A link between baseline neurofilament light chain and primary substrate accumulation in cerebrospinal fluid, and clinical outcomes in patients with MPS II from a phase 2/3 clinical trial and extension study of intrathecal idursulfase.

Mucopolysaccharidosis II (MPS II; Hunter syndrome) is a rare, X-linked, recessive lysosomal storage disorder that impacts approximately 1:162000 live births. It is caused by deficiencies in the lysosomal enzyme iduronate-2-sulfatase (I2S), resulting in harmful accumulation of specific glycosaminoglycans in cells, tissues and organs throughout the body. Clinical manifestations are varied and include airway obstruction, impaired mobility and, in two-thirds of cases, neurocognitive impairment (neuronopathic MPS II). Intravenous idursulfase enzyme replacement therapy (elaprase), improves many physical symptoms and signs of the disease but has limited neurological efficacy due to impaired crossing of the blood-brain barrier. TAK-609 is an intrathecal formulation of idursulfase (idursulfase-IT) that is delivered directly to the cerebrospinal fluid (CSF) of patients with neuronopathic MPS II to attenuate the neurocognitive decline. This study investigated the relationship between clinical outcomes of patients treated with TAK-609 and levels of neurofilament light chain (NfL), a component of the neuronal cytoskeleton that accumulates under neurodegenerative conditions. We report an association between the severity of I2S gene (IDS) variants and baseline CSF NfL levels in patients with neuronopathic MPS II that corresponded to primary substrate burden as measured by heparan sulfate and total GAGs. Supraphysiological (high) NfL levels corresponded to a more rapid rate of cognitive decline than physiological (normal) baseline levels. Taken together, this study establishes a clear link between genetic status, accumulation of primary substrate and circulating CSF NfL levels, allowing for bioanalytical stratification of patient outcomes in MPS II. TAKE-HOME MESSAGE: Baseline cerebrospinal neurofilament light chain levels correspond to the severity of iduronate-2-sulfatase gene (IDS) genotype, the degree of primary substrate burden and subsequent clinical outcomes in patients with neuronopathic mucopolysaccharidosis II, and can complement clinical assessments of disease heterogeneity.