably, SBC-103 was not detected in any of the CSF samples, suggesting that SBC-103 might not have sufficiently crossed the blood-brain barrier, recognizing that the timing of sample collection may not have been optimal to detect SBC-103,” researchers explained.
Over the course of the study, MPS IIIB patients showed signs of neurocognitive decline, reflected by an increase in cognitive age equivalent (+2.3 points and +1.0 point at 5.0 and 10.0 mg/kg, respectively) and a decrease in developmental quotient (−8.9 points and −14.4 points at 5.0 and 10.0 mg/kg, respectively) compared to baseline.
“In summary, SBC-103 was generally well-tolerated. However, reductions in heparan sulfate levels in CSF were small and were not maintained from earlier time points in the study. At the higher doses studied, there was no clear evidence of clinically meaningful improvement in cortical gray matter volume loss and no clear evidence of maintained or clinically relevant improvement in neurocognitive function. Overall, no dose-dependent effects were observed,” investigators concluded.