Tividenofusp Alfa for Hunter Syndrome

Not currently recruiting at 8 trial locations

Overseen By Clinical Trials at Denali Therapeutics

Age: < 65

Sex: Male

Trial Phase: Phase 1 & 2

Sponsor: Denali Therapeutics Inc.

Must be taking: ERT

Must not be taking: CNS-targeted ERT

Disqualifiers: Unstable conditions, Stroke, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment called tividenofusp alfa (also known as DNL310 or recombinant iduronate 2-sulfatase), which aims to help people with Hunter syndrome, a rare genetic disorder affecting the body's ability to break down certain sugars. The research examines the safety and effectiveness of this treatment, particularly for those with symptoms affecting both the body and the brain. The trial includes different groups to test various doses and effects, depending on whether participants have brain-related symptoms. Individuals with a confirmed diagnosis of Hunter syndrome who have received enzyme replacement therapy for at least four months may be suitable candidates for this trial. As a Phase 1, Phase 2 trial, this research seeks to understand how the treatment works in people and measure its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking research.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot participate if you have used any CNS-targeted MPS II enzyme replacement therapy within 3 to 6 months before the study, depending on your age.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that tividenofusp alfa, a treatment under study for Hunter syndrome, has promising safety results from earlier studies. Reports from Denali Therapeutics highlight long-term benefits and safety for patients using this treatment. Although the FDA is still reviewing it, the data so far suggest that tividenofusp alfa is generally well-tolerated. Previous studies compared tividenofusp alfa to existing enzyme replacement therapies, focusing on its safety. While more research is needed to fully confirm its safety, the available information is encouraging for those considering joining a clinical trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard enzyme replacement therapies for Hunter syndrome, Tividenofusp Alfa (DNL310) aims to cross the blood-brain barrier, potentially addressing both the systemic and neurological symptoms of the condition. Most current treatments, like idursulfase, primarily target peripheral symptoms but struggle to impact cognitive decline. Researchers are excited about Tividenofusp Alfa because it leverages a novel mechanism of action that could provide comprehensive treatment by reaching the brain, offering hope for improved quality of life for patients with both neuronopathic and non-neuronopathic forms of Hunter syndrome.

What evidence suggests that tividenofusp alfa could be an effective treatment for Hunter syndrome?

Research has shown that tividenofusp alfa (DNL310) may help treat Hunter syndrome (MPS II). Early results indicate that this treatment significantly lowers certain measurable signs of the disease in both the brain and the rest of the body, potentially alleviating symptoms in both areas. The treatment is a type of enzyme replacement therapy, designed to address the main cause of Hunter syndrome by reaching the brain. Although still under study, these early findings offer hope for those with MPS II. Participants in this trial will receive different dosing regimens of tividenofusp alfa across various cohorts, each designed to evaluate its effects in individuals with different manifestations of MPS II. ^{2 3 6 7 8}

Who Is on the Research Team?

Sam Lu, MD

Principal Investigator

Denali Therapeutics

Are You a Good Fit for This Trial?

This trial is for children with Hunter Syndrome (MPS II), including various subgroups based on age, whether they have neuronopathic or non-neuronopathic forms, and their treatment history. It's not for those who've had certain brain surgeries or conditions, significant bleeding disorders, recent CNS-targeted treatments outside specified windows, or contraindications to lumbar punctures.

Inclusion Criteria

I am over 6 with neuronopathic MPS II, under 6 or over 17 with non-neuronopathic MPS II, or had specific treatments for MPS II.

I have been diagnosed with MPS II.

I am between 5 and 10 years old with neuronopathic MPS II.

Exclusion Criteria

I don't have serious blood clotting issues or ongoing major bleeding.

I haven't used CNS-targeted MPS II ERT recently.

I have not used IDS gene or stem cell therapy before.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive tividenofusp alfa (DNL310) to assess safety, pharmacokinetics, and pharmacodynamics

12 weeks

Safety Extension

Participants who are deriving benefit may continue in a safety extension phase

Ongoing

Open-label Extension

Participants may opt into continuation of treatment long-term for further evaluation

Long-term

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• DNL310

Trial Overview The study tests Tividenofusp Alfa (DNL310), a new enzyme replacement therapy that could treat both body and brain symptoms of MPS II. The trial will monitor safety and how the drug works in the body over time. Participants benefiting may continue in extended phases for ongoing evaluation.

How Is the Trial Designed?

Group I: Cohort E Experimental Treatment 1 Intervention

A consistent dose level in participants with non-neuronopathic MPS II or neuronopathic MPS II

Group II: Cohort D Experimental Treatment 1 Intervention

A consistent dose level in participants with non-neuronopathic MPS II or neuronopathic MPS II

Group III: Cohort C Experimental Treatment 1 Intervention

A consistent dose level in participants with neuronopathic MPS II

Group IV: Cohort B Experimental Treatment 1 Intervention

A consistent dose level in participants with non-neuronopathic MPS II, neuronopathic MPS II, or unknown phenotype followed by dose escalation in some participants.

Group V: Cohort A Experimental Treatment 1 Intervention

Dose escalation followed by a consistent dose level in participants with neuronopathic MPS II

Who Is Running the Clinical Trial?

Denali Therapeutics Inc.

Lead Sponsor

Trials

24

Recruited

1,900+

Published Research Related to This Trial

Idursulfase (Elaprase) is the first approved enzyme replacement therapy for Hunter syndrome, showing significant benefits in a phase II/III clinical trial, including increased walking distance, improved pulmonary function, and reduced organ size and urinary glycosaminoglycans (GAGs) excretion in patients.

The treatment is generally well tolerated, although some patients may experience infusion reactions, marking idursulfase as a promising symptomatic therapy that addresses the underlying enzymatic deficiency in Hunter syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Idursulfase in Hunter syndrome treatment. Zareba, G.[2017]

Transplanted fibroblasts provided a long-lasting source of lysosomal enzymes for three patients with Hunter's syndrome, showing significant increases in enzyme activity over 2.5 to 3.75 years.

The therapy led to improved catabolism of heparan and dermatan sulfates, evidenced by changes in urinary oligosaccharide profiles, and these benefits persisted even with changes in immunosuppressive therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzyme replacement therapy by fibroblast transplantation: long-term biochemical study in three cases of Hunter's syndrome. Dean, MF., Stevens, RL., Muir, H., et al.[2018]

In a phase I/II trial involving 31 patients with MPS II, treatment with idursulfase beta resulted in a significant reduction of urinary glycosaminoglycan (GAG) levels, indicating effective clearance of the accumulated substance associated with the disorder.

Idursulfase beta also improved endurance as shown by the 6-minute walk test, and it was generally safe with manageable side effects, primarily mild skin reactions that were easily treated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/II clinical trial of enzyme replacement therapy with idursulfase beta in patients with mucopolysaccharidosis II (Hunter syndrome). Sohn, YB., Cho, SY., Park, SW., et al.[2021]

Pabinafusp alfa, a novel treatment for Hunter syndrome, successfully crosses the blood-brain barrier and has shown a significant reduction in glycosaminoglycan (GAG) accumulation in cerebrospinal fluid, indicating its potential effectiveness in treating central nervous system symptoms associated with the disease.

In a 26-week phase 2 study involving MPS-II patients in Brazil, the 2.0 mg/kg dosage of pabinafusp alfa demonstrated the best safety and efficacy profile, with positive neurocognitive signals observed despite the short duration of the study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Iduronate-2-sulfatase fused with anti-hTfR antibody, pabinafusp alfa, for MPS-II: A phase 2 trial in Brazil. Giugliani, R., Martins, AM., So, S., et al.[2022]

Long-term enzyme replacement therapy with idursulfase for Hunter syndrome showed sustained clinical improvements over 3 years, including a 25.1% increase in absolute forced vital capacity and significant enhancements in walking distance.

While 53% of patients experienced infusion-related adverse events, these decreased over time, and the presence of neutralizing antibodies in 23% of patients was associated with reduced pulmonary function improvements.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term, open-labeled extension study of idursulfase in the treatment of Hunter syndrome. Muenzer, J., Beck, M., Eng, CM., et al.[2022]

Intrathecal administration of iduronate-2-sulfatase in cynomolgus monkeys showed significantly better penetration into the cerebrospinal fluid compared to intravenous delivery, indicating it may effectively target the central nervous system manifestations of Hunter syndrome.

The study demonstrated a proportional dose/exposure relationship for intrathecal iduronate-2-sulfatase, with systemic bioavailability ranging from 40-83%, suggesting that this method could enhance treatment efficacy for neurological symptoms associated with the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and bioavailability of a therapeutic enzyme (idursulfase) in cynomolgus monkeys after intrathecal and intravenous administration. Xie, H., Chung, JK., Mascelli, MA., et al.[2018]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05371613

NCT05371613 | A Study to Determine the Efficacy and ... A Study to Determine the Efficacy and Safety of Tividenofusp Alfa (DNL310) vs Idursulfase in Pediatric and Young Adult Participants With Neuronopathic (nMPS II) ...

2. neurologylive.com neurologylive.com/view/fda-delays-review-deadline-hunter-syndrome-agent-tividenofusp-alfa

FDA Delays Review Deadline for Hunter Syndrome Agent ... The FDA extended the review period for tividenofusp alfa, a potential Hunter syndrome treatment, to April 5, 2026, after additional pharmacology ...

3. biospace.com biospace.com/press-releases/denali-therapeutics-announces-fda-review-extension-of-bla-for-tividenofusp-alfa-for-the-treatment-of-mps-ii-hunter-syndrome

Denali Therapeutics Announces FDA Review Extension of ... Hunter syndrome, also known as MPS II, is a rare genetic lysosomal storage disease caused by mutations in the iduronate-2-sulfatase (IDS) gene.

4. empr.com empr.com/news/fda-extends-review-for-tividenofusp-alfa-for-hunter-syndrome/

FDA Extends Review for Tividenofusp Alfa for Hunter ... Interim findings showed treatment with tividenofusp alfa significantly reduced central nervous system and peripheral biomarkers of disease, ...

5. primetherapeutics.com primetherapeutics.com/high-cost-therapy-profile-september-2025

High-Cost Therapy Profile: September 2025 A Phase 2/3, multicenter, double-blind, randomized study to determine the efficacy and safety of tividenofusp alfa (DNL310) vs idursulfase in ...

6. denalitherapeutics.com denalitherapeutics.com/patient-community/hunter-syndrome-mps-ii

Hunter Syndrome (MPS II) - Denali Therapeutics The objective of the COMPASS study is to determine the efficacy and safety of DNL310 vs idursulfase, an enzyme replacement therapy (ERT). To learn more about ...

7. nasdaq.com nasdaq.com/articles/denali-therapeutics-reports-promising-long-term-data-tividenofusp-alfa-hunter-syndrome

Denali Therapeutics Reports Promising Long-Term Data ... Denali Therapeutics reports long-term benefits and safety data for tividenofusp alfa in treating Hunter syndrome (MPS II).

8. clinicaltrials.gov clinicaltrials.gov/study/NCT04251026

NCT04251026 | A Study of Tividenofusp Alfa (DNL310) in ... This is a multicenter, multiregional, open-label study to assess the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of tividenofusp alfa (DNL310), ...