Tividenofusp Alfa for Hunter Syndrome

Enrolling by invitation at 24 trial locations

Overseen By Clinical Trials at Denali Therapeutics

Age: < 65

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: Denali Therapeutics Inc.

Disqualifiers: Unstable conditions, Significant comorbidities, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines the long-term safety and effectiveness of a new intravenous enzyme replacement therapy, DNL310 (Tividenofusp alfa), for individuals with Hunter syndrome, a genetic disorder affecting bodily functions. The trial focuses on the treatment's efficacy over time and participant tolerance. It includes various participant groups, such as those with long-standing Hunter syndrome, liver enlargement, and those who have previously received specific treatments like gene therapy. Individuals who completed a prior related study are well-suited for this trial. As a Phase 2, Phase 3 trial, this research measures the treatment's effectiveness in an initial, smaller group and represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. It is best to discuss this with the trial team or your doctor.

Is there any evidence suggesting that this trial's treatment is likely to be safe?

Research shows that tividenofusp alfa, a new treatment being tested for Hunter syndrome, appears safe. Earlier studies demonstrated improvements in health outcomes without serious side effects. Specifically, these trials found that the treatment lowered certain markers linked to the disease, indicating it worked as expected without causing harm.

While more information is always helpful, current results suggest that tividenofusp alfa is generally well-tolerated. Participants in these studies did not report major side effects, supporting the idea that the treatment is safe for people. Ongoing research will continue to closely monitor safety to ensure the best outcomes for participants. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for Hunter syndrome?

Researchers are excited about DNL310 for Hunter Syndrome because it offers a novel approach compared to existing enzyme replacement therapies (ERTs). Unlike traditional treatments that struggle to cross the blood-brain barrier, DNL310 is designed to effectively reach the central nervous system, potentially addressing neurological symptoms that current ERTs cannot. This innovative mechanism of action could lead to more comprehensive management of the disease, providing hope for improved outcomes in cognitive and behavioral functions in patients.

What evidence suggests that this trial's treatment could be effective for Hunter syndrome?

Research has shown that tividenofusp alfa, also known as DNL310, holds promise for treating Hunter syndrome. Studies have found that this treatment improves key disease indicators, including brain and body symptoms. Specifically, previous patients demonstrated a return to normal in these signs, suggesting the treatment's intended effect. This trial will evaluate tividenofusp alfa across various cohorts, each with specific participant criteria. Overall, this evidence supports the potential effectiveness of tividenofusp alfa for people with Hunter syndrome. ^{1 2 3 4 6}

Who Is on the Research Team?

Jose Alcantara Rodriguez, PharmD

Principal Investigator

Denali Therapeutics

Are You a Good Fit for This Trial?

This trial is for people with Hunter syndrome (MPS II) who have already been part of earlier studies DNLI-E-0002 or DNLI-E-0007. They must have completed the required weeks in those studies without early discontinuation and should not have any unstable medical conditions that could affect their safety or the study results.

Inclusion Criteria

For participants from Study DNLI-E-0007 only: Completed the treatment period of 96 weeks in Cohort A for nMPS II participants and 48 weeks in Cohort B for nnMPS II participants

For participants from Study DNLI-E-0002 only: Completed at least through the Week 49 visit in Study DNLI-E-0002 and did not discontinue study intervention early

Exclusion Criteria

Unstable or poorly controlled medical condition(s) or significant medical or psychological comorbidity or comorbidities that, in the opinion of the investigator, would interfere with safe participation in the trial or interpretation of study assessments

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Open-label Extension

Participants receive long-term treatment with tividenofusp alfa (DNL310) for up to 5 years

5 years

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 trial is testing Tividenofusp Alfa, a new IV therapy designed to treat Hunter syndrome by reaching the central nervous system. Participants will receive this treatment for up to five years to evaluate its long-term safety and effectiveness.

How Is the Trial Designed?

Group I: Cohort E2 Experimental Treatment 1 Intervention

Participants with nMPS II, aged ≥6 years; participants with nnMPS II, aged \<6 or ≥17 years; or participants with nMPS II, aged ≥1 to ≤18 years, with a history of prior HSCT or gene therapy and have completed at least 48 weeks in Study DNLI-E-0001

Group II: Cohort D2 Experimental Treatment 1 Intervention

Participants with nMPS II or nnMPS II, aged ≤18 years with preexisting hepatomegaly who have never taken standard-of-care ERT

Group III: Cohort C2 Experimental Treatment 1 Intervention

Participants with nMPS II, aged \<4 years

Group IV: Cohort B7 Experimental Treatment 1 Intervention

Participants with nnMPS II, aged ≥6 to \<17 years

Group V: Cohort B2 Experimental Treatment 1 Intervention

Participants with nMPS II or nnMPS II, aged ≥1 to ≤18 years

Group VI: Cohort A7 Experimental Treatment 1 Intervention

Participants with nMPS II, aged ≥2 to \<6 years

Group VII: Cohort A2 Experimental Treatment 1 Intervention

Participants with nMPS II, aged ≥5 to ≤10 years

Who Is Running the Clinical Trial?

Denali Therapeutics Inc.

Lead Sponsor

Trials

24

Recruited

1,900+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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 ... Tividenofusp alfa showed promising results in a phase 1/2 trial, with improvements in biomarkers and clinical outcomes, including normalized ...

3. 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).

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. neurologyadvisor.com neurologyadvisor.com/news/tividenofusp-alfa-gets-priority-review-for-hunter-syndrome/

Tividenofusp Alfa Gets Priority Review for Hunter Syndrome The FDA has accepted for Priority Review the BLA for tividenofusp alfa for the treatment of Hunter syndrome, also known as MPS II.