Idursulfase (Elaprase)

Idursulfase is a recombinant enzyme-replacement drug for Hunter syndrome (mucopolysaccharidosis type II, or MPS II), a rare, X-linked inherited disorder in which a missing enzyme lets sugar molecules accumulate throughout the body. Approved in 2006 as the first disease-specific treatment for Hunter syndrome, the infused drug cannot cross the blood-brain barrier and does nothing for the neurocognitive decline seen in the disease's more severe form — a gap Shire spent more than a decade, and one failed pivotal trial, trying to close with an injected-into-the-spine version, before Takeda formally discontinued that separate program in 2022.

An X-linked disease, and an enzyme that can't reach the brain

Hunter syndrome (mucopolysaccharidosis type II, or MPS II) is a rare, X-linked recessive disorder caused by deficient activity of iduronate-2-sulfatase, an enzyme that — like the alpha-L-iduronidase missing in MPS I, covered on this site's laronidase page — normally breaks down the glycosaminoglycans dermatan sulfate and heparan sulfate. Because the gene sits on the X chromosome, Hunter syndrome affects boys and men almost exclusively. Roughly two-thirds of patients have the more severe, "neuronopathic" form, in which glycosaminoglycan buildup in the brain causes progressive cognitive decline and behavioral change on top of the disease's physical features; the remaining "non-neuronopathic," or attenuated, patients keep normal intelligence but still face the same organ enlargement, joint stiffness, airway narrowing and cardiac valve disease. Before 2006, no disease-specific drug existed for Hunter syndrome. Idursulfase was developed by Transkaryotic Therapies (TKT), acquired by Shire in 2005 shortly before the drug reached the FDA, and approved on 24 July 2006 under the brand name Elaprase — the first treatment specifically for Hunter syndrome anywhere. Because the infused enzyme is too large to meaningfully cross the blood-brain barrier, it treats the disease's physical, somatic manifestations without addressing the neurocognitive decline in the neuronopathic form — a limitation intrinsic to the drug's biology, not a shortfall in its trial evidence, and one the rest of this page follows into Shire's attempt to solve it directly.

The trial that won approval

The pivotal evidence was a randomized, double-blind, placebo-controlled trial of 96 patients with MPS II, aged 5 to 31, all with the more attenuated, non-neuronopathic phenotype. Patients were randomized to weekly idursulfase (0.5 mg/kg), the same dose given every other week, or placebo, for one year. The primary endpoint was a composite of change in percent-predicted forced vital capacity (FVC) and six-minute walk test (6MWT) distance: both idursulfase groups showed statistically significant improvement in this composite endpoint over placebo, alongside significant reductions in liver and spleen volume and urinary glycosaminoglycan excretion (Muenzer J, Wraith JE, Beck M, Giugliani R, Harmatz P, Eng CM, Vellodi A, Martin R, Ramaswami U, Gucsavas-Calikoglu M, Vijayaraghavan S, Wendt S, Puga AC, Ulbrich B, Shinawi M, Cleary M, Piper D, Conway AM, Kimura A, "A phase II/III clinical study of enzyme replacement therapy with idursulfase in mucopolysaccharidosis II (Hunter syndrome)," Genet Med 2006;8(8):465-473, PMID 16912578, DOI: 10.1097/01.gim.0000232477.37660.fb).¹ This trial enrolled only the attenuated phenotype, so it demonstrated real benefit for the disease's physical manifestations without ever attempting to test — and therefore without ever claiming — any effect on the cognitive decline that defines the more severe, neuronopathic form.

Trying to reach the brain: a decade-long intrathecal program

Because IV idursulfase cannot cross the blood-brain barrier, Shire developed a separate, specially formulated version — idursulfase-IT, internally SHP609 — delivered directly into the cerebrospinal fluid via an implanted intrathecal drug-delivery device, aimed specifically at the neurocognitive decline in children with the severe, neuronopathic form of Hunter syndrome. The FDA granted the program Fast Track designation in 2015, and Shire moved from early-phase dose-ranging and safety studies into a Phase 2/3 randomized trial testing idursulfase-IT given alongside standard IV Elaprase, against IV Elaprase alone, in children with neuronopathic MPS II and early cognitive impairment. This was a genuine, well-resourced attempt to solve idursulfase's central limitation directly, not a minor line extension — Shire and, later, Takeda kept the program in active development for roughly a decade.

2017 and 2022: the trial that missed, and the program that ended

This is a genuinely different kind of regulatory story than the manufacturing shortages and consent decrees that run through several other enzyme-replacement pages on this site: a real, well-designed attempt to extend a working drug's benefit into the one part of the disease it couldn't reach, tested honestly in a randomized trial, that simply did not work — and was discontinued because of that negative result rather than kept alive on hope alone.

Current status

Intravenous Elaprase (idursulfase) remains FDA-approved and currently marketed by Takeda under BLA 125151, and remains the standard treatment for the physical, somatic manifestations of Hunter syndrome across both the attenuated and neuronopathic phenotypes. The neurocognitive component of severe, neuronopathic Hunter syndrome remains without an FDA-approved treatment following the 2022 discontinuation of the intrathecal program described above — a real, unresolved gap that other research approaches, including gene therapy and hematopoietic stem-cell-based gene-modification programs, are still trying to address, none of them FDA-approved as of this writing.