Drug Update · Rare Disease

FDA Approves tividenofusp alfa for Hunter syndrome: 91% CSF HS Drop

July 11, 2026

Approval date

03/24/2026

Indication

treatment of neurologic manifestations of Hunter syndrome (MPS II) when initiated in presymptomatic or symptomatic pediatric patients weighing at least 5 kg prior to advanced neurologic impairment

Primary result

CSF heparan sulfate mean reduction 91% from baseline at Week 24

Urine result

Urinary heparan sulfate reduction 88% from baseline at Week 24

Trial

Trial 1 (NCT04251026), phase 1-2, open-label

Study size

47 participants

Approved maintenance dose

15 mg/kg once weekly (intravenous infusion)

Clinical Perspective

This approval directly affects clinicians treating pediatric patients with MPS II by providing an FDA-approved, brain-penetrant enzyme therapy for neurologic manifestations when started in presymptomatic or symptomatic children weighing at least 5 kg ^[3]^[4]. The source-confirmed reductions in CSF heparan sulfate (mean 91% at Week 24) support the biologic activity of tividenofusp alfa against the primary substrate that accumulates in the CNS in MPS II and formed the basis for accelerated approval ^[1]^[4]. Will the observed reductions in CSF HS translate into durable, clinically meaningful neurocognitive and functional benefits in confirmatory randomized trials?

Editorial Team · Rare Disease

The FDA approved tividenofusp alfa (AVLAYAH) for the treatment of neurologic manifestations of Hunter syndrome (Mucopolysaccharidosis type II, MPS II) on 03/24/2026 based on a phase 1-2 trial showing reductions in cerebrospinal fluid (CSF) heparan sulfate (HS) levels of 91% from baseline at Week 24 ^[4]^[1]. The approval applies when treatment is initiated in presymptomatic or symptomatic pediatric patients weighing at least 5 kg prior to advanced neurologic impairment ^[3]^[4].

Clinical Context

Tividenofusp alfa is an engineered fusion protein that provides iduronate-2-sulfatase (IDS) linked to a transferrin receptor–binding Fc domain designed to cross the blood–brain barrier and deliver IDS to the central nervous system and peripheral tissues ^[4]^[1]. It was developed by Denali Therapeutics to target both neurologic and peripheral manifestations of MPS II ^[1]^[3]. The FDA granted marketing approval for neurologic manifestations of Hunter syndrome under an accelerated approval pathway based on reduction of CSF HS as a surrogate endpoint, with continued approval contingent on verification of clinical benefit in confirmatory trial(s) ^[3]^[4]. Denali lists the product under the tradename AVLAYAH and holds orphan designation for treatment of MPS II ^[2]^[3].

Key Findings

The phase 1-2, open-label trial (Trial 1; ClinicalTrials.gov number NCT04251026) in pediatric patients with MPS II showed a mean percent reduction in CSF heparan sulfate of 91% from baseline at Week 24 (95% CI: 89%, 92%) among 44 patients with Week 24 measurements ^[1]^[4].
Urinary heparan sulfate decreased from baseline by 88% at the 24-week primary analysis in the same cohort ^[1].
At baseline 0% (0 of 47) of participants had CSF HS below the upper limit of normal (ULN); at Week 24, 93% (41 of 44) of AVLAYAH-treated patients had CSF HS levels below the ULN ^[4]^[1].
The trial enrolled 47 male pediatric participants; at the 24-week primary analysis all 47 participants reported at least one adverse event during the treatment period, and 46 completed Part 1 up to Week 24 ^[1]^[4].
Secondary observations reported that reductions in heparan sulfate appeared to be maintained through week 153 in extension periods, adaptive behavior stabilized or improved, and liver volumes normalized or remained normal across study periods ^[1].

Safety & Tolerability

Infusion-related reactions (IARs) were commonly reported; pyrexia, urticaria, and vomiting were the most frequently reported symptoms of IARs, occurring in more than 40% of participants despite routine premedication ^[1].
Anaphylaxis and life-threatening hypersensitivity reactions are described in the boxed warning; initiation should occur in a healthcare setting with appropriate monitoring and support measures ^[3].
Upper respiratory tract infection was listed among the common adverse reactions ^[3].
Ear infection was listed among the common adverse reactions ^[3].
Anemia was listed among the common adverse reactions ^[3].
Cough was listed among the common adverse reactions ^[3].
Diarrhea was listed among the common adverse reactions ^[3].
Rash was listed among the common adverse reactions ^[3].
COVID-19 was listed among the common adverse reactions ^[3].
Rhinorrhea was listed among the common adverse reactions ^[3].
Nasal congestion was listed among the common adverse reactions ^[3].
Fall was listed among the common adverse reactions ^[3].
Headache was listed among the common adverse reactions ^[3].
Skin abrasion was listed among the common adverse reactions ^[3].
Urticaria was listed among the common adverse reactions and was noted as a frequent symptom of IARs ^[1]^[3].
Three participants had serious treatment-related adverse events in the trial; all continued to receive treatment ^[1].

Study Design

Trial 1 (NCT04251026) was a phase 1-2, open-label, multi-center study that enrolled 47 male pediatric participants with MPS II and included a 24-week primary analysis followed by an 80-week safety extension and a 157-week open-label extension; the primary objective was safety and secondary objectives included CSF and urinary heparan sulfate, adaptive behavior, and liver volume ^[1]^[4]. At the 24-week primary analysis, 46 of 47 participants completed Part 1; efficacy assessments reported CSF and urine HS reductions and functional observations ^[1]^[4]. Additional trial details and the ongoing randomized trial to further evaluate clinical effects were noted in the primary publication ^[1].

FAQ

Q1 What is tividenofusp alfa (AVLAYAH) approved for?

AVLAYAH (tividenofusp alfa-eknm) is approved for the treatment of neurologic manifestations of Hunter syndrome (Mucopolysaccharidosis type II, MPS II) when initiated in presymptomatic or symptomatic pediatric patients weighing at least 5 kg prior to advanced neurologic impairment. The indication was approved under accelerated approval based on reduction of cerebrospinal fluid heparan sulfate; continued approval may be contingent upon verification of clinical benefit in confirmatory trial(s).

Q2 How does tividenofusp alfa work?

Tividenofusp alfa is a fusion protein that provides iduronate-2-sulfatase (IDS) linked to an engineered transferrin receptor–binding Fc domain; the Fc component binds the transferrin receptor to mediate transport across the blood–brain barrier and deliver IDS to brain and peripheral cells, where it is internalized and directed to lysosomes to hydrolyze accumulated glycosaminoglycans such as heparan sulfate and dermatan sulfate.

Q3 What is the recommended dose of tividenofusp alfa (AVLAYAH)?

The FDA-approved maintenance dosage for pediatric patients weighing at least 5 kg is 15 mg/kg administered once weekly as an intravenous infusion over approximately 4 hours. Initiation and dose escalation, infusion administration, and monitoring recommendations are provided in the full prescribing information; clinicians should consult current prescribing information for complete dosing guidance.

Q4 What are the most common side effects of AVLAYAH?

Common adverse reactions include infusion-associated reactions (IARs) with symptoms such as pyrexia, urticaria, and vomiting (each reported in more than 40% of participants in the trial), as well as upper respiratory tract infection, ear infection, anemia, cough, diarrhea, rash, COVID-19, rhinorrhea, nasal congestion, fall, headache, skin abrasion, and urticaria. The label includes a boxed warning for hypersensitivity reactions including anaphylaxis and recommends initiating therapy in a healthcare setting with appropriate monitoring and support.

Clinicians should consult current prescribing information for complete dosing guidance.

FDA Approves tividenofusp alfa for Hunter syndrome: 91% CSF HS Drop

FDA Approves tividenofusp alfa for Hunter syndrome: 91% CSF HS Drop

Clinical Perspective

Clinical Context

Key Findings

Safety & Tolerability

Study Design

FAQ

References

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