Tividenofusp Alfa for Hunter Syndrome

Recruiting at 7 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

47 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a multicenter, multiregional, open-label study to assess the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of tividenofusp alfa (DNL310), an investigational central nervous system (CNS)-penetrant enzyme replacement therapy (ERT), designed to treat both the peripheral and CNS manifestations of Mucopolysaccharidosis type II (MPS II; Hunter syndrome). Participants, whose physicians feel they are deriving benefit, will have the opportunity to be reconsented into a safety extension and then an open-label extension for continued evaluation.

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.

What data 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 walking distance, lung function, and reduce organ size and harmful substances in the body for patients with Hunter Syndrome. Additionally, a similar drug, pabinafusp alfa, has shown promise in reducing harmful substances in the brain, which is important for treating neurological symptoms of the disease. ^{1 2 3 4 5}

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

Katia Meirelles, MD

Principal Investigator

Denali Therapeutics

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

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]