Sanfilippo Type B Progression Has Similar Trajectory to Type A: Study
The declines underscore need for early treatment to prevent further neurodegeneration, assist trial design
Most children with Sanfilippo syndrome type B show predictable downward trajectories in cognitive function, behavior, and brain volume that resemble those of children with rapidly progressing type A, according to data from two natural history studies.
Also, most reach their lowest cognitive and adaptive behavior scores by age 8 on average and all exhibit an enlarged liver.
These findings support the importance of early treatment to prevent further neurodegeneration and may help the design and interpretation of future clinical trials testing experimental therapies, the researchers noted.
The study, “Longitudinal Natural History of Pediatric Subjects Affected with Mucopolysaccharidosis IIIB,” was published in The Journal of Pediatrics.
Sanfilippo syndrome, also known as mucopolysaccharidosis type III (MPS III), is caused by the absence or reduced activity of one of four enzymes involved in the breakdown of a complex sugar molecule called heparan sulfate.
This leads to the toxic accumulation of heparan sulfate inside cells, nerve cells being particularly sensitive to this and resulting in progressive and severe neurodegeneration along with a short life expectancy. No treatments have been approved to date.
Focus on Sanfilippo type B
Type B is caused by low or no activity of the alpha-N-acetylglucosaminidase (NAGLU) enzyme due to mutations in the NAGLU gene.
Children with this type usually show developmental delays in the first years of life followed by behavioral symptoms, sleep disturbances, and intellectual disability. They also show an enlarged liver and lose their mobility in later stages of the disease.
Previous studies suggest the existence of an attenuated form of MPS III type B (MPS IIIB) that’s associated with residual NAGLU activity and a median life expectancy of 43.5 years.
While the progression of Sanfilippo type A, the most common and severe form, has been well described, “much less longitudinal and population data have been published for MPS IIIB,” the researchers wrote.
With this in mind, Allievex launched two international, longitudinal natural history studies to investigate the natural course of Sanfilippo type B and help interpret the results of future treatment trials: the completed 250-901 study (NCT02493998) and the ongoing 250-902 study (NCT03227042).
Allievex is developing tralesinidase alfa (AX 250), an experimental enzyme replacement therapy for Sanfilippo type B originally developed by BioMarin Pharmaceutical. It works by delivering a modified version of the missing NAGLU enzyme directly into the brain.
After interim data from a previous Phase 1/2 trial (NCT02754076) showed tralesinidase alfa safely normalized heparan sulfate levels, halted cognitive decline, and reduced liver size in children with Sanfilippo type B, an extension Phase 2 trial (NCT03784287) has been evaluating its long-term effects.
A total of 65 children (33 females and 32 males) with Sanfilippo type B were enrolled into the two natural history studies and followed for up to four years.
Cognitive function and adaptive behavior, or skills that people need to function independently, were analyzed in all the children through validated measures. Heparan sulfate levels and liver, spleen, and brain volume were assessed in only a subset of them.
The children were diagnosed at an average age of 36 months (about 3 years), with most (93.8%) receiving a diagnosis between 3–77 months (nearly 6.5 years). Females were generally diagnosed about a year later than males.
Genetic testing identified 66 NAGLU mutations, 30 of which had not been previously reported. Three of the four children diagnosed after age 6 — which in Sanfilippo patients is thought to be linked to a milder form — were found to carry mutations known to be associated with an attenuated disease and were not included in the overall analyses.
Treatment should begin early
Results showed most children with Sanfilippo type B achieved their higher cognitive and adaptive behavior scores between ages 3 and 6 and their lowest by an average age of 8, or 13.5 years at the latest. These lowest scores, maintained thereafter, reflected a cognitive function and adaptive behavior of a 2-year-old.
In general, cognitive function and adaptive behavior showed a linear reduction with age, even though the rates of change varied greatly between children up to age 5. These became more similar between patients after age 8.
This suggests that “treatment should start as early as possible, but assessment of efficacy of a treatment on cognitive decline between age 8 and 10 years may be most appropriate,” the researchers wrote.
In addition, the levels of heparan sulfate in the blood and cerebrospinal fluid (the liquid that surrounds the brain and spinal cord) were higher than normal in all 22 tested children.
Brain volume, as measured in 20 children, was significantly reduced (by 2.7%) over a year and this was found to be entirely derived from a loss of nerve cells in the outer layer of the brain (a shrinkage of 6.5%).
At study start, all 14 evaluated children showed an enlarged liver (but no signs of liver dysfunction) and some had a larger than normal spleen. After a year, liver size was significantly increased while the spleen remained largely stable.
Evidence also suggested that genetic mutations, heparan sulfate levels, or volumetric measures were not predictors of disease onset or severity. This does not support “a distinction between slow and rapid progressors as has been described for individuals with MPS IIIA,” the researchers wrote.
The three children with mutations previously linked to a milder disease had much higher scores for cognitive function and adaptive behavior that nearly reached normal for one of them. Still, most followed the predicted disease trajectories of those with non-attenuated disease.
Brain volume was not assessed in these children, but they “are also likely to have limited brain atrophy [shrinkage],” the research team wrote.
These findings underscore that children with non-attenuated Sanfilippo type B “exist along a single disease continuum and have predictable progression and predefined trajectories in terms of cognition, adaptive behavior, and brain atrophy equivalent to individuals with … rapid MPS IIIA,” the researchers wrote.
“Quantifying either a deviation in the slopes of cognitive and adaptive behavior before subjects [reach] their nadir [lowest scores] or the respective proportions of treated [versus untreated patients] who did not reach their nadir might be 2 options to demonstrate the efficacy of an experimental therapeutic modality in this population of patients,” they wrote.