In preparation for the ongoing clinical trial of their enzyme replacement therapy for children with Sanfilippo syndrome type B, biotech company Allievex studied the natural course of the disease in individuals. Their findings were recently published in the Journal of Pediatrics.
The natural history study has observed the typical progression of this subtype of Sanfilippo in participants 18 years old and under. Natural history studies are important as they allow scientists, clinicians and biotech companies to better understand what a disease does to the body, allowing for better interpretation of results from future clinical treatment studies. This is crucial, as clinical trials in rare diseases don’t often include a placebo-treated group to compare the treatment effects to. Instead, a comparison is made between the course of the disease of the patients treated in the trial to the untreated ‘natural history’ of the disease.
Sixty-five participants were recruited for the study and were allocated into one of two groups.
The first part of the study followed a group of children aged between one and eleven for 48 weeks. MRI scans were used to assess the damage Sanfilippo type B causes to the liver, spleen and brain over this period of time. MRIs were conducted at the beginning of the study, 24 weeks later, and at the conclusion of the study at 48 weeks.
The MRI results showed that all subjects between the ages of two and nine-and-a-half had an enlarged liver. Despite having an enlarged liver no evidence of liver failure was found and spleen volumes remained stable throughout the time period. However, a larger liver does mean that concentrations of medications may need to be higher, which is an important factor for considering side-effects.
Overall, the volume of the brain in all subjects did decrease over time which appeared to be mainly caused by a loss of grey matter. This is the brain tissue where the neuronal cell bodies are found, which is involved in the retrieval and processing of messages. The size of the cerebellum, the part of the brain responsible for speech and coordinated movement, was not affected by disease progression. The researchers combined this data with data they have from other age groups and discovered infants under 24 months old have grey matter volume within a normal range, but as they get older than 24 months, this decreases below the normal range, contributing to the significant decline in cognitive function and loss of memory.
They also looked at the levels of heparan sulfate in the participants’ plasma and cerebrospinal fluid. All subjects in this study were found to have elevated levels of heparan sulfate at all time points compared to a child without this disease. However, heparan sulfate levels remained at a relatively stable level throughout the study. As a result, the scientists concluded that heparan sulfate can be a sign of the presence of the disease, but it is not a useful indicator of disease severity or progression.
The second part of the study followed 43 patients, ranging from a couple of months old to adolescents aged 18 years old, for a duration of four years. They looked at the participants’ cognitive and adaptive behaviour as determined by questionnaires completed by their parents. Increasing chronological age was directly correlated with a reduction in cognitive function. However, the relationship between chronological age and adaptive function as reported by parents was less clear. This part of the natural history study is ongoing and the final results are expected in 2024.
These findings provide a better understanding of Sanfilippo type B, which will help in developing treatments for the disease. By comparing a treatment group in a clinical trial to the natural disease trajectory, it will be possible to demonstrate the efficacy of an experimental therapy.
This data underpinned the ongoing clinical trial of tralesinidase-alpha, an enzyme replacement therapy for Sanfilippo type B. Full trial results are not yet available.
You can read more about this trial and others on our webpage here:
