Highlights
Survival Advantage
Patients treated with idursulfase demonstrated a median increase in survival time of approximately 10 years compared with an unmatched cohort of untreated patients.
Reduced Mortality Risk
Long-term enzyme replacement therapy (ERT) was associated with a 57.9% lower risk of death.
Sustained Clinical Efficacy
Final data showed consistent declines in urinary glycosaminoglycans (GAGs), reductions in hepatosplenomegaly, and improvements in cardiac and functional capacity.
Safety Profile
Over 18 years of monitoring, idursulfase remained well-tolerated, with most infusion-related reactions being mild or moderate in severity.
Background: The Burden of Mucopolysaccharidosis II
Mucopolysaccharidosis II (MPS II), also known as Hunter syndrome, is a rare, life-limiting, X-linked lysosomal storage disorder caused by a deficiency in the enzyme iduronate-2-sulfatase (IDS). This enzymatic deficit leads to the progressive accumulation of glycosaminoglycans (GAGs)—specifically dermatan sulfate and heparan sulfate—within the lysosomes of virtually all cell types. The resulting multisystemic manifestations include coarse facial features, obstructive airway disease, skeletal deformities (dysostosis multiplex), hepatosplenomegaly, cardiovascular complications, and, in severe phenotypes, progressive neurocognitive decline.
Since its approval in 2005, intravenous idursulfase has been the standard of care for ERT in MPS II. However, given the rarity of the disease and the heterogeneity of clinical presentation, long-term real-world data are essential to understand the true impact of ERT on survival and disease progression. The Hunter Outcome Survey (HOS) was established as a global, multicenter registry to fulfill this need, providing a comprehensive longitudinal perspective on the safety and effectiveness of idursulfase over nearly two decades.
Study Design and Methodology
The Hunter Outcome Survey (NCT03292887) represents one of the most extensive clinical registries in the field of rare metabolic diseases. It enrolled patients with a biochemically or genetically confirmed diagnosis of MPS II. The study design allowed for both prospective enrollment (patients alive at the time of entry) and retrospective enrollment (deceased patients), ensuring a broad data capture of the natural history and treated course of the disease.
Study Populations
For the final analysis, two primary populations were defined:
1. Safety Population (SP): Included 1,014 patients who received at least one dose of idursulfase and were alive at the time of HOS entry. This group was used to assess adverse events and infusion-related reactions (IRRs).
2. Treatment Outcomes Population (TOP): Included 989 patients from the SP, excluding those who received bone marrow transplants or had missing critical demographic data. This cohort served as the basis for efficacy and survival analyses.
Endpoints included changes in urinary GAG levels, organ volume (liver and spleen size), cardiac parameters (left ventricular mass index), functional capacity (6-minute walk test), and overall survival. Descriptive statistics were employed to analyze these longitudinal trends over the 18-year surveillance period.
Key Findings: Survival and Clinical Outcomes
The final report of the HOS provides robust evidence of the transformative impact of idursulfase on the natural history of MPS II. The median age at the initiation of ERT was 5.7 years, though the range was remarkably wide (0.0 to 65.5 years), reflecting the global reach of the registry and the inclusion of both pediatric and adult-onset cases.
Impact on Mortality and Survival
Perhaps the most significant finding of the study is the marked extension of life expectancy. Treated patients in the TOP cohort demonstrated a median increase in survival of approximately 10 years compared to an unmatched cohort of untreated patients documented in the registry. Furthermore, the risk of death was 57.9% lower in the treated group. This survival benefit underscores the importance of addressing the underlying enzymatic deficiency to mitigate the life-threatening systemic complications of the disease.
Biochemical and Organ Response
Biochemical markers of disease activity showed a consistent and sustained response to idursulfase. There was a significant decline in urinary GAG levels across the treatment period, which correlated with clinical improvements. Specifically, the survey noted substantial reductions in liver and spleen size (hepatosplenomegaly), which are common features of MPS II that contribute to abdominal discomfort and respiratory restriction.
Cardiovascular and Functional Capacity
Cardiovascular disease is a leading cause of morbidity in MPS II. The HOS data indicated trends toward sustained improvements in the left ventricular mass index (LVMI), suggesting that ERT may stabilize or partially reverse the cardiac remodeling associated with GAG deposition. Additionally, functional capacity, as measured by walking capacity, showed sustained improvements, highlighting the impact of treatment on the musculoskeletal and respiratory systems.
Safety Profile and Immunogenicity
Safety monitoring over the 18-year period confirmed the manageable nature of idursulfase therapy. In the safety population, 68.1% of patients experienced at least one adverse event (AE), and 26.5% experienced at least one infusion-related reaction (IRR). Critically, the majority of these IRRs were classified as mild or moderate. The incidence of IRRs did not show a clear relationship with anti-drug antibody (ADA) status, a finding that provides reassurance regarding the long-term immunogenicity profile of the recombinant enzyme.
Expert Commentary: Clinical Implications
The final results of the HOS represent a landmark in the management of lysosomal storage diseases. For clinicians, these findings provide clear evidence that idursulfase significantly alters the trajectory of MPS II. The 10-year survival gain is a powerful metric that validates the use of ERT as the cornerstone of therapy.
However, it is important to note the limitations inherent in registry data. The comparison to an “unmatched” untreated cohort may introduce bias, as patients who receive treatment might have better access to overall healthcare or different baseline disease severities. Furthermore, while intravenous ERT is highly effective for somatic symptoms, its ability to cross the blood-brain barrier is limited, meaning that the neurocognitive aspects of severe MPS II remain a significant unmet medical need. Future therapeutic strategies, including intrathecal enzyme delivery and gene therapy, are currently being explored to address these CNS manifestations.
Early diagnosis remains the most critical factor in optimizing outcomes. The initiation of ERT before irreversible organ damage occurs is essential to maximize the benefits seen in the HOS. Newborn screening (NBS) for MPS II, which has already been implemented in several jurisdictions, will likely play a pivotal role in ensuring that patients begin treatment as early as possible.
Conclusion
Data from the Hunter Outcome Survey, collected over 18 years, constitute the largest and most comprehensive dataset of patients with MPS II ever assembled. The final results provide definitive evidence of the long-term effectiveness and safety of idursulfase. By significantly extending survival and improving multisystemic clinical parameters, idursulfase has redefined the prognosis for individuals living with Hunter syndrome. These findings reinforce the necessity of long-term ERT and support its continued use as the standard of care for patients with MPS II.
Funding and ClinicalTrials.gov
The Hunter Outcome Survey (HOS) was sponsored by Takeda (formerly Shire). The registry is registered at ClinicalTrials.gov under the identifier NCT03292887.
References
1. Muenzer J, Botha J, Amartino H, et al. Clinical characteristics and real-world outcomes in patients with mucopolysaccharidosis II over 18 years: final report of the Hunter Outcome Survey. Mol Genet Metab. 2025;146(4):109284. doi:10.1016/j.ymgme.2025.109284.
2. Wraith JE, Scarpa M, Beck M, et al. Mucopolysaccharidosis type II (Hunter syndrome): a clinical review and recommendations for treatment in the era of enzyme replacement therapy. Eur J Pediatr. 2008;167(3):267-277.
3. D’Avanzo F, Tomanin R, Scarpa M. Mucopolysaccharidosis Type II: One Hundred Years of Research, Ten Years of Enzyme Replacement Therapy. Mol Genet Metab. 2020;130(2):81-92.