A group of experts has discussed and released a series of recommendations for future trials’ design in Sanfilippo syndrome.
The study, “Recommendations on clinical trial design for treatment of Mucopolysaccharidosis Type III” was published in the journal Orphanet Journal of Rare Diseases.
Sanfilippo syndrome, or mucopolysaccharidosis type III, belongs to a group of metabolic diseases characterized by the body’s deficiency to break down large sugar molecules (mucopolysaccharides).
The accumulation of these sugars has detrimental effects, particularly a decline in brain function. Sanfilippo syndrome is a progressive neurodegenerative disorder where patients begin to show impairments in speech and language, followed by behavioral changes — aggression, hyperactivity and sleep disturbances — and cognitive decline.
In the last phase of the disease, motor function is affected, with patients losing the ability to walk and swallow.
Given the variable and progressive nature of the disease’s symptoms, “understanding the natural history of the disease is essential for informing clinical trial design and selection of appropriate outcome measures,” researchers stated.
Special attention needs to be paid when selecting outcome measures and clinical trials’ objectives (endpoints) to “improve the quality and impact of research in this area,” they said.
In their position statement, researchers summarize a list of recommendations regarding the protocol of clinical research, outcome measures and management of natural history data of Sanfilippo syndrome that originated after a June 2015 workshop that included an international group of academic researchers, clinical experts and industry groups.
Researchers propose that because of the universal presence of central nervous system manifestations in this patient population, clinical trials should assess candidate therapies’ effects on neurological function. They agree that both cognitive and behavioral manifestations are mandatory for therapeutic development.
Since cognitive manifestations are less noticeable in toddlers (under 2 years old), trials involving young children should promote long-term follow-up over a period of years, making use of appropriate development scales, such as the Bayley Scales of Infant and Toddler Development (third edition) and/or the Kaufman Assessment Battery for Children (second edition).
Assessing behavioral manifestations — hugely relevant to quality of life — including hyperactivity, aggression, temper tantrums, unusual affect and orality, should also be considered in the development of clinical trials.
Potentially useful tools include the Sanfilippo Behavior Rating Scale — a tool to track behavioral changes through different stages of disease — and actigraphy, which measures level of activity over time and allows discrimination between states of sleep and wakefulness.
This is particularly relevant, as the circadian rhythm — our 24-hour biological cycle — in Sanfilippo patients is not regular, with a phase delayed sleep-wake cycle in some children.
Researchers also highlighted the need to include biomarkers of neurological disease — currently the most used biomarker includes levels of heparan sulfate, whose faulty accumulation within cells and tissues, including cerebral spinal fluid (CSF), underlies Sanfilippo syndrome.
However, there is ongoing debate regarding which method of quantitating heparan sulfate and its derived structures is most suitable.
“An ideal biomarker is easily and reliably measurable, correlates closely with disease burden and relevant clinico-pathological parameters, and responds rapidly to treatment,” researchers said.
Obtaining CSF samples is invasive, as it requires lumbar puncture; however, CSF heparan sulfate levels are more likely to reflect neurological disease than those found in urine or plasma.
“While it is possible to measure heparan sulfate in blood and urine, these have less relevance to neurological outcomes in clinical trials,” researchers explained.
Surrogate GAG biomarkers that are directly dependent on heparan sulfate levels, such as heparin cofactor II thrombin complex, are also possibilities. However, the link between additional biomarkers and patients’ clinical outcomes needs to be clearly established.
The usefulness of brain imaging using magnetic resonance techniques, although associated with deterioration in neurocognitive outcomes, is limited in toddlers. As such, other brain parameters, such as measuring the cerebral ventricular volume, might be more beneficial as a primary endpoint.
Clinical trials for Sanfilippo syndrome are limited by the progressive nature of the disease, the lack of effective therapies and the small number of patients. This means that including a control group of non-treated subjects might be a challenge, highlighting the need for a detailed understanding of the natural history of the disease.
The team also stressed that “due to the numerous challenges in performing research in MPS III and the urgent need for the development of effective therapies,” all studies should be published as soon as possible “and within a year of study completion.”
“Improving the quality of clinical research in Mucopolysaccharidosis type III will require an open, collaborative and systematic approach between academic researchers, clinicians and industry,” researchers concluded.