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Encouraging Signs of Efficacy Observed with Intrathecal Idursulfase in Children with Hunter Syndrome and Cognitive Impairment

Muenzer - Speaker World Symposium 2017Joseph Muenzer, MD, PhD

February 18, 2017—San Diego, California—Encouraging signs of efficacy have been observed with intrathaecal idursulfase in children with Hunter syndrome and cognitive impairment.

This outcome of a long-term extension study was reported at the 13th Annual WORLDSymposium, from February 13–18.

Joseph Muenzer, MD, PhD, of the University of North Carolina, Chapel Hill, explained, “Hunter syndrome is a rare genetic disorder with progressive neurological disease in the severe form. No treatment is available for this disease.”

Hunter syndrome, or mucopolysaccharidosis II, primarily affects males (X-linked recessive). It interferes with the body's ability to break down and recycle specific mucopolysaccharides, also known as glycosaminoglycans. Hunter syndrome is one of several related lysosomal storage diseases called the mucopolysaccharide diseases. An estimated 2000 persons are afflicted with Hunter syndrome worldwide, 500 of whom live in the United States.

In Hunter syndrome, the problem concerns the breakdown of two glycosaminoglycans: dermatan sulfate and heparan sulfate. The first step in the breakdown of dermatan sulfate and heparan sulfate requires the lysosomal enzyme I2S.

A definitive diagnosis of Hunter syndrome is made by measuring I2S activity in serum, white blood cells, or fibroblasts from a skin biopsy. In some patients with Hunter syndrome, analysis of the I2S gene can determine clinical severity. Prenatal diagnosis is routinely available by measuring I2S enzymatic activity in amniotic fluid or chorionic villus tissue.

In patients with Hunter syndrome, this enzyme is either partially or completely inactive. As a result, 12S builds up in cells throughout the body, particularly in tissues that contain large amounts of dermatan sulfate and heparan sulfate. As this build-up continues, it interferes with the way certain cells and organs function and leads to a number of serious symptoms. The rate of glycosaminoglycan build-up varies from patient to patient, resulting in a wide spectrum of abnormalities.

Intravenous enzyme replacement therapy with idursulfase, manufactured by Shire Pharmaceuticals, is efficacious for somatic manifestations of Hunter syndrome (mucopolysaccharidosis II), but does not cross the blood-brain barrier enough to address cognitive impairment.

An idursulfase formulation for intrathecal administration, idursulfase-IT, is under evaluation. “This formulation, iduronate-2 sulfatase, differs from idursulfase,” said Dr. Muenzer.

Idursulfase-IT is being evaluated in a 6-month phase I/II trial and ongoing extension study. By January 2016, 15 patients, age 3.6–11.2 years at baseline, had received monthly idursulfase-IT injections (with weekly intravenous idursulfase infusions) for a median of 205 (78–306) weeks.

In the extension study, 10 patients received 10 mg and five patients, 30 mg idursulfase-IT. Thirteen patients were scored for neurodevelopmental status scores prior to treatment. General Conceptual Ability scores in eight patients assessed using the Differential Abilities Scale II (the main cognitive test used for the study) ranged from 32–74 and developmental quotient scores in five patients assessed using the Bayley Scales of Infant and Toddler Development III were 13–63.

Five patients were scored serially post baseline. Scores stabilised in three patients, one patient became untestable, and one patient had experienced cognitive decline. Seven patients did not test positive for anti-idursulfase antibodies at any time. Five patients tested positive for antibodies in serum or cerebrospinal fluid but their titres were similar over time.

In three patients, increasing or high antibody titres were observed, and in two of these three, pharmacodynamic responses to idursulfase-IT were attenuated (reflected in a less convincing reduction in cerebrospinal fluid glycosaminoglycan concentration). One participant discontinued following intrathecal device failure and cerebrospinal fluid infection that resolved without sequelae, and one was withdrawn for behavioural concerns.

Of 54 serious adverse events, two were causally related to idursulfase-IT (pyrexia and vomiting).

Dr. Muenzer concluded that encouraging signs of clinical efficacy were observed with intrathecal idursulfase in three patients with Hunter syndrome. Phase II/III study results of the 1-year study will be available later in 2017.

He added, “I am very encouraged by the potential impact of intrathecal enzyme replacement therapy for the brain disease of the severe form of Hunter syndrome.”

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Molecular Genetics and Metabolism is a contribution to the understanding of the metabolic basis of disease. The journal publishes articles describing investigations that use the tools of biochemistry and molecular biology for studies of normal and diseased states. In addition to original research articles, occasional minireviews reporting timely advances as well as brief communications and letters to the editor are considered.

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