An enzyme engineered to cross into the brain cut a Hunter syndrome marker by 91%

The New England Journal of Medicine has published phase 1/2 results for tividenofusp alfa, an enzyme replacement therapy engineered to cross the blood-brain barrier, in children with Hunter syndrome. Denali Therapeutics announced the publication today; it appears in the journal's 1 January issue [s1].

Hunter syndrome, or mucopolysaccharidosis type II, is caused by deficiency of the enzyme iduronate-2-sulfatase. Without it, glycosaminoglycans including heparan sulfate accumulate in tissues. Conventional enzyme replacement therapy supplies the missing enzyme intravenously, but the enzyme does not meaningfully reach the brain — which is why the neurological manifestations of the disease have remained largely untreated even in children receiving therapy.

Tividenofusp alfa is iduronate-2-sulfatase fused to a transport module designed to carry it across the blood-brain barrier. The central question of this trial was whether that engineering works in humans, measured by what happens to heparan sulfate in cerebrospinal fluid.

The biomarker results

In 47 participants with a median age of 5 years (range 0.3 to 13), mean cerebrospinal fluid heparan sulfate fell 91% from baseline by week 24, and was maintained at a 92% reduction through week 153 [s1]. Ninety-three per cent of participants reached the normal range [s1].

Urine heparan sulfate fell 88% by week 24 and was maintained at 91% through week 153, with 58% of participants reaching the normal range [s1].

Serum neurofilament light chain — a general marker of neuronal injury, not specific to this disease — declined 21% by week 49 and 76% by week 153, with 85% of participants reaching the normal range [s1].

The cohort included 15 participants who had never received enzyme replacement therapy and 32 who had been treated previously, spanning less severe to severe forms of the disease [s1].

Taken on its own terms, the CSF result is the headline. A 91% reduction in the substrate that accumulates in the brain is direct evidence that the transport engineering did what it was designed to do. That is a real advance in a field where getting large molecules into the central nervous system has been the limiting step for decades.

The clinical results, and why they carry less weight

Denali reports normalisation of liver volume after 24 weeks, improved hearing thresholds across frequencies, and gains in measures of adaptive behaviour and cognition [s1].

Here the design matters. This was an open-label phase 1/2 study [s1]. There was no randomised placebo group. Everyone in the trial knew they were receiving the drug, as did the clinicians assessing them.

For an objective, machine-measured endpoint like liver volume, open-label design is a modest concern. For hearing thresholds it is a larger one. For adaptive behaviour and cognition — which are assessed through caregiver report and structured observation — it is a substantial one. Those measures are sensitive to expectation on the part of both the assessor and the family.

There is a second, subtler problem specific to paediatric neurodevelopmental disease. Children gain skills over time as a matter of ordinary development. In a progressive disease, the clinical question is whether the trajectory bends — whether skills that would have been lost are retained. Establishing that requires a comparison, either a randomised control arm or a well-matched natural history cohort with the same measures. A single-arm trial reporting "stabilisation or improvement" is describing what happened, not isolating what the drug caused.

None of that makes the clinical findings wrong. It means the biomarker evidence and the clinical evidence in this paper are not of the same strength, and should not be cited as though they were.

Safety

The most common treatment-related adverse events were infusion-related reactions, which decreased with continued dosing [s1]. Infusion reactions are a familiar feature of enzyme replacement therapies generally; a pattern of attenuation with repeated exposure is what is typically described.

The regulatory position

The FDA granted Priority Review to the Biologics License Application, with a decision expected by 5 April 2026 [s1].

That timeline puts the agency in a position it faces regularly in ultra-rare disease: a large, mechanistically coherent biomarker effect; clinical data from an uncontrolled trial; and a small patient population in which a conventional randomised trial is difficult to run and arguably difficult to justify once a plausible therapy exists.

How the FDA weighs CSF heparan sulfate as a surrogate endpoint is the substantive question in this review, and it is not one the publication answers.

What this does not establish

That the drug slows or prevents the neurocognitive decline characteristic of severe Hunter syndrome. The trial demonstrates target engagement in the central nervous system with high confidence and reports clinical measures without a control group [s1]. Those are different claims.

Duration is a partial answer to some of these concerns — week 153 is roughly three years of follow-up [s1] — but length of follow-up does not substitute for a comparator.

This article is informational and is not medical advice. Tividenofusp alfa is not approved; its BLA is under review [s1].

What to watch

The FDA decision due by 5 April 2026, and specifically whether any approval is full or accelerated — the distinction turns on whether CSF heparan sulfate is accepted as a surrogate reasonably likely to predict clinical benefit. And whether a controlled or natural-history- comparator study is required as a condition of approval.

Sources

• [s1] Denali Therapeutics, "The New England Journal of Medicine Publishes Phase 1/2 Study of Denali Therapeutics' Tividenofusp Alfa (DNL310) for Hunter Syndrome (MPS II)," 30 December 2025. https://bioutah.org/the-new-england-journal-of-medicine-publishes-phase-1-2-study-of-denali-therapeutics-tividenofusp-alfa-dnl310-for-hunter-syndrome-mps-ii/