Tividenofusp Alfa for Hunter Syndrome

Recruiting at 11 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

99 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a multiregional open-label extension (OLE) to assess the safety, tolerability, and efficacy of long-term treatment with tividenofusp alfa (DNL310), an investigational central nervous system (CNS)-penetrant intravenous (IV) enzyme replacement therapy (ERT) for Hunter syndrome (MPS II). Participants who complete at least through the Week 49 visit in Study DNLI-E-0002 and do not discontinue study intervention early and participants who complete Study DNLI-E-0007 will be enrolled in this OLE. All participants will receive DNL310 for up to 5 years from the time of entry in this OLE. Participants, site staff, and the Sponsor will remain blinded to the original treatment assignment for participants entering this OLE from Study DNLI-E-0007.

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.

What evidence supports the effectiveness of the drug Tividenofusp Alfa for Hunter Syndrome?

Research shows that enzyme replacement therapy with iduronate-2-sulfatase, a component of Tividenofusp Alfa, can improve symptoms in Hunter Syndrome by increasing walking distance, improving lung function, and reducing organ size and harmful substances in the body. Additionally, similar treatments have shown promise in addressing brain-related symptoms by crossing the blood-brain barrier. ^{1 2 3 4 5}

Is Tividenofusp Alfa safe for humans?

Studies on similar treatments for Hunter syndrome, like idursulfase, show that they are generally safe, with similar safety profiles across different doses. These treatments have been tested in both humans and animals, showing favorable safety signals. ^{1 2 3 6 7}

How is the drug Tividenofusp Alfa different from other treatments for Hunter Syndrome?

Tividenofusp Alfa is unique because it is designed to cross the blood-brain barrier, potentially addressing the neurological symptoms of Hunter Syndrome, which other enzyme replacement therapies cannot effectively treat. ^{1 2 3 4 6}

Research Team

Jose Alcantara Rodriguez, PharmD

Principal Investigator

Denali Therapeutics

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Long-term, open-labeled extension study of idursulfase in the treatment of Hunter syndrome. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Iduronate-2-sulfatase fused with anti-hTfR antibody, pabinafusp alfa, for MPS-II: A phase 2 trial in Brazil. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and bioavailability of a therapeutic enzyme (idursulfase) in cynomolgus monkeys after intrathecal and intravenous administration. [2018]

4. Spain pubmed.ncbi.nlm.nih.gov

Idursulfase in Hunter syndrome treatment. [2017]

5. United States pubmed.ncbi.nlm.nih.gov

Enzyme replacement therapy by fibroblast transplantation: long-term biochemical study in three cases of Hunter's syndrome. [2018]

6. England pubmed.ncbi.nlm.nih.gov

Phase I/II clinical trial of enzyme replacement therapy with idursulfase beta in patients with mucopolysaccharidosis II (Hunter syndrome). [2021]

7. United States pubmed.ncbi.nlm.nih.gov

A phase I/II clinical trial of enzyme replacement therapy in mucopolysaccharidosis II (Hunter syndrome). [2022]