Tividenofusp Alfa for Hunter Syndrome

(COMPASS Trial)

Recruiting in Palo Alto (17 mi)

+42 other locations

Age: < 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2 & 3

Recruiting

Sponsor: Denali Therapeutics Inc.

Must be taking: Enzyme replacement

Must not be taking: Investigational drugs

Disqualifiers: Genetic mutation, Gene therapy, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial is testing a new treatment called tividenofusp alfa for patients with a rare genetic disorder called MPS II. The treatment aims to replace missing enzymes to help break down harmful substances in the brain and body.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on enzyme replacement therapy (ERT), you must have either not received it continuously for 4 months before screening or be on maintenance ERT and have tolerated idursulfase for at least 4 months before screening.

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

Research shows that enzyme replacement therapy with idursulfase, a component of Tividenofusp Alfa, can improve walking distance, lung function, and reduce organ size and harmful substances in the body for Hunter Syndrome patients. 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 (a protective shield around the brain) to treat neurological symptoms of Hunter Syndrome, which other enzyme replacement therapies cannot effectively address. ^{1 2 3 4 6}

Research Team

Jose Alcantara Rodriguez, PharmD

Principal Investigator

Denali Therapeutics Inc.

Eligibility Criteria

This trial is for kids with Hunter Syndrome (MPS II), aged 2-6 or 6-17, depending on the group. They must have been treated with idursulfase for at least 4 months. Kids can't join if they've had gene or stem cell therapy for MPS, are unable to undergo lumbar punctures/MRIs, received CNS-targeted ERT recently, or participated in other drug trials within the last 60 days.

Inclusion Criteria

I have been diagnosed with MPS II.

I am between 2 and 17 years old.

I have been on enzyme replacement therapy and tolerated idursulfase for at least 4 months.

Exclusion Criteria

I haven't had CNS-targeted enzyme replacement therapy in the last 6 months.

Participated in any other investigational drug study or used an investigational drug within 60 days prior to screening or intend to receive another investigational drug during the study

I have had gene or stem cell therapy for my condition.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either tividenofusp alfa (DNL310) or idursulfase in a double-blind, randomized manner

Phase 2/3 duration not specified

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Open-label extension

Participants may opt into continuation of treatment with DNL310 or idursulfase based on pre-specified criteria

Treatment Details

Interventions

• DNL310 (Enzyme-replacement Therapy)
• Idursulfase (Enzyme-replacement Therapy)

Trial Overview The study compares Tividenofusp Alfa (DNL310), a new treatment that reaches the brain better than current therapies, against Idursulfase, which is standard care. It's randomized and double-blind meaning neither participants nor researchers know who gets which treatment until after results are collected.

Participant Groups

Group I: Open-label Treatment Phase Experimental Treatment 2 Interventions

Participants who meet pre-specified criteria may receive DNL310 or idursulfase

Group II: Cohort B: Participants with nnMPS II Experimental Treatment 2 Interventions

Group III: Cohort A: Participants with nMPS II Experimental Treatment 2 Interventions

Who Is Running the Clinical Trial?

Denali Therapeutics Inc.

Lead Sponsor

Trials

24

Recruited

1,900+

Findings from Research

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]