Mucopolysaccharidosis Type II (MPS II), also called Hunter syndrome, is a progressive, rare genetic lysosomal disorder. This condition causes multisystemic and neurologic decline because a missing enzyme allows large sugar molecules, or glycosaminoglycans (GAGs), to build up in tissues. An important new study published in the New England Journal of Medicine details the Phase 1–2 findings for Tividenofusp alfa, a novel, brain-penetrant enzyme replacement therapy (ERT). This investigational drug is specifically designed to address both the peripheral and central nervous system (CNS) manifestations of MPS II, which standard ERT cannot reach.
Study Design and Mechanism of Action
Investigators conducted a multicenter, open-label study involving 47 male participants with MPS II, up to 18 years of age. Participants received weekly intravenous infusions of Tividenofusp alfa for 24 weeks, followed by long-term extensions lasting up to 157 weeks. The primary objective focused on evaluating the drug’s safety profile. Secondary measures, conversely, assessed both CNS and peripheral effects, which included tracking cerebrospinal fluid (CSF) and urinary heparan sulfate levels, adaptive behavior using the Vineland Adaptive Behavior Scales (VABS), and liver volume. The drug is a recombinant fusion protein. It consists of the deficient enzyme, iduronate-2-sulfatase (I2S), fused to an engineered protein that binds to the transferrin receptor. Consequently, this design allows the enzyme to be actively transported across the blood-brain barrier (BBB) and into the brain.
Efficacy Results: Normalizing Disease Biomarkers
The study demonstrated encouraging results regarding the primary accumulating substrate, heparan sulfate (a GAG). Investigators observed a significant reduction in heparan sulfate levels from baseline. Specifically, CSF heparan sulfate levels decreased by an average of 91%, while urinary levels dropped by 88%. Therefore, these reductions moved the biomarker levels into the range seen in unaffected children. Moreover, this normalization of heparan sulfate appeared maintained over the long-term, lasting through week 153 of the open-label extension. The clinical measures also showed positive signals. Adaptive behavior, as assessed by VABS, stabilized or improved in participants. Furthermore, liver volumes, which are often pathologically enlarged in MPS II, either normalized or remained normal throughout the study period.
Safety and Tolerability of Tividenofusp alfa
Safety was the primary endpoint, and the findings indicated that adverse events (AEs) were common. Initially, all 47 participants reported at least one treatment-emergent adverse event by the 24-week analysis. Infusion-related reactions (IRRs) were the most frequently reported AEs. Despite routine premedication, more than 40% of participants experienced common IRR symptoms, including pyrexia (fever), urticaria (hives), and vomiting. Three participants experienced serious treatment-related AEs; however, all three continued to receive the study treatment. AEs remained common throughout the entire study period, across all extensions. The importance of this CNS-penetrant therapy means that, given the progressive and life-limiting nature of untreated MPS II, the adverse event profile is weighed differently than in other conditions. Researchers are now conducting a randomized trial to further assess the full efficacy and safety profile against standard care.
Frequently Asked Questions
Q1: What is Tividenofusp alfa and how does it work?
Tividenofusp alfa is a novel, intravenous enzyme replacement therapy (ERT) developed for Mucopolysaccharidosis Type II (MPS II), or Hunter syndrome. It uses an engineered protein to carry the deficient enzyme, iduronate-2-sulfatase, across the blood-brain barrier to treat both peripheral and central nervous system symptoms.
Q2: What were the key efficacy findings of the study?
The study found significant decreases in heparan sulfate, the primary substrate that accumulates in MPS II. Cerebrospinal fluid (CSF) levels dropped by 91%, and urinary levels dropped by 88%, reaching levels comparable to those found in unaffected children. Additionally, participants showed stabilized or improved adaptive behavior.
Q3: Is Tividenofusp alfa associated with side effects?
Yes, adverse events were common. All participants reported at least one adverse event, with infusion-related reactions (IRRs) being the most frequent, occurring in over 40% of the cohort. The most common symptoms were fever, hives (urticaria), and vomiting.
References
- Muenzer J et al. An Intravenous Brain-Penetrant Enzyme Therapy for Mucopolysaccharidosis II. N Engl J Med. 2026 Jan 01. doi: 10.1056/NEJMoa2508681. PMID: 41467650.
- Hunter Syndrome (MPS II). Denali Therapeutics.
- Tividenofusp alfa: What is it and is it FDA approved? Drugs.com.
- Turning Point for Hunter Syndrome? MedPage Today.
- Savant S, et al. Genotype-phenotype spectrum of 130 unrelated Indian families with Mucopolysaccharidosis type II. Mol Genet Genomic Med. 2022 Mar;10(3):e1877.